Children with HIV in Africa – Pharmacokinetics and adherence/acceptability of simple antiretroviral regimens
African paediatric HIV trial
What was this study about?
CHAPAS-3 compared the toxicity, pharmacokinetics, efficacy, adherence and acceptance of two fixed-dose combinations of abacavir +lamivudine+nevirapine/efavirenz and zidovudine +lamivudine+nevirapine/efavirenz to the first fixed-dose drug Triomune (stavudine +lamivudine+nevirapine/efavirenz) over a median of 2.3 years. We found that all three regimens tested were well tolerated and that there was no difference in the primary toxicity end-point. Only two children developed new signs of abnormal fat distribution (called lipodystrophy) – both had received stavudine for more than 2.5 years. Clinical/sub-clinical lipodystrophy was not observed in children <5 years regardless of how much stavudine they had taken before or during the study. No child had a hypersensitivity reaction to abacavir. Children randomised to zidovudine did not get anaemia (low haemoglobin) more frequently than other children. At 48 weeks, of those children who had not previously received anti-retroviral drugs, 85% of those randomised to stavudine, 80% of those randomised to zidovudine and 81% of those randomised to abacavir had HIV viral load (a measure of HIV virus in the blood) below 400 copies/ml; these differences were compatible with chance. All the children who had previously received anti-retroviral treatment had no evidence of HIV in their blood, and most of them maintained this regardless of which drug they were randomised to take. Children who had detectable levels of HIV virus in their blood had less evidence of resistance to other anti-HIV drugs that would be used in second-line regimens. All children had good clinical responses to the different treatments, and their immune systems all responded well to the different treatments. Overall the trial showed that absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favoured abacavir for African children, supporting WHO 2013 guidelines, as well as confirming that the anti-retroviral therapy given as WHO-recommended fixed-dose combinations is highly effective in children. The trial findings, which were published in The Lancet Infectious Diseases in 2015, indicate that priority must be given to early diagnosis and treatment in order to expand treatment to all HIV-infected children.
The study also collected information about the levels of drugs in the children’s blood. The data on efavirenz was shared with the USA FDA for preregistration of the new, scored 600mg efavirenz tablet used in the trial, and the CHAPAS-3 trial results were shared with the WHO for prequalification of these fixed-dose combination drugs.“
What difference did this study make?
This study has been incorporated into WHO 2015 guidelines to recommend abacavir first-line for HIV-infected children.
Type of study
Who funded the study?
The trial was funded by the European Developing Countries Clinical Trials Partnership (EDCTP), Medical Research Council UK (MRC UK), Department for International Development (DfID UK), the Ministerio de Sanidad y Consumo Spain and the Health Research Board Ireland. Drugs were supplied by Cipla Ltd, India.
When did it take place?
The first child was randomised on 8th November 2010 and the last child on 28th December 2011. The overall duration of the trial was three and a half years, with all children being followed-up for a minimum of 96 weeks. The children started to exit the trial at the end of October 2013, with the final children being transferred into the National Programmes in January 2014.
Where did it take place?
University Teaching Hospital, Lusaka, Zambia; Baylor Centre of Excellence at Mulago Hospital, Kampala, Uganda; Joint Clinical Research Centre, Kampala, Uganda and a JCRC satellite clinic in Gulu, Northern Uganda.
Who was included?
CHAPAS-3 enrolled 480 children between the ages of 1 month and 13 years from Uganda and Zambia. The children were either treatment naïve (had never received antiretroviral drugs before, except at birth to prevent mother to child transmission) or, if they had already been taking antiretrovirals including stavudine, had an undetectable viral load.