“
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

TB is one of the most difficult infections to treat, and presents major challenges to drug development. Current treatment regimes last six months and require patients to take multiple medications. Shorter and simpler regimens would improve adherence, reduce side effects and lower costs.

Unfortunately, evaluation of new TB drugs, and new combinations and doses of existing drugs, is highly challenging. In particular, methods for determining the impact of drugs on TB bacteria are imperfect, making it harder to determine whether drug treatments should be progressed. In addition, long and costly phase III trials are required, and several promising treatments have failed at this stage. As a result, there are many possible improvements to TB treatment, and a key challenge is to determine as efficiently as possible which are most likely to succeed so they can be rigorously evaluated in large-scale trials.

The PanACEA Consortium, funded in the first EDCTP programme, was set up not just to evaluate novel TB drugs and combinations, but also to build capacity for TB drug trials in Africa and, importantly, to advance clinical trial methodology to improve the efficiency of drug development and enhance the likelihood of success. It carried out landmark trials aiming to shorten TB treatment and introduced novel clinical trial designs never before used in infectious disease research.

PanACEA2 will build on this foundation. With higher doses of rifampicin showing promise in trials, it will carry out studies to identify the maximum tolerated dose that could be evaluated in future trials. In addition, it plans to assess the safety of promising new drugs entering the TB drug development pipeline, using a novel design that will allow determination of slow-acting effects and evaluation of multiple combinations in one study.

In a third strand of work, multiple combinations will be assessed in an adaptive trial, allowing for discontinuation of poorly performing therapies. Long-term follow-up will be undertaken – addressing the issue that early responses to drugs do not necessarily provide an accurate indicator of long-term treatment success. This will provide a key step towards reducing the risk of failure in phase III trials.

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.

PanACEA2 will generate key data on TB drug treatments, pilot innovative methodologies for drug evaluation that could greatly accelerate drug development and reduce the risk of failure, and build capacity for trials of the highest international regulatory standard. Furthermore, by operating as an open partnership, it can carry out studies in partnership with multiple drug developers, and also coordinate activities with other international TB drug consortia, minimising duplication of efforts.

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