d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E In 2007, only 8% of the estimated 1 800 000 children (0 - 14 years) living with HIV in sub-Saharan Africa were receiving antiretroviral therapy (ART). Coverage will need to be expanded greatly if the goal of provid- ing ART to 80% of children in need by 2010 is to be met.1 Moreover, recent evidence highlights early initia- tion of ART as particularly critical for infants with HIV.2 Clinical guidelines issued by the World Health Organi- zation (WHO) now recommend immediate initiation of ART for all HIV-infected infants.3 Paediatric ART management involves a complex proc- ess of interactions between patients, families, health care providers and the antiretrovirals (ARVs) them- selves. Barriers to the delivery of effective treatment occur both within the health care system and in the home. These include delayed diagnosis, limited avail- ability of health care providers trained in paediatric ART, few available paediatric ARV formulations, com- plicated regimens and dosing schedules, and poor pal- atability of some ARVs. Difficulties in the home include overcrowding, difficult work schedules of the parents and the stresses associated with parental disclosure in the home. Unlike adults, children require changes in antiretroviral dose as they grow and become older, and rely upon adult caregivers to administer medicines.4 Children have traditionally been dosed according to body surface area (BSA) (e.g. zidovudine (AZT), dida- nosine (ddI), lopinavir/ritonavir (LPV/r)), weight (mg/kg) (e.g. stavudine (d4T), lamivudine (3TC), abacavir (ABC), nevirapine (NVP)) or dose per weight band (efavirenz (EFV)). Manufacturers’ recommendations for some ARV drugs (e.g. LPV/r) include both BSA and weight-based dosing methods.5 The calculation of BSA generally re- quires accurate measurement of the child’s weight and length or height (ideally with a stadiometer or meas- uring box), and a normogram or mathematical formu- la (e.g. Mosteller formula).6 For both BSA and mg/kg weight-based dosing approaches, the calculated dose of each ARV drug must be rounded up or down as a ‘best-fit’ dosage according to which solid or liquid for- mulations of the ARV drug are available. This may lead to confusion and uncertainty on the part of the pre- scriber. In resource-limited settings (RLS), primary care doctors and nurses rather than paediatricians are responsible for the majority of paediatric ART initiation and fol- low-up. Lack of accurate measuring equipment and the relative complexity of BSA dosing may inhibit initiation of ART in infants and young children or mean that in- appropriate doses are given. While the most ‘accurate’ dosing may be obtained with the use of liquid formula- tions, large volumes of solutions (which may require refrigeration, e.g. d4T solution) may be challenging for caregivers to administer to young children, particularly if palatability is poor (e.g. LPV/r). ART simplification strategies are required to help health care providers manage ART in children, and to help caregivers and children adhere to therapy. Interventions include the use of adult or preferably paediatric fixed-dose combinations (FDCs), selection of doses based on weight band rather than individual mg/kg or BSA doses, prescription of pills or capsules rather than liquids, and identification of reliable once- daily regimens. Weight-band dosage tables assist health care providers by assigning a fixed dose of medication for a particular weight range (e.g. 1.5 ml of LPV/r solution for children weighing 4 - 9.9 kg, or half a 150 mg 3TC tablet for children weighing 14 - 19.9 kg). In large public sector WEIGHT-BAND DOSING TABLES: SIMPLIFYING PAEDIATRIC ART C l i n i C a l James J C Nuttall, MB ChB, DTM&H Paediatric Infectious Diseases Unit, Red Cross Children’s Hospital and University of Cape Town One of the obstacles to scaling up paediatric antiretroviral therapy (ART) coverage in resource-limited settings is the relative complexity of paediatric dosing. There is a need to simplify ART in order to facilitate treatment initiation and ongoing management of infants and children by health care providers, as well as to support adherence in the home. This article reviews the development of weight-band dosing tables as a strategy for simplifying the delivery of paediatric ART. 62 MOVinG FROM BSa anD WEiGHT-BaSED DOSinG aPPROaCHES TO WEiGHT-BanD DOSaGE TaBlES T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 treatment programmes, tables can reduce the time and risk of dosing errors involved in calculating multiple ARV doses by weight or BSA. They can also facilitate easier checking of doses against weight gain by cli- nicians, nurses, pharmacists or adherence counsellors. Under-dosing of ARVs, due in part to a lack of regu- lar dose adjustments for ongoing growth, has been described in a large cohort of children in the UK and Ireland.7 A study in Thailand found that 17 of 18 doc- tors using a standardised drug dosage table avoided miscalculations and reported more confidence with prescriptions.8 In 2006, the WHO published simplified weight-band dosing tables on all ARV drugs for which there were available paediatric indications, formulations or suf- ficient information and evidence to provide guidance on prescribing and doses.9 Decisions about dosing were based upon manufacturers’ information, ARV formula- tion choices, available data from clinical studies and expert paediatric pharmacology consultation. What was considered to be the ‘optimal’ dose for a particular weight band, given the limitations imposed by current- ly available drug formulations, was selected. Weight- band doses were determined by using BSA values calculated from median height-for-weight from inter- national growth charts using the following formula: BSA = square root [[weight (kg) × height (cm)]/3 600]. The dosing tables are directed at RLS and are based on the following principles: 1. It is preferable to use one formulation or fixed com- bination of any given drug(s). 2. Syringes or other standardised devices of various sizes should be available to support accurate dos- ing of liquid formulations. 3. Large volumes of liquid or syrup formulations should be avoided where possible. 4. In general, children should be switched to available solid formulations as soon as possible or as soon as they are tolerated. 5. If liquids or syrups are difficult because of storage, large volumes required or palatability, solid dosage formulations are preferable. 6. If solid formulations of first-line and second-line drugs developed for children are unavailable, sol- id formulations currently used for adults can be used. 7. Many tablets, but not all, may be divided in half but not beyond as drug content cannot be guar- anteed. Scored tablets are more easily split. Some tablets cannot be split, and the WHO recommends that where possible tablet splitting be done in the dispensing pharmacy using appropriate tablet cut- ters. 8. Some adult FDCs may result in under-dosing of individual components in children. This is of con- cern, particularly with drugs such as NNRTIs and 3TC where there is a low threshold for resistance. NVP requires a ‘lead-in’ dosage. During the first 2 weeks, therefore rather use individual components of the regimen. 9. Different dosing between a.m. and p.m. should be avoided where possible. However, in order to keep all regimens to no more than twice daily, there are instances where different quantities of solid dos- age forms can be administered a.m. as opposed to p.m. 10. The doses in the tables are presented in weight bands, accepting that some deviation from target dosing will occur. 11. Children have to be weighed at each clinic visit, and dose changes are required as children grow and/or gain weight. 12. When capsules are opened or tablets dissolved or crushed and added to food or liquid, it is important that the entire volume/amount of vehicle be taken to ensure administration of the full dose. The dosing tables are based on standardised weight bands starting from 5 kg body weight for the individual ARV drugs (excluding EFV, which starts from 10 kg) and 10 - 14 kg for the fixed-dose combinations (AZT + 3TC, d4T + 3TC, AZT + 3TC + ABC, d4T + 3TC + NVP). The weight bands are in 1 kg divisions from 5 to 11 kg, and 2 - 5 kg divisions from 12 to 35 or 40 kg. Dosing tables may be adapted according to the spe- cific drug formulations available to a regional or na- tional treatment programme. For example, dual (d4T + 3TC) or triple (d4T or AZT + 3TC + NVP) FDCs play an important role in paediatric ART in many countries (e.g. Thailand and many African countries), but are not widely used in South Africa. Satisfactory early clini- cal and immunological outcomes have been described following the use of fractions of generic adult FDCs in children dosed according to a weight-band table method in Thailand.10 In another project, a visual dosing aid (VDA) incorpo- rating coloured dosing bands for five first-line ARV drugs was developed to assist clinicians in prescribing paediatric ART consisting of syrups, generic adult tab- lets or a combination. It compared well with generic paediatric FDC tablets and could help facilitate paedi- atric ART roll-out in RLS.11 The South African national guidelines for the manage- ment of HIV-infected children (2005) incorporate a weight-band dosing chart12,13 developed by the Cent- ers for Disease Control and Prevention (CDC) and a number of international paediatric AIDS programmes 63 aDaPTinG WEiGHT-BanD DOSinG TaBlES FOR DiFFEREnT SETTinGS d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 64 prior to the more widespread availability of FDCs. BSA dosing recommendations were converted to weight- band doses using approximations of weight-for-age and height-for-age derived from standardised growth charts of girls from birth to 36 months and 20 years in the USA (National Center for Health Statistics). Dose for each weight band was based on the practicality of the available dosage forms for each drug, and practi- cal storage and dosing instructions were included with the chart. The chart lacks dose recommendations for children weighing less than 5 - 7 kg and for HIV-TB co-infection. The Western Cape Antiretroviral Drug Dosing Chart for Children (2007), based on the 2006 WHO recommen- dations, was developed by the author and colleagues as a pilot project for the HIV Directorate of the Western Cape (South Africa) provincial health department. The chart was directed at both clinicians and pharmacists involved in prescribing and dispensing ART for children, and it was successfully piloted at a number of HIV clin- ics before being distributed across the province. It was produced as a laminated A4 colour copy. Standard first- and second-line ART regimens (including regi- mens compatible with rifampicin-based TB treatment) as well as general comments relating to storage, ad- ministration and common drug interactions and side- effects of the individual ARV drugs were printed on the reverse side. Only ARV formulations available at public sector treatment facilities were included (no FDCs were available), and there was an emphasis on the early in- troduction of solid formulations where possible. Frac- tions of tablets (not less than half a tablet) were only incorporated for scored tablets. The target dose in mg/ kg or mg/m2 for each drug as well as the formula for calculating BSA was included to facilitate comparison of dosing methods when necessary. The following local practices were incorporated: 1. The off-label ‘opened capsule’ d4T dosing method whereby a d4T capsule is opened and the pow- der contents dispersed in a standardised volume of water and the required dose drawn up with a syringe and administered to the child (e.g. to ad- minister a standardised d4T dose of 10 mg for the weight bands 7 - 9.9 kg, a 20 mg d4T capsule is opened and dispersed into 5 ml of water and 2.5 ml is withdrawn with a syringe and administered and the remaining 2.5 ml is discarded). The rationale for this method is to minimise the use of stavu- dine solution (1 mg/ml when reconstituted), which is expensive, requires refrigeration, and results in relatively large medication volumes for administra- tion to young infants at the usual dosing sched- ule (1 mg/kg/dose). There are now data based on high-performance liquid chromatography analysis of active drug concentration in dispersed capsule solutions, supporting the accuracy of this method for certain brands of d4T capsules.14 2. Standardised doses of ritonavir used for pharmaco- logical boosting of LPV/r (in order to achieve a ratio of 1:1) in children receiving concurrent LPV/r and rifampicin-based TB treatment.15 3. Colour coding of ARVs on the chart corresponding to colour coding methods used in the pharmacy for medication containers and syringes to assist par- ents and caregivers with correct dosing. 4. The chart incorporated co-trimoxazole and multivi- tamin syrup dosing according to weight bands. 5. Since there were no standard weight-band dosing recommendations for infants weighing <5 kg in the WHO document (2006), it was recommended that a clinician experienced in ARV prescribing be con- sulted for such cases. There are a number of approaches to validation of weight-band dosing. Direct methods include pharma- cokinetic (Pk) studies and therapeutic drug monitoring. Indirect methods include comparison of weight-based with BSA doses, and safety and efficacy studies. Quali- tative studies assessing the usefulness of a weight- band dosing table to prescribing clinicians and dis- pensing pharmacists should be undertaken. Differing growth rates and the prevalence of malnutri- tion could have a significant impact on the accuracy of weight-band dosing of drugs that are usually dosed by BSA. A study comparing the calculated BSA dose range with WHO weight-band doses for AZT, ddI, NVP and LPV/r using actual heights and weights of 601 children at the time of ARV initiation was undertaken at a terti- ary hospital in South Africa in 2007.16 The median age was 28 months (interquartile range 13 - 62), 49% of children weighed <10 kg, and 59% and 63% of chil- dren had weight-for-age and height-for-age z-scores <–2 (moderate to severe underweight or stunting), respectively. Children with body weight <5 kg were ex- cluded as weight-based dosing recommendations were unavailable for this category, and children <6 months of age were excluded as LPV/r BSA dosing recommenda- tions are different in this age group. The BSA dose rang- es used were AZT 180 - 240 mg/m2, ddI 90 - 120 mg/m2, NVP 160 - 200 mg/m2, and L/r 230 - 300 mg/m2. Results are presented in Table I. The conclusion of this study was that the 2006 WHO simplified weight band- dosing method effectively avoided under-dosing chil- dren in relation to existing BSA dose recommendations for AZT, NVP and LPV/r suspensions. However, the au- thors noted that the risk of over-dosing is greater with weight-band recommendations for existing capsule or tablet formulations of these ARVs. Further studies are recommended for the WHO weight-band dosing method. ValiDaTiOn OF WEiGHT-BanD DOSinG TaBlES T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 65 Weight-band dose relative to calculated BSA dose range (N=601 children) (using anthropometric data ARV drug, BSA dose range, at time of starting ART) formulations assessed Under-dosing (% of children) Over-dosing (% of children) AZT 180 - 240 mg/m2 Oral solution (10 mg/ml) 2 0.5 Capsules (100 mg) 8.5 19 ddI 90 - 120 mg/m2 Tablets (25, 50, 100 mg, chewable or dispersable in water) 0 87 NVP 160 - 200 mg/m2 Oral suspension (10 mg/ml) 0 53 Tablets (200 mg) 0 61 Lopinavir/ritonavir 230 - 300 mg/m2 Oral solution (80/20 mg/ml) 1.2 26 Capsules (133.3/33.3 mg soft) 0 38 TaBlE i. WEiGHT-BanD DOSE RElaTiVE TO CalCUlaTED BODY SURFaCE aREa DOSE RanGE A VDA to facilitate dosing calculations in response to children’s growth and weight during ARV treatment developed by Callens et al.11 was evaluated using an- thropometric data from 55 children from the USA and 324 children from the Democratic Republic of Congo (DRC). In comparison with WHO-recommended dosing, the authors noted a relative dosing difference of >20% in <3% of children for NVP, AZT and d4T but in 20% of children for 3TC, over-dosing being more frequent.11 A detailed review of Pk studies and clinical outcome, safety and efficacy studies undertaken in children treated with individual or FDC ARV drugs dosed ac- cording to weight bands is beyond the scope of this article. There are no reported Pk or clinical studies di- rectly comparing weight band with mg/kg or BSA dos- ing approaches. In July 2008, the WHO published a revised weight- band dosing table for individual ARVs as well as dual and triple FDCs applicable to children >6 weeks of age, indicating the number of tablets or millilitres of so- lution to be administered twice daily by weight band from 3 kg to 34.9 kg (Fig. 1).17 The table focuses on ARVs used in first-line regimens and was developed by the WHO Paediatric Antiretroviral Working Group us- ing the 2006 WHO treatment recommendations, target doses and weight bands as a benchmark and reviewing currently available published and unpublished data to assess dosing. DdI is not included in the dosing table. Key supporting references are provided in the docu- ment.18 See Table II for target doses or dosing ranges. A WHO generic tool was used to assess and evaluate the expected dose delivered of any product in relation to intended target doses. For all formulations, changes in the number of pills and switches from one formula- tion to another occur at the same weight bands. There was an attempt to avoid dosing any single ARV com- ponent below 90% of the intended delivered dose and not more than 25% above the intended dose (or dose range for products with an established dose range). For NVP, the aim was to avoid dosing below 100% of the minimum of the dose range (150 mg/m2). Discrepancies between dose delivered and intended dose were justi- fied based on available Pk data, consideration of toxicity, and threshold for development of HIV drug resistance. Higher dosing for children who would fall into the lower weight bands (under 3 years) was accepted for drugs with known increased metabolism or clearance in the young child (NVP, 3TC, d4T, abacavir, LPV/r). In South Africa, the Antiretroviral Drug Dosing Chart (2009) is an update of the 2007 Western Cape version and incorporates elements of the WHO 2008 table; in particular, dosing recommendations for weight bands 3 - 3.9 kg and 4 - 4.9 kg (Fig. 2). Many of the for- mulations in the WHO table, in particular the FDCs, are not currently available to public sector treatment programmes in South Africa and so are excluded. The registration and availability of the paediatric strength heat-stable LPV/r tablet (Aluvia; 100 mg lopinavir/25 mg ritonavir) is still awaited, but it has been included. Local dosing practices described in the 2007 chart have been retained with modification, e.g. the d4T opened- capsule method is now used from 5 kg body weight. A comparative analysis of the revised weight band dosing in comparison with BSA dosing for AZT, NVP and L/r has been completed but not yet published. An analysis of the dose of LPV/r solution in mg/m2 that revised WHO weight band dose recommendations would provide, us- ing anthropometric data on 976 children initiating ART at median age of 11.2 months, indicated doses con- siderably in excess of 300/75 mg/m2, particularly for children <6 months of age.19 A protocol for an infant Pk study using the revised WHO weight-band dosing CURREnT WEiGHT-BanD TaBlES d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 66 Fi g. 1 . P ae di at ric a nt ire tr ov ira l d os in g ta bl e, W or ld H ea lt h O rg an iz at io n (2 00 8) .17 N u m b e r o f ta b le ts o r m l b y w e ig h t b a n d ( tw ic e d a il y ) C h il d re n 6 w e e k s o f a g e a n d a b o v e (0 .7 5 B D i s d e li v e re d a s 1 t a b le t A M a n d 0 .5 t a b le ts P M a n d 1 .5 B D i s d e li v e re d a s 2 t a b le ts A M a n d 1 t a b le t P M ) N u m b e r o f ta b le ts b y w e ig h t b a n d ( tw ic e d a il y ) D ru g S tr e n g th o f ta b (m g ) o r li q u id m g /m l 3 -3 .9 k g 4 -4 .9 k g 5 -5 .9 k g 6 -6 .9 k g 7 -7 .9 k g 8 -8 .9 k g 9 -9 .9 k g 1 0 - 1 0 .9 k g 1 1 - 1 1 .9 k g 1 2 - 1 3 .9 k g 1 4 - 1 6 .9 k g 1 7 - 1 9 .9 k g 2 0 - 2 4 .9 k g S tr e n g th o f a d u lt t a b (m g ) 2 5 - 2 9 .9 k g 3 0 - 3 4 .9 k g A Z T 6 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 1 1 A Z T ( n e w a n n e x E ) 3 0 0 ; 1 0 m g /m l 6 m l 6 m l 6 m l 9 m l 9 m l 9 m l 9 m l 1 2 m l 1 2 m l 1 2 m l 0 .5 0 .5 0 .7 5 3 0 0 1 1 A Z T /3 T C 6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 1 1 A Z T /3 T C /N V P 6 0 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 /2 0 0 1 1 A B C 6 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 1 1 A B C ( n e w a n n e x E ) 3 0 0 ; 2 0 m g /m l 3 m l 3 m l 3 m l 4 m l 4 m l 4 m l 4 m l 6 m l 6 m l 6 m l 0 .5 0 .5 0 .7 5 3 0 0 1 1 A B C /3 T C 6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 1 1 A B C /3 T C /N V P 6 0 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 /2 0 0 1 1 A B C /A Z T /3 T C 6 0 /6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /3 0 0 /1 5 0 1 1 3 T C 3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 1 5 0 1 1 3 T C ( n e w a n n e x E ) 1 5 0 ; 1 0 m g /m l 3 m l 3 m l 3 m l 4 m l 4 m l 4 m l 4 m l 6 m l 6 m l 6 m l 0 .5 0 .5 0 .7 5 1 5 0 1 1 d 4 T 6 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 1 1 d 4 T ( n e w a n n e x E ) v a ri o u s ; 1 m g /m l 6 m l 6 m l 6 m l 9 m l 9 m l 9 m l 9 m l 1 x 1 5 m g 1 x 1 5 m g 1 x 1 5 m g 1 x 2 0 m g 1 x 2 0 m g 1 x 2 0 m g 3 0 1 1 d 4 T /3 T C 6 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 /1 5 0 1 1 d 4 T /3 T C /N V P 6 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 /1 5 0 /2 0 0 1 1 N V P 5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 2 0 0 1 1 N V P ( n e w a n n e x E ) 2 0 0 ; 1 0 m g /m l 5 m l 5 m l 5 m l 8 m l 8 m l 8 m l 8 m l 1 0 m l 1 0 m l 1 0 m l 0 .7 5 0 .7 5 0 .7 5 2 0 0 1 1 L o p in a v ir /r it o n a v ir 1 0 0 /2 5 n /r n /r n /r n /r n /r n /r n /r 1 .5 1 .5 1 .5 2 2 2 .5 1 0 0 /2 5 * (p a e d ) 3 3 L o p /r it ( n e w a n n e x E ) 8 0 /2 0 m g /m l 1 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 2 m l 2 m l 2 m l 2 .5 m l 2 .5 m l 3 m l 8 0 /2 0 m g /m l 3 .5 m l 4 m l * 3 t a b le ts B D o f 1 0 0 /2 5 m a y b e s u b s ti tu te d w it h 2 t a b le ts a m a n d 1 t a b le t p m o f 2 0 0 /5 0 N o te : h ig h e r d o s e s o f L o p /r it m a y b e r e q u ir e d w h e n c o -a d m in is te re d w it h e n z y m e -i n d u c in g d ru g s s u c h a s N V P , E F V ; fo s a m p re n a v ir , ri fa m p ic in . T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 table and incorporating safety and efficacy end-points has been developed. The use of weight-band ARV dosing approaches, adapt- ed in accordance with locally available formulations and treatment programme conditions, is a key com- ponent of simplifying paediatric ART for health care providers as well as children and their caregivers, and will contribute to expanding treatment coverage for HIV-infected infants and children. REFEREnCES 1. UNICEF, UNAIDS, WHO and UNFPA. Children and AIDS: Third Stocktaking Report, 2008. Geneva: UNICEF, 2009. http://www.childinfo.org/files/StocktakingReport08.pdf (accessed 29 September 2009). 2. Violari A, Cotton M, Gibb D, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359: 2233-2244. 3. World Health Organization. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting WHO Headquarters, Geneva, Switzerland, 10 - 11 April 2008. http://www.who.int/hiv/pub/paediatric/WHO_ Paediatric_ART_guideline_rev_mreport_2008.pdf (accessed 8 October 2009). 4. Sohn A, Ananworanich J. How can we simplify antiretroviral therapy in children? Curr Opin HIV AIDS 2007; 2: 426-430. 5. Package insert for Abbott Kaletra®, Abbott Laboratories, June 2005. 6. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098. 7. Menson E, Walker A, Sharland M, et al. Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997-2005: cohort study. BMJ 2006; 332: 1183-1187. 8. Ponnet M, Frederix K, Petdachai W, et al. A drug dosage table is a useful tool to facilitate prescriptions of antiretroviral drugs for children in Thailand. Int J STD AIDS 2005; 16: 420-426. 9. World Health Organisation. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings, towards universal access: Recommendations for a public health approach. 2006. http://www.who.int/hiv/pub/guidelines/en/ (accessed 8 October 2009). 10. O’Brien DP, Sauvageot D, Zachariah R, Humblet P. In resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination 67 Drug Target dosing range Considerations ABC 8 - 10 mg/kg/dose twice daily Clearance in children <3 years old is increased, but recent data on once-daily dosing in children from 3 months of age suggest favourable Pk profile AZT 180 - 240 mg/m2 /dose twice daily Twice-daily dosing is acceptable and preferred Dosing at the upper end of the range is recommended for central nervous system HIV disease; dosing at the lower end may be preferred in settings where anaemia is prevalent d4T 1 mg/kg/dose twice daily Needed as a priority product despite well-recognised longer-term toxicities (lipodystrophy), as it is initially well tolerated, is safer to use in anaemia than AZT, and has lower laboratory monitoring requirements Avoid over-dosing wherever possible (noting recent revision to adult dosing recommendation to reduce dose) and especially for extended periods to minimise toxicity ddI <3 months of age: 50 mg/m2/dose; Enteric-coated formulations are preferred over the buffered form >3 months: 120 mg/m2/dose twice daily Needs to be given 1 hour before or 2 hours after food Once-daily dosing accepted over 6 years of age 3TC 4 mg/kg/dose twice daily Clearance in children <3 years old is increased, and minimal observed toxicity allows for higher dosing in younger children (up to 5 mg/kg/dose twice daily) NVP A BSA dose range of 150 - 200 mg/m2/dose Under-dosing must be avoided wherever possible owing to low twice daily is used to generate weight-band dosing barrier development of HIV drug resistance A reduced dose (150 - 200 mg/m2/dose once daily) is recom- mended for the first 2 weeks when initiating NVP treatment regimens Young children require a higher NVP dose relative to the NRTI components than delivered in current adult FDCs EFV By weight band (15 - 18.75 mg/kg/dose Dosing not established for children <3 years solid formulation or 19.5 mg/kg/dose suspension, Suspension is over 30% less bio-available than solid formulations once daily) LPV/rtv Approved dose is 230/75.5 mg/m2/dose twice daily; Clearance in children <2 years is increased 300/75 mg/m2/dose is recommended in children Actual exposure depends on metabolism and inter-patient vari- <2 years of age, if taken with NNRTI, or for ability, which is considerable PI-experienced patients Heat-stable paediatric formulation recently approved (awaiting registration in SA) RTV Co-formulated with lopinavir (L:r ratio 4:1) Needed for use as a pharmacological booster with PI-based treat- For patients receiving rifampicin, additional RTV ment and for children receiving rifampicin-based antituberculosis dosed at 0.75 x L/r dose to achieve L:r ratio of 1:1 therapy TaBlE ii. DOSinG COnSiDERaTiOnS FOR inDiViDUal anTiRETROViRal DRUGS inClUDED in THE REViSED WHO DOSinG TaBlE (2008) anD aDaPTED FOR THE anTiRETROViRal DRUG DOSinG CHaRT (2009)18 COnClUSiOn Acknowledgements For assistance with the development, analysis and implementation of the Western Cape Antiretro- viral Drug Dosing Chart (2007): Shenaaz Raiman (pharmacist), Heather Jaspan, Brian Eley, Mary-Ann Davies, Brenda Smuts, David Pienaar, Heli Moeng, staff at the HIV clinic at Red Cross War Memorial Children’s Hospital, Cape Town and Nolungile HIV clinic, Khayelitsha. d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 68 T ar ge t do se St av ud in e (d 4T ) L am iv ud in e (3 T C ) Z id ov ud in e (A Z T ) D id an os in e (d dI ) A ba ca vi r (A B C ) E fa vi re nz (E F V ) N ev ir ap in e (N V P ) L op in av ir /r it on av ir (L P V /r tv ) R it on av ir bo os ti ng (R T V ) C o- tr im ox az ol e M ul ti - vi ta m in s T ar ge t do se 1m g/ kg /d os e T W IC E d ai ly 4- 6m g/ kg /d os e T W IC E d ai ly 24 0m g/ m 2 /d os e T W IC E d ai ly 90 -1 20 m g/ m 2 /d os e T W IC E d ai ly 8m g/ kg /d os e T W IC E d ai ly B y w t. ba nd O N C E d ai ly 15 0m g/ m 2 /d os e * T W IC E d ai ly 30 0/ 75 m g/ m 2 /d os e L PV /r tv T W IC E d ai ly ** O N L Y a s bo os te r f or L PV /r tv w he n on R if am pi ci n T W IC E d ai ly O N C E d ai ly O N C E da ily A va ila bl e fo rm ul - at io ns So l. 1m g/ m l C ap s 15 ,2 0, 30 m g So l. 10 m g/ m l T ab s 15 0m g (s co re d) So l. 10 m g/ m l C ap s 10 0m g T ab s 30 0m g (n ot s co re d) T ab s 25 ,5 0, 10 0m g (d is pe rs ib le in 30 m l w at er ) C ap s 25 0m g E C So l. 20 m g/ m l T ab s 30 0m g (n ot s co re d) C ap s 50 , 20 0m g T ab s 50 , 2 00 , 60 0m g (n ot s co re d) So l. 10 m g/ m l T ab s 20 0m g (s co re d) So l. 80 /2 0m g/ m l T ab s 20 0/ 50 m g, 10 0/ 25 m g So l. 80 m g/ m l So l. 40 /2 00 m g/ 5m l T ab s 80 /4 00 m g (s co re d) So l. T ab s (B C o) A va ila bl e fo rm ul - at io ns W t. (k g) W t. (k g) <3 C on su lt w ith a c lin ic ia n ex pe ri en ce d in p ae di at ri c A R V p re sc ri bi ng fo r n eo na te s (< 28 d ay s of a ge ) a nd in fa nt s w ei gh in g <3 kg 2. 5m l 2. 5m l <3 3- 3. 9 6m l 3m l 6m l av oi d 3m l D os in g <1 0k g no t es ta bl is he d 5m l 1m l ** 1m l 3- 3. 9 4- 4. 9 1. 5m l ** 1. 2m l 4- 4. 9 5- 5. 9 7. 5m g: o pe n 15 m g ca ps ul e in to 5 m l w at er : gi ve 2 .5 m l & di sc ar d re st 2x 25 m g ta bs 5m l O R ½ ta b 5- 5. 9 6- 6. 9 4m l 9m l 8m l 6- 6. 9 7- 7. 9 10 m g: o pe n 20 m g ca ps ul e in to 5 m l w at er : gi ve 2 .5 m l & di sc ar d re st 4m l 7- 7. 9 8- 8. 9 8- 8. 9 9- 9. 9 9- 9. 9 10 -1 0. 9 15 m g: o pe n 15 m g ca ps ul e in to 5 m l w at er 6m l 12 m l 1x 50 m g+ 1x 25 m g ta bs a m ; 2x 25 m g ta bs p m 6m l 20 0m g ca p/ ta b 10 m l 2m l t w ic e da ily O R 10 0/ 25 m g ta bs : 2 ta bs a m , 1 ta b pm ** 1. 5m l 5m l 10 -1 0. 9 11 -1 1. 9 1x 50 m g+ 1x 25 m g ta bs 11 -1 1. 9 12 -1 3. 9 12 -1 3. 9 14 -1 6. 9 20 m g: o pe n 20 m g ca ps ul e in to 5m l w at er ½ ta b 2 ca ps a m ; 1 ca p pm 2x 50 m g ta bs a m ; 1x 50 m g+ 1x 25 m g ta bs p m 7m l 20 0m g ca p/ ta b + 50 m g ca p/ ta b 1 ta b am ; ½ ta b pm 2. 5m l t w ic e da ily O R 10 0/ 25 m g ta bs : 2 ta bs tw ic e da ily ** 2m l 10 m l O R 1 ta b 14 -1 6. 9 17 -1 9. 9 2x 50 m g ta bs 8m l 17 -1 9. 9 20 -2 4. 9 20 m g am ; 30 m g pm 1 ta b am ; 1/ 2 ta b pm 2 ca ps 1x 10 0m g ta b+ 1x 25 m g ta b tw ic e da ily O R 1x 25 0m g E C c ap on ce d ai ly 10 m l 20 0m g ca p/ ta b + 2x 50 m g ca ps /ta bs 3m l t w ic e da ily O R 10 0/ 25 m g ta bs : 3 ta bs a m , 2 ta bs p m ** 2. 5m l 20 -2 4. 9 25 -2 9. 9 30 m g 1 ta b 1 ta b 1 ta b 20 0m g ca p/ ta b + 3x 50 m g ca ps /ta bs 1 ta b 3. 5m l t w ic e da ily O R 20 0/ 50 m g ta bs : 2 ta bs a m , 1 ta b pm ** 3m l 25 -2 9. 9 30 -3 4. 9 2x 20 0m g ca ps /ta bs 4m l t w ic e da ily O R 20 0/ 50 m g ta bs : 2 ta bs a m , 1 ta b pm 2 ta bs 1 ta b 30 -3 4. 9 35 -3 9. 9 5m l t w ic e da ily O R 20 0/ 50 m g ta bs : 2 ta bs tw ic e da ily ** 4m l 35 -3 9. 9 >4 0 60 0m g ta b >4 0 B od y Su rf ac e A re a (B SA ) m 2 = M as s (k g) x H ei gh t ( cm ) 36 00 N EE D H EL P ? C A LL N A TI O N A L H IV H C W H O TL IN E 08 00 2 12 5 06 / 0 21 4 06 6 78 2 O R se n d a n s m s o r “ p le as e ca ll m e” m es sa g e to 07 1 84 0 15 72 * A le ad -i n do se o f n ev ir ap in e is g iv en fo r th e fir st 1 4 da ys o f t re at m en t e qu iv al en t t o ha lf o f m ai nt en an ce d os e i.e . u su al m ai nt en an ce d os e bu t g iv en o nc e- da ily . I nc re as e to fu ll m ai nt en an ce d os e af te r 14 d ay s if n o ra sh d ev el op s. C om pi le d by J . N ut ta ll & S . R ai m an fo r th e P ae di at ri c H IV /T B P ol ic y R ef er en ce G ro up , W es te rn C ap e. A da pt ed fr om W or ld H ea lt h O rg an is at io n gu id el in es , 2 00 6 & 2 00 8. A n ti re tr o vi ra l D ru g D o si n g C h ar t fo r C h il d re n ( 2 0 0 9 ) Fi g. 2 . A nt ire tr ov ira l d ru g do si ng c ha rt fo r c hi ld re n (2 00 9) (c op ie s av ai la bl e vi a N at io na l H IV H ea lt h Ca re W or ke r H ot lin e 08 00 2 12 5 06 ). T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 antiretroviral therapy. AIDS 2006; 20: 1955-1960. 11. Callens SF, Westreich D, Kitetele F, et al. A visual dosing aid for first-line pediatric antiretroviral treatment in resource-poor settings. J Trop Pediatr 2008; 55: 135- 137. 12. National Department of Health, South Africa. Guidelines for the Management of HIV-infected Children. 1st ed. National Department of Health, South Africa, 2005. 13. Weidle PJ, Abrams EJ, Gvetadze R, Rivadeneira E, Kline MW. A simplified weight-based method for pediatric drug dosing for zidovudine and didanosine in resource-limited settings. Pediatr Infect Dis J 2006; 25: 59-64. 14. Innes S, Smuts M, Cotton M, Seifart H, Rosenkranz B. Comparative study of different brands of stavudine capsules for the off-label ‘opened capsule’ method recommended for HIV-infected infants and children in resource-limited settings. South African Journal of Child Health 2009; 3: 44-47. 15. Ren Y, Nuttall J, Egbers C, et al. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr 2008; 47: 566-569 16. Nuttall J, Eley B, Davies M. Comparison of body surface area-based dosing and a simplified weight-based dosing method for zidovudine, didanosine, nevirapine and lopinavir/ritonavir in children starting antiretroviral therapy. Paper presented at the 3rd South African AIDS Conference, 5 - 8 June 2007, Durban (Abstract 538). 17. World Health Organization. Annex E: Simplified weight based Paediatric dosing for antiretroviral medicines http://www.who.int/hiv/topics/paediatric/technical/en/ index.html (accessed 17 November 2009). 18. World Health Organization. Report of the WHO expert working group meeting to determine preferred ARV medicines for treating and preventing HIV infection in younger children, 2008 http://www.who.int/hiv/topics/paediatric/technical/en/ index.html (accessed 17 November 2009). 19. Nuttall J, Eley B, Davies M-A. How well do the revised World Health Organization weight-based dosing guidelines for lopinavir/ritonavir in infants and children correlate with body surface area-based dosing recommendations? Paper presented at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, 19 - 22 July 2009, Cape Town (Abstract MOAB105). 69