Since 2003, EDCTP has funded 17 grants on HIV treatment. Experts advised that in Africa clinical trials were needed with the following specific aims: to test treatment regimens with lower overall antiretroviral exposure; to investigate the optimal time for initiating treatment; and to investigate the ways to best monitor and manage drug use both in children and in adults. The objectives of these trials were to simplify and standardise antiretroviral regimens in adults and children, and develop new treatment regiments. Two projects addressed issues of HIV and tuberculosis co-infection.

The CHAPAS-1 trial in Zambia started in 2005 and was completed in 2009. Professor Chifumbe Chintu and his team studied the appropriate dosing of and adherence to Triomune Baby/Junior. This is a fixed-dose combination of stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) in a new dose escalating formulation specifically developed for children. CHAPAS-1 specifically aimed to address the then complete lack of appropriate first-line antiretroviral regimens available for children in developing countries.

The research team shared its preliminary pharmacokinetics data with the USA Food and Drug Authority (FDA) and the data contributed to the approval of Triomune Baby/Junior for use in HIV-infected children in 2007. This approval enabled many HIV-infected children to be placed on treatment in various developing countries. The drug was also made available under programmes such as the US President’s Emergency Plan for HIV/AIDS Relief (PEPFAR) and the Clinton HIV/AIDS Initiative (CHAI). The study findings contributed to the WHO recommendations on the optimal drug ratios in fixed-drug combinations and on weight band dosage for antiretroviral in children worldwide.

Unfortunately, the stavudine drug, contained in the Triomune fixed-dose combination, turned out to have cumulative toxicity side effects and was discontinued. This necessitated many adults and children on treatment to switch to other antiretroviral drug regimens. As the number of children under antiretroviral treatment still falls behind that of adults because of the lack of antiretroviral options, the CHAPAS-3 study, led by Dr Veronica Mulenga, followed on CHAPAS-1 to contribute to addressing this gap and increase options of first-line fixed-dose ART for children. CHAPAS-3 evaluates three fixed-dose combination first-line antiretroviral drugs.

The study compared the toxicity, pharmacokinetics, efficacy, adherence and acceptance of two newer fixed-dose combinations of ABC (abacavir) +3TC+NVP/EFZ (efavirenz) and AZT (zidovudine) +3TC+ NVP/EFZ to the first fixed-dose drug Triomune. CHAPAS-3 provided important data on optimal first-line anti-retroviral (ARV) regimens for treatment of HIV-infected children in Africa. The trial also included analyses of adherence/acceptability, cost-effectiveness and viral load suppression. Adherence among children taking fixed-dose combination ART was high and sustained over two years. However, certain groups were at risk for treatment failure, including children with disrupted routines, no knowledge of their HIV diagnosis among older children, and relatively high household income, possibly reflecting greater social support in the setting of greater poverty.

The findings were presented at the Seventh EDCTP Forum (2014) and showed that the three regimens tested were well tolerated and that there was no difference in the primary toxicity end-point. These important results confirm that ART given as WHO-recommended fixed-dose combinations is highly effective in children.

The data on efavirenz have been shared with the USA FDA for preregistration of the new, scored 600mg efavirenz tablet and the CHAPAS-3 trial results will be shared with WHO for prequalification of these fixed-dose combination drugs. The trial findings, which were published in the Lancet in 2015, indicate that priority must be given to early diagnosis and treatment in order to expand treatment to all HIV-infected children, supporting WHO 2013 guidelines.

 

Relevant publications:

1. 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. 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 Oct 5. pii: S1473-3099(15)00319-9. doi: 10.1016/S1473-3099(15)00319-9. [Epub ahead of print]
2. Fillekes, Q; Mulenga, V; Kabamba, D; Kankasa, C; Thomason, MJ; Cook, A; Ferrier, A; Chintu, C; Walker, AS; Gibb, DM; Burger, DM. (2012) ‘Pharmacokinetics of nevirapine in HIV-infected infants weighing 3 kg to less than 6 kg taking paediatric fixed dose combination tablets’. AIDS. 26(14):1795-1800
3. Haberer, JE; Cook, A; Walker, AS; Ngambi, M; Ferrier, A; Mulenga, V; Kityo, C; Thomason, M; Kabamba, D; Chintu, C; Gibb, DM; Bangsberg, DR. (2011) ‘Excellent Adherence to Antiretrovirals in HIV plus Zambian Children Is Compromised by Disrupted Routine, HIV Nondisclosure, and Paradoxical Income Effects’. PLOS ONE. 21;6(4):e18505
4. Mulenga, V; Cook, A; Walker, AS; Kabamba, D; Chijoka, C; Ferrier, A; Kalengo, C; Kityo, C; Kankasa, C; Burger, D; Thomason, M; Chintu, C; Gibb, DM. (2010) ‘Strategies for Nevirapine Initiation in HIV-Infected Children Taking Pediatric Fixed-Dose Combination “”Baby Pills”” in Zambia: A Randomized Controlled Trial’. Clinical Infectious Diseases. 51(9):1081-1089
5. Burger, D; Ewings, F; Kabamba, D; L’homme, R; Mulenga, V; Kankasa, C; Thomason, MJ; Gibb, DM; Chintu, C; and Walker, AS. (2010) ‘Limited Sampling Models to Predict the Pharmacokinetics of Nevirapine, Stavudine, and Lamivudine in HIV-Infected Children Treated With Pediatric Fixed-Dose Combination Tablets’. Therapeutic Drug Monitoring. 32(3):369-72.
6. Ryan, M; Griffin, S; Chitah, B; Walker, AS; Mulenga, V; Kalolo, D; Hawkins, N; Merry, C; Barry, MG; Chintu, C; Sculpher, MJ; and Gibb, DM. (2008) ‘The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia’. AIDS. 30;22(6):749-57
7. L’homme, R; Kabamba D; Ewings, FM; Mulenga, V; Kankasa, C; Thomason, MJ; Walker, AS; Chintu, C; Burger, DM; and Gibb, DM. (2008) ‘Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets’. AIDS. 12;22(5):557-65