Triple artemisinin combination therapies: A new paradigm for the treatment of malaria?

Abstract

Artemisinin Combination Therapies (ACT) are first-line treatments for malaria. The Tracking Resistance to Artemisinin Collaboration (TRAC) mapped the spread of artemisinin resistance in 10 countries in Asia (7) and Africa (3) and described artemisinin resistance in Southeast Asia (SEA). In Cambodia, Thailand, and Vietnam, artemisinin resistance is compounded by partner drug resistance resulting in dihydroartemisininpiperaquine (DHA-PPQ) treatment failure rates of >60%. The TRACII study conducted in 8 countries in Asia (7) and Africa (1) explored the concept of combining an ACT with a third antimalarial drug and assessed efficacy, safety and tolerability of two Triple ACT (TACT): DHA-PPQ+mefloquine (DHA-PPQ+MQ) and artemether-lumefantrine+amodiaquine (AL+AQ). Both TACT were safe, well tolerated and highly efficacious against ACTresistant parasites in SEA. TACT could become standard treatment for malaria worldwide as part of strategies to prevent or delay emergence of drug resistant malaria in regions outside of SEA. A new project titled Development of Triple Artemisinin Combination Therapies (DeTACT) will take a multifaceted approach to assess potential benefits and disadvantages of deploying TACT as first-line antimalarial treatments. In a randomized, controlled, non-inferiority trial, we will compare safety, tolerability and efficacy of dose-optimised artesunate-PPQ+MQ and AL+AQ TACT in blistered co-packages versus ACT+placebo in 13 countries in Asia (5) and Africa (8). The potential of TACT to delay emergence and spread of antimalarial resistance and cost-effectiveness of deploying TACT will be assessed through mathematical modelling. We will address ethical issues such as balancing individual and community disadvantages versus public benefits of introducing TACT in regions where ACT are still efficacious. Market and demand related issues involved in development, implementation and deployment of TACT will be studied to guide future introduction in the global marketplace and communicated to stakeholders via a strategic engagement plan. Development of the project and progress to date will be presented.