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test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

The success of malaria control programmes has contributed to a decrease in malaria mortality rates by approximately 50% worldwide over the past 15 years. To maintain this gain, WHO recommends use primaquine, in conjunction with artemisinin-based combination therapy (ACT), to block Plasmodium falciparum transmission in areas approaching malaria elimination and/or facing artemisinin resistance. East Africa including Tanzania faces artemisinin resistance which may justify adopting the recommendation.

Only one African country, Swaziland, has included PQ as part of the first-line treatment for P. falciparum in its national policy. Concerns related to safety monitoring of this new treatment recommendation is likely the key barrier for adoption of the regimen.

Primaquine (PQ) may cause haemolytic side effects in individuals who have G6PD deficiency; the potential for haemolysis depends on the dose. The current WHO-recommended dose of 0.25mg/kg is low enough to mitigate the side risk of haemolysis in G6PD deficiency individuals. This low dose also enables treatment without requiring G6PD testing.

Dr Mosha aims to determine the readiness, challenges and policy options for the effective roll-out of PQ with ACT in routine healthcare.  He is conducting a repeated cross-sectional study involving clinicians as a primary study population, who are treating uncomplicated malaria patients with ACT+PQ regardless of their G6PD status, with a 7 days follow-up and management of adverse events. Malaria patients are therefore the secondary study population.

The project will assess 16 randomly selected facilities in two rural districts (human resources, laboratory capacity and medical supplies) and equip 6 randomly sampled intervention facilities with the tools and supplies needed for monitoring and managing G6PD adverse events. Health care providers will then be trained to use the PQ Roll-Out Monitoring Pharmacovigilance Tool, which will subsequently be adopted and used by healthcare providers in malaria treatment using ACT+PQ, for a period of six months with minimal supervision. Healthcare provider challenges will be assessed and the training package will be revised. The revised training package and safety monitoring tool will then be used for four months. Finally, a comprehensive safety training package will be developed, including on the basis of in-depth interviews. ‘Key Informant’ interviews will be used to determine the needs for a successful roll-out of the PQ+ACT treatment regimen. The interviews will involve officers from the Ministry of Health, the National Malaria Control Programme, and the Safety Drug Monitoring Board.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

The study’s findings may provide useful evidence to facilitate the roll-out of the PQ+ACT regimen thus contributing to lowering the barriers for countries in sub-Saharan Africa to adopt the WHO recommended regimen when confronted with growing artemisinin resistance.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact