“
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

Some 30 million pregnant women are at risk of malaria in Africa, and 10,000 die from malaria each year. In addition, malaria is responsible for the deaths of 100,000 infants, and 900,000 are born underweight because of malaria infections.

To prevent infections, pregnant women receive a series of preventive treatments with sulfadoxine-pyrimethamine (SP), as well as insecticide-treated bednets. However, resistance to SP is growing, and the hunt is on for safe and effective alternatives. Unfortunately, several possible options have been ruled out because, although they prevent malaria infections, many women experience side effects such as dizziness and vomiting.

The IMPROVE team has been exploring the use of a recently developed antimalarial drug, dihydroartemisinin–piperaquine (DP), to replace SP in areas where resistance to SP is high. Small-scale trials in Kenya and Uganda have shown that DP is better than SP at preventing malaria infections and is well-tolerated, but were not large enough to judge the effect of DP on pregnancy outcomes. Trial data were reported to WHO in 2015, which stated that supportive evidence from a large-scale trial was required before DP could be recommended in pregnancy.

In two new larger-scale trials in ten sites in three countries, involving more than 4500 women, the IMPROVE team is aiming to generate confirmatory evidence of DP’s efficacy against malaria infection, as compared with SP, and new data on birth outcomes – such as fetal loss, premature birth and low birthweight. As well as comparing SP and DP, the phase III IMPROVE-1 study has a third arm, which includes the antibiotic azithromycin as well as DP. Azithromycin is used to prevent sexually transmitted and reproductive tract infections, which are common in East Africa and can also affect birth outcomes.

Furthermore, the team is running a complementary phase III trial (IMPROVE-2) in pregnant women with HIV, who cannot receive SP because of its interactions with co-trimoxazole, an antibiotic used prophylactically to prevent infection. A previous small-scale study suggested that DP is safe and well-tolerated, but this larger study will show whether it also protects against negative birth outcomes and whether azithromycin provides any further benefits to mother or offspring.

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 trials should provide definitive evidence on the suitability of DP as a preventive treatment against malaria in pregnancy. They will also reveal whether azithromycin provides any additional benefits.

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