access.html ORIGINAL ARTICLE ACCESS TO ANTIRETROVIRAL TREATMENT IN SOUTH AFRICA, 2004 - 2011 Leigh F Johnson, PhD Centre for Infectious Disease Epidemiology and Research, University of Cape Town Background. South Africa’s National Strategic Plan (NSP) for 2007 - 2011 aimed to achieve new antiretroviral treatment (ART) enrolment numbers equal to 80% of the number of newly eligible individuals in each year, by 2011. Objectives. To estimate ART coverage in South Africa and assess whether NSP targets have been met. Methods. ART data were collected from public and private providers of ART. Estimates of HIV incidence rates were obtained from independent demographic projection models. Adult ART data and incidence estimates were entered into a separate model that estimated rates of progression through CD4 stages, and the model was fitted to South African CD4 data and HIV prevalence data. Results. By the middle of 2011, the number of patients receiving ART in South Africa had increased to 1.79 million (95% CI 1.65 - 1.93 million). Adult ART coverage, at the previous ART eligibility criterion of CD4 <200/μl, was 79% (95% CI 70 - 85%), but reduced to 52% (95% CI 46 - 57%) when assessed according to the new South African ART eligibility criteria (CD4<350/μl). The number of adults starting ART in 2010/11 was 1.56 times (95% CI 1.08 - 1.97) the number of adults who became ART-eligible in 2010/11, well in excess of the 80% target. However, this ratio was substantially higher in women (1.96, 95% CI 1.33 - 2.51) than in men (1.23, 95% CI 0.83 - 1.58) and children (1.13, 95% CI 0.74 - 1.48). Conclusion. South Africa has exceeded the ART targets in its 2007 - 2011 NSP, but men and children appear to be accessing ART at a lower rate than women. Antiretroviral treatment (ART) is a powerful tool for reducing both AIDS mortality1 , 2 and HIV transmission.3 The monitoring of access to ART is therefore critical to the evaluation of the impact of HIV treatment and prevention programmes. Previous monitoring exercises have shown that, since the announcement of a comprehensive care, management and treatment programme by the South African Department of Health in late 2003, access to ART in South Africa has increased dramatically.4 , 5 These assessments suggested that South Africa was on track to meet the targets laid out in the 2007 - 2011 National Strategic Plan (NSP) for HIV/AIDS and Sexually Transmitted Infections, which aimed to achieve new ART enrolment numbers equal to 80% of the number of newly eligible individuals in each year, by 2011.6 However, there has not as yet been any formal assessment of whether this target has been met. The monitoring of access to ART in South Africa is challenging for several reasons. The interpretation of public sector statistics is complicated by changes in reporting practices in late 2009, with most provinces switching from reporting numbers of patients cumulatively started on ART to numbers of patients currently on ART. Statistics from disease management programmes and programmes run by non-governmental organizations (NGOs) have not been routinely collected and reported. In addition, there is generally a lack of information on the age and sex of patients. This is particularly problematic in view of concerns that ART initiation rates may be lower among men than women.7 The estimation of ART coverage is also hampered by uncertainty regarding the ‘treatment need’, the denominator in the coverage calculation. Mathematical models have been used to estimate numbers of HIV-positive individuals with CD4 counts below different thresholds, but there is substantial uncertainty surrounding the rates of CD4 decline that are assumed in these models, and there is also growing recognition that these rates of CD4 decline may differ between populations.10 There is also concern that cross-sectional measures of ART coverage may fail to give a sense of recent programme performance, which is better reflected in the ratio of the number of patients starting ART in a year to the number of individuals becoming eligible for ART in the same year.11 The latter measure has the advantage of being consistent with the way in which the South African NSP targets are expressed, and is also less sensitive to model assumptions about rates of CD4 decline and ART eligibility criteria.11 The objective of this paper is to assess recent changes in access to ART in South Africa, and to evaluate the extent to which the 2007 - 2011 NSP treatment targets have been met. This study also aims to improve on previous work4 by including more recent programme statistics, by using locally relevant CD4 data in the estimation of the treatment need, by including 95% confidence intervals (CIs) in coverage estimates, and by estimating coverage separately for men, women and children. Methods ART programme statistics Public sector ART programme statistics to the end of June 2011 were obtained from the South African Department of Health, and were adjusted to achieve consistency of definition (cumulative/current), using a previously described formula,4 for each province. Unpublished data on the sex ratio of adult patients enrolled in public ART programmes in four provinces, collected up to March 2009, were used to estimate the sex ratio of adults starting ART in the public sector. Private sector data and data from NGOs were obtained through surveys conducted every two years, since mid-2006.12 Linear interpolation and extrapolation was used to estimate numbers for programmes with missing data and for years in which no survey was conducted. Estimates of the proportion of private sector patients who were men, women and children were obtained from submissions by medical schemes to the Risk Equalization Fund up to March 2008, and the geographical distribution of private sector patients was estimated from early private sector statistics.13 Detailed data collected from NGO programmes in the 2008 survey were used to determine the profile of NGO patients by age, sex and province. Mathematical model To estimate the numbers of adults needing ART, a mathematical model was developed to simulate the growth of the South African population over time, the incidence of HIV and the decline in CD4 counts in HIV-positive adults. The model stratifies the population by age and sex, and projects the change in population in one-year intervals, starting in the middle of 1985. Assumptions regarding the age- and sex-specific population profile, non-HIV mortality, fertility, migration and HIV incidence are based on the ASSA2008 AIDS and Demographic model.14 Once infected, individuals are assumed to progress through a four-stage model of CD4 decline, in the absence of ART (Fig. 1). Individuals are assumed to experience AIDS mortality in the CD4 200 - 349/µl category at a fraction θ of the AIDS mortality rate in the CD4<200/µl category, if untreated. Up to mid-2009, adults of sex g are assumed to start ART only once their CD4 count has dropped below 200/µl, at a rate of r g (t) per annum in year t. Between mid-2009 and mid-2011, the model also allows individuals to start ART in the CD4 200 - 349 category if they develop tuberculosis or become pregnant, following the change in South African ART guidelines in early 2010.15 The r g (t) rates in each year are calculated from the ART programme statistics (further detail is provided in the online appendix). Adults who start ART are assumed to be lost to the ART programme with probability κ0 during the first 6 months after starting ART, and with probability κ1 for each year after the first 6 months. This does not include individuals who temporarily interrupt ART. Of those leaving the ART programme permanently, a proportion ν are assumed to leave the programme owing to HIV-related mortality, and the remaining proportion (1 – ν) are assumed to stop taking their drugs, after which their mortality risk is assumed to be the same as that of ART-naïve adults with CD4 counts below 200/µl. Estimates of annual numbers of new paediatric HIV infections were obtained from a separate model of paediatric HIV in South Africa.16 Since paediatric ART guidelines recommend ART initiation in all HIV-infected children aged <12 months, regardless of their immunological or clinical status,17 the annual number of new paediatric HIV infections is used to approximate the annual number of children newly eligible for ART (the denominator in the ART enrolment ratio). Calibration and uncertainty analysis The parameters determining the rates of CD4 decline, HIV-related mortality and ART discontinuation are estimated by fitting the model to HIV prevalence data from the 2005 and 2008 Human Sciences Research Council (HSRC) household surveys,18 , 19 and to CD4 data from HIV-positive adults in three South African surveys,20 using a Bayesian melding procedure.23 , 24 A detailed explanation is provided in the online appendix. Briefly, prior distributions are specified to represent uncertainty regarding the parameters of interest, including the range of plausible values for the average time to starting ART after becoming eligible (1/r g (t)). Prior distributions are also specified to represent uncertainty regarding the accuracy of the reported ART programme statistics in each year. This uncertainty and the uncertainty regarding ART attrition rates affect the model ART enrolment inputs. A likelihood function is specified to represent how well the model fits the CD4 data and HIV prevalence data, for a given set of parameter values. The posterior distribution, representing the parameter combinations from the prior distributions that have the highest likelihood values, is then simulated by Sampling Importance Resampling.25 Results The posterior estimates of the model parameters are summarised in Table 1, and posterior estimates of numbers of patients receiving ART are summarised in Table 2. Over the period mid-2004 to mid-2011, the total number of patients receiving ART in South Africa increased from 47 500 (95% CI 42 900 – 51 800) to 1.79 million (95% CI 1.65 - 1.93 million). Of the latter, 85% were receiving ART through the public health sector, 11% were receiving ART through disease management programmes in the private sector, and the remaining 4% were receiving ART through community treatment programmes run by NGOs. The majority (61%) of patients were women aged 15 or older, men accounted for 31% of patients, and children under the age of 15 comprised the remaining 8% of patients. KwaZulu-Natal and Gauteng were the two provinces with the largest numbers of patients, together accounting for 56% of all patients receiving ART. Changes over time in numbers of treated and untreated adults in different CD4 stages are shown in Fig. 2. As at mid-2011, untreated HIV-positive adults included 58 000 (95% CI 13 000 – 147 000) individuals who had stopped ART, 385 000 (95% CI 247 000 – 634 000) ART-naive adults with CD4 <200/μl, 1.06 million (95% CI 0.88 - 1.29 million) with CD4 counts of 200 - 349/μl, 0.74 million (95% CI 0.61 - 0.91 million) with CD4 counts of 350 - 500/μl, and 0.94 million (95% CI 0.77 - 1.16 million) with CD4 counts >500/μl. The total unmet need in the middle of 2011 (ART-naïve adults with CD4 <350/μl plus all adults who had stopped ART) was 1.50 million (95% CI 1.24 - 1.84 million), which is 32% lower than the total unmet need four years previously. Estimates of adult ART coverage and ART enrolment ratios are shown in Fig. 3. Using previous CD4 thresholds for defining ART eligibility (CD4 <200/μl), the fraction of adults eligible to receive ART who were actually on ART increased from 5.1% (95% CI 4.2 - 6.1%) in the middle of 2004 to 79% (95% CI 70 - 85%) by the middle of 2011. However, using the new CD4 thresholds for defining ART eligibility (CD4 <350/μl), adult ART coverage by the middle of 2011 was 52% (95% CI 46 - 57%). As noted previously,11 ART enrolment ratios are similar when using different CD4 thresholds to define ART eligibility. For example, over the period from mid-2010 to mid-2011, the ratio of the number of adults starting ART to the number of adults whose CD4 counts fell below the CD4 threshold was 1.64 (95% CI 1.11 - 2.10) when the CD4 threshold was 200, and 1.56 (95% CI 1.08 - 1.97) when the CD4 threshold was 350. Both ratios are roughly double the target of 80% set in the 2007 - 2011 NSP, and indicate substantial progress in removing the ‘backlog’ of unmet need that accumulated in previous years. Estimates of ART access are presented separately for men, women and children in Fig. 4. Using the CD4 threshold of 350/μl as the criterion for ART eligibility, the fraction of ART-eligible women who were receiving ART by the middle of 2011 (60%, 95% CI 53 - 65%) was significantly higher than the fraction of ART-eligible men who were on treatment (41%, 95% CI 36 - 46%). A similar difference in magnitude is seen in the ART enrolment ratio over the period mid-2010 to mid-2011: using the same ART eligibility criterion of CD4 <350/μl, the enrolment ratio was 1.96 (95% CI 1.33 - 2.51) in women and 1.23 (95% CI 0.83 - 1.58) in men. Over the same period, the ratio of the number of children starting ART to the number of new infections in children was 1.13 (95% CI 0.74 - 1.48). In most previous years, this ratio was below both the male ART enrolment ratio and the female ART enrolment ratio. DISCUSSION South Africa has made impressive progress in the rollout of ART since the start of the public sector ART programme in 2004. The number of patients who started ART in 2010/2011 was well in excess of the number of individuals who became eligible to receive ART over the same period, exceeding the targets set in the 2007 - 2011 NSP. The unmet need for ART was also reduced by 32% between 2007 and 2011. According to the ART initiation criteria that were in place at the time, adult treatment coverage by mid-2011 was close to 80%. However, there appear to be substantial differences between men, women and children in the rate of ART initiation. The low rate of ART initiation in men relative to women may be a reflection of gender differences in health-seeking behaviour and perceptions that men who seek care are ‘weak’.9 Alternatively, the high rate of ART initiation in women may be due to higher rates of HIV diagnosis through antenatal screening. The relatively low rates of ART initiation in children are probably attributable to the lower rates of HIV testing in children and the greater complexity of paediatric ART relative to adult ART.26 However, it is difficult to compare adult and paediatric measures of ART access meaningfully because the course of HIV infection is so different in children, with many HIV-infected infants dying in the first few months of life before there is an opportunity for testing. This analysis extends previous work4 by including assessment of uncertainty and by incorporating several new data sources. The 95% CIs that have been estimated reflect uncertainty regarding rates of CD4 decline, rates of mortality and rates of ART retention, and also reflect uncertainty regarding the accuracy of reported ART programme statistics. However, the CIs do not reflect the uncertainty regarding the HIV incidence rates that have been estimated from the ASSA2008 model, and this may lead to some exaggeration of precision. CIs around the ART enrolment ratios are considerably wider in 2009/10 and 2010/11 than in previous years, owing to the change in the way that the Department of Health has reported public sector ART programme statistics. Various attempts were made to validate the reported ART programme statistics using data from external sources, with limited success. Lamivudine sales figures from Aspen Pharmacare, which until recently supplied 80% of lamivudine in the public sector, were used to obtain crude estimates of numbers of public sector patients on treatment in each quarter. These estimates were not significantly different from the model estimates in Table 2 up to the end of 2008, and from October 2009 to March 2010, but were substantially lower than the model estimates from January to September of 2009. Numbers of viral load tests performed by the National Health Laboratory Service for public sector clinics were also used to obtain theoretical estimates of numbers of patients receiving ART, on the assumption that patients went for viral load testing twice per annum on average. The resulting estimates were slightly higher than the corresponding model estimates up to 2008, but were 18% lower than the model estimates in 2009. Finally, the model estimate of the fraction of the 15 - 49-year-old population on ART in the middle of 2008 was compared with the corresponding proportion estimated in the 2008 HSRC national household survey,27 based on testing for the presence of antiretroviral drugs in blood samples: the model estimate of 1.8% (95% CI 1.6 - 2.0%) was found to be significantly lower than that measured in the survey (3.0%). External data sources therefore do not provide a clear and consistent assessment of the plausibility of the model estimates derived from reported ART programme statistics. Although attempts were made to produce estimates of ART coverage for each province, it was not possible to produce plausible results for two provinces (Gauteng and Western Cape) because the estimated numbers of patients starting ART in recent years exceeded the estimated numbers of patients eligible to receive ART, in both of these provinces. This could possibly be due to individuals with advanced HIV migrating to urban areas because of the perceived superiority of health services in the major urban centres of Gauteng and Western Cape. The model assumes migration to be independent of HIV status, and may therefore under-estimate the number of HIV-infected ART-eligible individuals who migrate into these provinces. Alternatively, the problems experienced in producing plausible results for Gauteng and Western Cape may be due to assumed HIV incidence rates in these provinces being too low, or reported numbers of ART patients in these provinces being exaggerated. Many challenges exist, both in achieving future ART rollout targets and in monitoring future progress towards meeting these targets. The new NSP for the 2012 - 2016 period28 proposes targets that are much more ambitious than those in the previous NSP: the ART enrolment target in 2016 is 80% of the new ART need in that year plus 80% of the unmet need from previous years. High levels of HIV testing and counselling, as well as expansion of capacity to deliver ART, will be required to meet these targets. The new NSP for the 2012 - 2016 period proposes several measures to strengthen the monitoring and evaluation of South Africa’s ART programme, including the introduction of a single patient identifier in the health sector and a single registry at the primary care level. It is hoped that these measures will lead to greater precision in the estimation of ART coverage in future, as well as a deeper understanding of the factors determining access to care and retention in care. Appearing only in the online version of this article is an appendix that provides further detail regarding the method used to model adult ART initiation. It also includes a detailed explanation of the Bayesian melding procedure: the prior distributions and the data sources on which they are based, the method used to define the likelihood function and the method used to simulate the posterior distribution. 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Challenges to pediatric HIV care and treatment in South Africa. J Infect Dis 2007;196(Suppl 3):S474-481. [http://dx.doi.org/10.1086/521116] [PMID:18181697]. 27. Rehle TM, Hallett TB, Shisana O, et al. A decline in new HIV infections in South Africa: estimating HIV incidence from three national HIV surveys in 2002, 2005 and 2008. PLoS One 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] [PMID:20559425]. 27. Rehle TM, Hallett TB, Shisana O, et al. A decline in new HIV infections in South Africa: estimating HIV incidence from three national HIV surveys in 2002, 2005 and 2008. PLoS One 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] [PMID:20559425]. 28. South African National AIDS Council. National Strategic Plan on HIV, STIs and TB, 2012-2016. 2011. http://www.doh.gov.za/docs/stratdocs/2011/summary_hiv_nsp.pdf (accessed 6 December 2011). 28. South African National AIDS Council. National Strategic Plan on HIV, STIs and TB, 2012-2016. 2011. http://www.doh.gov.za/docs/stratdocs/2011/summary_hiv_nsp.pdf (accessed 6 December 2011). TABLE 1. POSTERIOR ESTIMATES OF MODEL PARAMETERS Symbol Mean (95% CI) Parameters for untreated adults Annual rate of progression from CD4 >500 to 350 - 500 λ1 0.34 (0.28 - 0.39) Annual rate of progression from CD4 350 - 500 to 200 - 349 λ2 0.48 (0.40 - 0.58) Annual rate of progression from CD4 200 - 349 to <200 λ3 0.32 (0.25 - 0.39) Annual rate of HIV mortality if CD4 <200 λ4 0.21 (0.16 - 0.27) Ratio of HIV mortality at CD4 200 - 349 to HIV mortality at CD4 <200 θ 0.13 (0.05 - 0.24) Parameters for treated adults Probability of permanent loss to care in first 6 months after ART start κ0 0.078 (0.028 - 0.141) Annual probability of permanent loss to care after first 6 months of ART κ1 0.048 (0.018 - 0.087) Proportion of permanent loss to care that is due to death ν 0.74 (0.53 - 0.92) TABLE 2. NUMBERS OF PATIENTS RECEIVING ART IN SOUTH AFRICA 2004 2005 2006 2007 2008 2009 2010 2011 Currently on ART* Total 47 500 110 900 235 000 382 000 588 000 912 000 1 287 000 1 793 000 By sex/age Men 17 700 37 500 75 000 120 000 183 000 283 000 396 000 551 000 Women 25 600 63 600 138 000 228 000 354 000 553 000 777 000 1 090 000 Children (<15) 4 200 9 800 22 000 35 000 51 000 76 000 113 000 152 000 By provider Public sector 9 600 60 600 163 000 290 000 470 000 748 000 1 073 000 1 525 000 Private sector 34 100 43 800 57 000 68 000 86 000 117 000 154 000 190 000 NGO programmes 3 900 6 400 15 000 24 000 32 000 47 000 60 000 78 000 By province Eastern Cape 5 300 12 600 26 000 43 000 65 000 98 000 137 000 187 000 Free State 2 200 4 900 10 000 18 000 29 000 47 000 66 000 91 000 Gauteng 13 800 30 800 62 000 95 000 145 000 219 000 280 000 439 000 KwaZulu-Natal 12 800 30 300 67 000 110 000 174 000 282 000 409 000 558 000 Limpopo 2 000 4 800 12 000 21 000 36 000 60 000 101 000 124 000 Mpumalanga 3 300 5 800 12 000 24 000 38 000 61 000 96 000 142 000 Northern Cape 400 1 500 3 000 7 000 9 000 13 000 16 000 19 000 North West 2 700 8 800 21 000 34 000 48 000 70 000 96 000 126 000 Western Cape 5 000 11 400 21 000 31 000 45 000 64 000 85 000 107 000 Started ART last year† Men 8 400 22 400 43 000 52 000 75 000 118 000 138 000 189 000 Women 13 700 42 600 84 000 104 000 149 000 235 000 273 000 380 000 Children (<15) 2 700 6 400 13 000 15 000 20 000 29 000 45 000 48 000 Total 24 800 71 300 140 000 172 000 243 000 382 000 456 000 617 000 All numbers are rounded to the nearest 1000 (except in the case of 2004 and 2005 totals, which are rounded to the nearest 100). Due to rounding, some rows may not sum to the total. All estimates are posterior averages (95% confidence intervals not shown). *Totals reflect numbers at the middle of each year. †Totals reflect ART enrolment over the 12 months up to the middle of the year. Fig. 1. Multi-state model of decline in CD4 count and ART initiation by HIV-infected adults. All states are stratified by age and sex, and all HIV-infected adults are assumed to experience age-specific mortality unrelated to HIV (not shown). Fig. 2. Numbers of HIV-positive adults, by CD4 count and ART status. Numbers exclude paediatric HIV infections. Bars represent posterior means (95% confidence intervals not shown). Fig. 3. Adult ART access. Bars represent posterior means and error bars represent 95% confidence intervals. Dashed line in panel (b) represents 2007 - 2011 National Strategic Plan target. Fig. 4. Age and sex differences in ART access. Bars represent posterior means and error bars represent 95% confidence intervals. Dashed line in panel (b) represents 2007 - 2011 National Strategic Plan Target.