CHAPAS-3 fills the gap
Authors: Harry Moultrie, Annelies Van Rie
Journal: The Lancet Infectious Diseases (2015)

While the efficacy of protease inhibitors versus non-nucleoside reverse transcriptase inhibitors for first-line paediatric antiretroviral treatment (ART) has been carefully assessed in clinical trials, only one small trial (PENTA-5)1Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial.Lancet. 2002; 359: 733-740Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar has compared different nucleoside reverse transcriptase inhibitor (NRTIs) backbones in children. The PENTA-5 trial noted that abacavir-containing regimens were more effective than zidovudine plus lamivudine, but was done in resource-rich settings and the regimen included nelfinavir in nearly half of participants, restricting its relevance to current treatment decision in Africa, where most paediatric HIV infections occur. Consequently, to inform its recommendations on the optimum dual NRTI backbone for paediatric ART, the WHO has relied on data from randomised trials without head-to-head comparisons of NRTIs, observational cohort data, and expert opinion. The near complete absence of trial data in children is unacceptable in the context of lifelong ART, which requires a good understanding of the effect of different NRTI backbones on toxicity, achievement and maintenance of viral suppression, and implications of mutations on future treatment options. The CHAPAS-3 trial2Mulenga V Musiime V Kekitiinwa A et al.Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.Lancet Infect Dis. 2015; (published online Oct 6.)http://dx.doi.org/10.1016/S1473-3099(15)00319-9PubMed Google Scholar now fills this gap by providing the first trial data comparing abacavir, stavudine, and zidovudine in combination with lamivudine and nevirapine or efavirenz for first-line treatment in HIV-positive children in Africa. In 2013, the WHO recommended abacavir plus lamivudine as the preferred dual NRTI backbone in children because “abacavir can be used once daily, is available as a fixed-dose combination with 3TC [[lamivudine], and harmonises with TDF [tenofovir]from a resistance perspective”.3WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. World Health Organisation, Geneva2013Google Scholar This change occurred despite the relatively high cost of abacavir and the association of abacavir with hypersensitivity reactions.4Kline MW Blanchard S Fletcher CV et al.A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team.Pediatrics. 1999; 103: e47Crossref PubMed Scopus (37) Google Scholar Furthermore, observational data from two cohort studies indicated that abacavir might be less effective in achieving and maintaining viral suppression compared with similar regimens containing stavudine, raising concerns among clinicians and policy makers about the WHO recommendation.5Technau KG Lazarus E Kuhn L et al.Poor early virologic performance and durability of abacavir-based first-line regimens for HIV-infected children.Pediatr Infect Dis J. 2013; 32: 851-855PubMed Google Scholar, 6Technau KG Schomaker M Kuhn L et al.Virologic response in children treated with abacavir-compared with stavudine-based antiretroviral treatment: a South African multi-cohort analysis.Pediatr Infect Dis J. 2014; 33: 617-622Crossref PubMed Scopus (23) Google Scholar In the multicentre CHAPAS-3 trial,2Mulenga V Musiime V Kekitiinwa A et al.Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.Lancet Infect Dis. 2015; (published online Oct 6.)http://dx.doi.org/10.1016/S1473-3099(15)00319-9PubMed Google Scholar 478 children age 1 month to 13 years were randomly assigned to receive fixed-dose combination tablets of one of three NRTIs (abacavir, stavudine, or zidovudine) plus lamivudine in combination with nevirapine or efavirenz, all dosed according to WHO weight bands. The trial included 365 ART-naive children and 113 virologically suppressed ART-experienced children on a stavudine-containing first-line regimen for 2 years or more. The study achieved superb completion rates with only 5% of children lost to follow-up and 98% of scheduled nurse visits completed. Clinical outcomes were excellent for all three NRTIs, with low (4%) mortality, high (≥80%) viral load suppression rates in ART-naive children, high (>96%) maintenance of viral suppression at 48 weeks in ART-experienced children, and no evidence of differential CD4% recovery across randomised groups. In children with ongoing viral replication, sensitivity to second-line drugs remained high independent of the NRTI used. Toxicity was low and independent of NRTI group, with no differences noted in the proportion of children with grade 2 or more clinical or grade 3 or more laboratory adverse events (67% in stavudine group, 65% in zidovudine group, and 64% in abacavir group; p=0·63) with grade 2 respiratory tract infections accounting for more than half of all primary endpoints. Few children (4% who received stavudine, 8% who received zidovudine, and 3% who received abacavir) presented with grade 3 or more adverse events with possible relations to NRTIs, and only 6% of children changed regimens during the 2·3 years of median follow-up. Of note, a higher proportion of children in the zidovudine group then in the other two treatment groups had their ART regimen modified as a result of toxicity, even though there was no evidence that grade 3 or 4 anaemia was more frequent in that group. This finding potentially indicates a lower threshold among clinicians to modifying therapy in children receiving zidovudine. The endpoint review committee diagnosed nine children with a hypersensitivity reaction: five in the stavudine group, one child on zidovudine, and two receiving abacavir (p=0·21). Both children receiving abacavir continued the drug without adverse consequences, a finding that shows the difficulty in making an accurate clinical diagnosis of abacavir hypersensitivity. In conclusion, the CHAPAS-3 trial2Mulenga V Musiime V Kekitiinwa A et al.Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.Lancet Infect Dis. 2015; (published online Oct 6.)http://dx.doi.org/10.1016/S1473-3099(15)00319-9PubMed Google Scholar refutes the concerns of reduced efficacy of abacavir-containing NRTI backbone for first-line ART that was raised by observational studies, and strongly suggests that NRTI backbone with efavirenz or nevirapine in children is associated with very low toxicities and high viral load suppression rates independent of the NRTI used. These data are reassuring and support clinicians and policy makers in their implementation of the current WHO guidelines, which recommend abacavir plus lamivudine as the preferred NRTI backbone for paediatric ART. We declare no competing interests. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trialAll 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. Full-Text PDF Open Access