Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial

Abstract

SummaryBackgroundWHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz.MethodsIn this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2–4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957.FindingsBetween Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2–4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75–1·29]; abacavir vs stavudine: HR 0·88 [0·67–1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00).InterpretationAll NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines.FundingEuropean Developing Countries Clinical Trials Partnership.

Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

“…In this analysis, sparsely sampled data from the CHAPAS-3 trial (Children with HIV in Africa—Pharmacokinetics and Adherence of Simple Antiretroviral Regimens) 31 was enriched with intensive data from an earlier pharmacokinetic sub-study 1 (part of CHAPAS-1). 32 Both studies were conducted in African children from Uganda and Zambia, as briefly described below.…”

“…31 Depending on treatment allocation, patients received: Triomune Baby, Triomune Junior, Duovir-N Baby (50 mg nevirapine, 60 mg zidovudine and 30 mg lamivudine) or nevirapine (100 mg)—all paediatric formulations; or Duovir-N (200 mg nevirapine, 300 mg zidovudine and 200 mg lamivudine) or Triomune30 (200 mg nevirapine, 30 mg stavudine and 150 mg lamivudine), formulated for adults. Nevirapine-based regimens were dosed twice daily according to WHO 2010 guidelines.…”

Complications of Treatment in Youth with HIV

“…Another large clinical trial conducted in Zambia and Uganda included 477 HIV-infected children aged 1 month to 13 years who were randomized to either ABC, ZDV, or d4T [2]. Two children in the d4T group developed facial lipoatrophy compared to zero in the other two groups (P=0.08).…”

Brief Report: Should Abacavir Be a First-Line Alternative for Adults With HIV in Sub-Saharan Africa?

“…The CHAPAS-3 study demonstrated that ABC and AZT had comparable virological and immunological efficacy, and similar adverse effect frequencies in children [9], supporting the use of either in that patient population. However, several other studies have highlighted significant toxicities associated with longer term AZT use, including bone marrow suppression (severe anemia and neutropenia) [26–29], lipodystrophy [27,28,30–32], gastrointestinal side effects [33], and other metabolic complications [27,28].…”

“…In an effort to compare ART regimens in children, the CHAPAS-3 study compared ABC with two other nucleoside reverse transcriptase inhibitors (stavudine, AZT), and concluded all three drugs had low toxicity and good clinical, immunological, and virological responses. They also found no hypersensitivity reactions among 165 Zambian and Ugandan children <13 years old receiving ABC without genotyping for HLA-B * 57:01 [9]. The DART/NORA study demonstrated a similarly low rate of hypersensitivity reactions in Ugandan adults receiving ABC (6/300, 2%), although none of the six patients carried the HLA-B * 57:01 allele [10].…”