ASAAP-plus

The challenge

Malaria continues to pose a threat across a large swathe of sub-Saharan Africa. An estimated 250 million cases occur each year, leading to more than 600,000 deaths. 

Although effective antimalarial treatments exist, particularly artemisinin combination therapies (ACTs), there are concerning signs that their effectiveness is being compromised by the emergence and spread of drug-resistant parasites in sub-Saharan Africa. Although drugs remain effective, in some cases they are taking longer to kill parasites.

If ACT resistance takes hold, this would seriously undermine efforts to control malaria in sub-Saharan Africa. Delays in the introduction of ACTs after a previous generation of drugs were compromised led to the deaths of thousands of people, mostly children. It is therefore essential to act now so that steps can be taken immediately should ACT resistance become a major problem.

The project

Funded through the EDCTP2 programme, the ASAAP project focused on one possible strategy: developing ‘triple ACTs’ by adding an additional drug to existing antimalarial combinations. The idea is that the third drug protects the ACT, since parasites would need to develop resistance to each component of the combination to survive treatment. If the different components of the treatment have different mechanisms of action and different targets, a parasite would need to simultaneously acquire mutations in multiple genes, which is highly unlikely.

The ASAAP-plusproject has focused on a commonly used ACT, artemether–lumefantrine (AL), combined with atovaquone–proguanil (AP). AP is known to be an effective antimalarial, but until recently, its use in sub-Saharan Africa was limited by its high cost. However, a cheaper generic form is now available.

AP has an additional advantage: it targets more than one stage of the malaria life cycle. Unlike AL, AP also has activity on blood-stage parasites, so it could have an additional benefit by reducing transmission of parasites to new hosts via mosquitoes.

Although AL and AP are both highly effective antimalarials, a clinical trial is still needed to demonstrate that the triple combination treatment is equally effective and safe. The ASAAP-plus trial is comparing the AL–AP combination with AL alone in a trial involving more than 1,600 young children in Benin, Gabon, Ghana, and Mali, at sites with differing malaria transmission intensities.

The project team is also carrying out pharmacokinetic studies to determine whether administering the drugs together has any effect on their levels in different tissues, which might require modification of dosing. The project is investigating transmission-blocking effects by testing whether mosquitoes that feed on treated patients become infected with malaria parasites.

The study was severely affected by the COVID-19 pandemic, leading to delays in regulatory approvals and the supply of trial materials. The new funding will enable the ASAAP-plus project to complete the main trial, conduct the pharmacokinetic studies, investigate transmission-blocking activity, and explore whether the triple therapy has any impact on the presence of genetic markers of drug resistance.

Impact

The ASAAP-plus project will provide key data on a possible new approach to malaria treatment. It will:

• Demonstrate whether, as expected, the triple therapy is as effective as its individual components.
• Reveal whether the triple therapy has additional public health benefits by blocking transmission.

Should its safety and efficacy be confirmed, the triple therapy could be rapidly deployed should ACT resistance begin to spread within sub-Saharan Africa, ensuring that children can still benefit from a highly effective antimalarial treatment.