Tracking Resistance to Artemisinin Collaboration II

Epidemiology and Modelling

PI: Prof Arjen Dondorp (Mahidol Oxford Tropical Medicine Research Unit)

Co-Is: Multicentered incl Shunmay Yeung at LSHTM

Funding: DFID

Summary: The second iteration of the TRAC project, known as TRAC II, will not only monitor for the further extension or emergence of drug resistance, but will also investigate the safety, tolerability and efficacy of Triple Artemisinin-based Combination Therapies (TACTs) – the first of its kind. In areas with failing ACTs, the aim of TACTs is restoring antimalarial efficacy, whereas in areas where ACTs still work or artemisinin resistance has not yet arrived, it has the potential to delay the emergence of drug resistance.

Project details:

The imminent danger of untreatable falciparum malaria in the region urgently requires alternative treatment options. This will have to use existing drugs, since new compounds are years away. In TRAC II partner drugs with likely opposing resistance mechanisms will be combined into Triple Artemisinin-based Combination Therapies (TACTs). The TACTs that will be studied are dihydroartemisinin-piperaquine with mefloquine and artemether-lumefantrine with amodiaquine. The project will examine the safety, tolerability and efficacy of these TACT combinations, and study the pharmacokinetic and dynamic drug interactions.  In addition, TRAC II will study a recent developed synthetic trioxolane antimalarial arterolane, which is marketed in combination with piperaquine. The efficacy of this new combination will be tested in areas of artemisinin and partner drug resistance.

TRAC II will also study the important question whether intravenous artesunate is still an adequate treatment for patients with severe falciparum malaria.

Novel vector control measures are urgently needed to aid artemisinin resistance containment efforts in Southeast Asia. This is due in part to the outdoor and early evening blood feeding behaviors of Southeast Asian mosquitoes that transmit malaria, which renders bednets and indoor residual spraying with insecticides less effective. Treating people with ivermectin can make their blood lethal to mosquitoes, and thus could be an effective control measure to target outdoor-feeding malaria vectors. Ivermectin mass drug administration (MDA) shows promise as a vector control tool in West Africa as it reduces wild malaria vector survival up to one week and suppresses transmission for two weeks. Ivermectin could be combined with antimalarial drugs currently used in MDA format in Southeast Asia. These multi-drug MDAs would clear asymptomatic malaria cases from the human population while simultaneously suppressing transmission by local mosquitoes preventing new malaria cases. Here we propose a sequential clinical trial to assess the safety, tolerability, pharmacokinetic interaction, and mosquito-lethal efficacy of ivermectin, dihydroartemisinin-piperaquine, and primaquine.  []