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

”

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 antimalarial drug combination dihydroartemisinin–piperaquine (DHA-PPQ) is a highly efficacious treatment for uncomplicated malaria. Due to its long half-life, it is a good option for chemoprevention, as it should offer long-lasting protection against infection.

However, DHA-PPQ has a relatively narrow therapeutic range – concentrations at which it is both effective and safe. This creates a therapeutic challenge. There are concerns that young children or people on antiretroviral drugs are being under-dosed, while some groups may be at risk of cardiac side effects from PPQ if doses are too high. One solution for children would be complex weight-based dosing regimens, but these would make it less easy to use DHA-PPQ in large-scale control programmes.

The IMPACT study is collating data on the links between PPQ dosage and drug concentrations and the risk of cardiac side effects. This work includes data collected in previous EDCTP-funded safety trials, the ADAPT and ADJusT studies, which informed the WHO’s Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials, published in 2017.

Members of the IMPACT project team contributed to the identification of global evidence gaps and research priorities, highlighting the importance of standardised collection of cardiac safety data in antimalarial trials. This led to the development of guidelines on cardiac monitoring, published in collaboration with the Worldwide Antimalarial Resistance Network (WWARN). The project also worked with WWARN to develop guidelines on how ECG and other data will be curated by WWARN, to facilitate sharing and synthesis of cardiac safety data from antimalarial trials.

In clinical studies, the IMPACT project team found that people living with HIV on antiretroviral therapy were not at increased risk of DHA-PPQ-related adverse events. However, levels of PPQ were markedly lower in those on efavirenz-based regimens, which could compromise the effectiveness of antimalarial treatment. By contrast, people on nevirapine-based regimens were exposed to elevated levels of PPQ, raising potential safety concerns.

To assess the clinical significance of these findings, a trial of DHA-PPQ safety and efficacy was carried out in Malawi and Mozambique. This found that neither efavirenz- nor nevirapine-based regimens affected the efficacy of DHA-PPQ. Some changes to cardiac function were seen, but they were relatively minor, spontaneously resolved and had no clinical impact; they may have been linked to the resolution of fever rather than to DHA-PPQ.

The project has also used modelling to identify age-based therapeutic windows for primaquine, another antimalarial with potential for use in chemoprevention campaigns. These were adapted for particular regional settings, including Africa, through use of regional weight-for-age growth references. The findings provide a basis for establishing suitable age-based dose regimens for 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 IMPACT project has generated important data on antimalarial efficacy and safety in people living with HIV on antiretroviral therapy, and helped to establish a global platform for monitoring cardiac safety in antimalarial trials. It has also illustrated how modelling can identify appropriate age-based antimalarial dose regimens. At the national level, the IMPACT team has been working with national stakeholders in Malawi, including the National Malaria Control Programme, to raise awareness of the importance of antimalarial dose optimisation and the need for pharmacovigilance in certain populations.

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