“
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

Although care for people living with HIV has improved markedly in recent years, around a quarter only start treatment when their CD4 white blood cell numbers have been severely depleted. This places them at greatly increased risk of other infections, including TB. As many as 30% of people living with HIV succumb to TB, accounting for 19% of global TB mortality.

HIV infections increase the risk of active TB disease, and also lead to reduced concentrations of TB drugs in the bloodstream, owing to abnormalities in the adsorption of TB drugs. Antiretroviral therapy can also interfere with the action of TB drugs. Conversely, antiretroviral therapy can also trigger a potentially deadly exaggerated immune response to TB (immune reconstitution inflammatory syndrome, IRIS).

The DATURA trial is evaluating an intensified TB treatment regimen designed to address these challenges in people living with HIV and with low CD4 cell counts.

Recent trials have confirmed the safety of high doses of the key TB drug rifampicin. The DATURA trial is combining high-dose rifampicin with a higher than usual dose of isoniazid. The trial team will liaise with the EDCTP-funded INTENSE TBM project, which is using high-dose rifampicin to reduce mortality associated with tuberculosis meningitis.

The trial regimen will also incorporate a corticosteroid (prednisone), shown in the EDCTP-funded PREDART trial to reduce the risk of IRIS reactions in patients starting antiretroviral treatment.

The trial will compare the intensified approach – 8 weeks of high-dose anti-TB drugs followed by 16 weeks of classical treatment, plus 6 weeks of prednisone – with the standard 24-week TB treatment regime. The trial will include nearly 1,000 patients from all four regions of sub-Saharan Africa, generating definitive evidence on the efficacy and safety of this new approach.

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 DATURA trial is addressing a critical health issue in sub-Saharan Africa. If intensified treatment is shown to be more effective, it would have the potential to save the lives of a very vulnerable group of patients and also to reduce transmission of TB. The new regimen is based on existing widely used drugs so could be readily implemented in sub-Saharan Africa. The trial team is also maintaining close links with policymakers in the region, as well as global bodies involved in TB control, to ensure that findings are rapidly communicated to decision-makers and inform policy and practice.

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