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.
Highlights
In 2014, 91% of 3·2 million HIV-infected children lived in sub-Saharan Africa, but less than 25% of those needing antiretroviral therapy (ART) were receiving it.[1]
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. 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])
We identified no major differences between the nucleoside reverse-transcriptase inhibitors (NRTIs) in adverse events, toxicity, clinical, immunological, or viral load endpoints, but did find higher drug susceptibility to relevant second-line NRTIs if abacavir was used first-line, providing evidence to support the WHO 2013 recommendation for its use as the preferred first-line NRTI for children
Summary
In 2014, 91% of 3·2 million HIV-infected children lived in sub-Saharan Africa, but less than 25% of those needing antiretroviral therapy (ART) were receiving it.[1] Low-cost, scored, dispersible fixed-dose combination (FDC) paediatric tablets of stavudine plus lamivudine plus nevirapine in child-appropriate drug ratios[2] drove initial ART roll-out to African children, replacing separate syrups, which are costly for programmes and difficult for carers to transport and administer.[3] stavudine was discouraged in 20104 and 20135 WHO guidelines because of high lipodystrophy rates in adults and adolescents. Abacavir is associated with hypersensitivity reactions, these are rare in Africa[10] because of a lower risk-allele prevalence.[11] two South African cohorts recently reported lower virological suppression with abacavir than with stavudine,[12,13] and abacavir is the most costly NRTI.[14] whether stavudine, Lancet Infect Dis 2016; 16: 169–79
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