“
crucial in

widening African

children’s access

to antiretrovirals

”

Bringing antiretroviral drugs to children

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

The challenge

Infection with the fungal pathogen Cryptococcus is one of the main causes of death of people living with HIV in sub-Saharan Africa. Cryptococcal meningitis is responsible for an estimated 180,000 deaths a year, with mortality rates as high as 60%.

Flucytosine, originally developed as an anti-cancer drug, is part of the WHO-recommended treatment for cryptococcal meningitis. In 2018, it was shown to reduce the risk of death by 40% compared to an alternative widely used drug. However, it remains underutilised because of low availability in sub-Saharan Africa and because the recommended dosing schedule – four times daily – is difficult to implement.

The 5FC HIV-Crypto study aims to increase use of flucytosine by developing a more convenient formulation and promoting its wider implementation in sub-Saharan African countries.

The study has twin aims. The first is to develop an improved and affordable sustained-release formulation of flucytosine, allowing for twice-daily administration. The second is to encourage wider adoption of both the sustained-release and original immediate-release formulations.

Clinical research activities will initially compare the bioavailability of the sustained-release and immediate-release formulations, in fed and fasting states. If they are comparable, a phase II study will be undertaken to assess the fungicidal properties of the new formulation and its impact on clinical outcomes in patients with HIV-associated cryptococcal meningitis.

In parallel, the project team will develop locally appropriate educational tools and engage with ministries of health to raise awareness of cryptococcal meningitis and WHO treatment guidelines. Economic analyses will also be carried out, alongside estimation of national treatment needs. The plan is to promote the implementation of flucytosine in selected ‘trailblazer’ countries in sub-Saharan Africa.

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 project will generate the data necessary for submissions for WHO prequalification and for licensing approvals in sub-Saharan African countries. It has the potential to increase use of an effective but underutilised treatment for one of the most serious infections affecting people living with HIV. As part of coordinated efforts to improve timely detection and treatment of cryptococcal infections, the project could significantly reduce mortality in this vulnerable group.

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