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Project Topic
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Human immunodeficiency virus (HIV) is a virus that damages the cells in the immune system and weakens the body’s ability to fight everyday infections and disease. HIV is treated with antiretroviral medications which stop the virus replicating in the body. In 2014, an estimated 823,000 HIV-infected children and adolescents aged up to 15 years were receiving anti-retroviral therapy (ART) in low- and middle-income countries. From 2015, World Health Organisation (WHO) guidelines recommended all HIV-infected adults and children take ART, regardless of the strength of their immune system (CD4 count) or their clinical status. The numbers of HIV-infected children on first-line ART in low-income countries is therefore likely to continue to increase, despite reductions in many countries of new infections through mother-to child transmission. The growing number of children on ART, coupled with increased detection of ART treatment failure, will increase the number of children needing to switch from their first ART drug treatment (first line) to second-line treatment. This raises the question of whether current second-line ART is optimal in terms of maximising children’s health gains and minimising toxicity (side effects) from the treatment long-term, given the need for children to receive life-long ART. The current WHO-recommended second-line ART for children failing standard first-line treatment is not ideal, as it is based on a fixed dose combination drug which needs to be taken as whole (non-crushed) pills, mini-pill pellets or unpalatable liquid, and also interacts with anti-tuberculosis drugs. The aim of this study is to optimise second-line treatment in HIV-infected children by testing new antiretroviral drugs/formulations, in order to maximise long-term health gains. Publication website: http://www.isrctn.com/ISRCTN22964075 The principal objective of this study is to improve the second-line treatment options for children living with HIV in sub-Saharan Africa. It is comparing 3 new options for the third drug in second-line combination antiretroviral therapy to the current standard (twice daily lopinavir/ritonavir): • once daily atazanavir/ritonavir • once daily darunavir/ritonavir • once daily dolutegravir CHAPAS-4 is also comparing an NRTI backbone of tenofovir alafenamide plus emtricitabine to the current standard of abacavir or zidovudine plus lamivudine. CHAPAS-4 will also provide information on second-line antiretroviral therapy dosing needed for children receiving tuberculosis treatment, the side-effects of the different regimens, and the cost-effectiveness of different regimens. The primary outcome will be: Alive with HIV viral load (VL) <400 copies/ml at 96 weeks after switch to second-line therapy Secondary Outcome Measure(s): Through 96 weeks ? Percentage alive with VL <50 and <1000 copies/mL ? Change in Stanford drug resistance, accumulation of new NRTI, PI and INI resistance-associated mutations in those with VL> 400 copies/mL ? Percentage modifying ART due to adverse events (AEs) ? Incidence/type of grade 3/4 AEs and serious AEs ? Changes in total, LDL, HDL cholesterol and triglycerides ? Changes in renal function (creatinine clearance estimated using bedside-Schwartz) and bilirubin ? Changes in absolute and percentage CD4 ? New or recurrent WHO 3 or 4 events or death ? Self-reported adherence and acceptability Randomisation Who can participate? HIV-infected children aged 3-15 years weighing 14 kg or higher and failing first-line antiretroviral treatment During year 2 of the study, five sites (Uganda, Zimbabwe and Zambia) have been activated and are actively recruiting, one site (Zimbabwe) is in set-up.
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