Which NRTI backbone is best for children?

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

Mulenga V, Musiime V, Kekitiinwa A, Cook AD, Abongomera G, Kenny J, Chabala C, Mirembe G, Asiimwe A, Owen-Powell E, Burger D, McIlleron H, Klein N, Chintu C, Thomason MJ, Kityo C, Walker AS, Gibb DM, CHAPAS-3 trial team. Lancet Infect Dis. 2015 Oct 5. pii: S1473-3099(15)00319-9. doi: 10.1016/S1473-3099(15)00319-9. [Epub ahead of print]

Background: WHO 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.

Methods: In 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.

Findings: Between 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).

Interpretation: All 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.

Abstract [1]  Full-text [free] access [2]

Editor’s notes: Since 2013, the World Health Organization (WHO) has recommended abacavir as the preferred first-line nucleoside reverse transcriptase inhibitor (NRTI) in children. This recommendation was largely based on expert opinion, observational studies and issues such as cost and availability as a fixed dose combinations (FDC).

The CHAPAS-3 open-label trial is the only trial in African children that has conducted a direct head-to-head comparison of the three most relevant NRTIs (abacavir, stavudine and zidovudine) used for paediatric treatment. These were co-formulated in non-NRTI/NRTI generic fixed-dose combination paediatric tablets, with dosing based on WHO drug ratios and weight bands. The other drugs in the triple regimen were lamivudine with either efavirenz or nevirapine.

The primary aim of the trial was a comparison of the toxicity profile of the three NRTIs. The trial found no major difference in any adverse event or toxicity endpoint during nearly two and a half years of follow-up in both ART-naïve and ART-experienced children. There were no hypersensitivity reactions to abacavir, in agreement with other studies that have reported its rarity in Africans. Haemoglobin increased regardless of the NRTI and severe anaemia occurred no more frequently in children who received zidovudine versus children who received either of the two other drugs. This should reassure clinicians that zidovudine substitution is rarely necessary for anaemia among children on ART. However, an important caveat is that severe anaemia was an exclusion criteria in the trial. Clinical lipodystrophy was also rare. This is in contrast to older children and adolescents where lipodystrophy is much more common. At least in young children, stavudine could be safely used if other alternatives are not available, supporting WHO guidelines that stavudine for children should not be discontinued completely.       

Overall, CHAPAS-3 demonstrates that children respond well to all NRTI/non-NRTI recommended FDCs with minimal toxicity. Unlike previous trials, there was no difference in immunological or virologic outcomes between the three drugs. Importantly, choice of the NRTI backbone should not be a barrier to widening treatment access globally for HIV-positive children. Children receiving abacavir in their first-line regimen who had unsuppressed viral load at the end of the study were less likely to have resistance mutations compromising second-line NRTIs. In addition to its excellent tolerability profile, abacavir is the only NRTI available as a once-daily FDC licenced for children. This would support WHO recommendation of abacavir as the first choice NRTI in children. However, it does remain more expensive than the other two NRTIs and further price reductions will be required if abacavir use is to be widened.

Health care delivery [5], HIV Treatment [6]
Africa [7]
Uganda [8], Zambia [9]
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