High-resolution malaria parasite and drug dynamics in the context of antimalarial treatment and drug resistance selection

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Malaria is a leading cause of morbidity and mortality globally. Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria and combine a potent short-acting artemisinin with a longer-acting partner drug. ACTs rapidly clear the initial infection while providing a post-treatment prophylactic period that reduces the risk of reinfection. In Southeast Asia, artemisinin and partner drug resistance has dramatically decreased ACT efficacy. In sub-Saharan Africa, where artemisinin resistance has not been widely established, artemether- lumefantrine (AL) is the most widely prescribed ACT. A challenge to treatment in sub-Saharan Africa is the substantial overlap of malaria and human immunodeficiency virus (HIV) infections. Child development and antiretroviral therapy significantly alter AL exposure, which can significantly impact treatment outcomes and contribute to drug resistance selection. Therefore, we conducted a randomized clinical trial to evaluate the safety and efficacy of 5-day (10-dose) versus standard 3-day (6-dose) AL to improve drug exposure and therapeutic efficacy in children with and without HIV living in a high endemic region of Uganda. A potential disadvantage of ACT regimens is the inherent mismatch in ACT component half-lives, resulting in an extended period of subtherapeutic lumefantrine “monotherapy” following treatment. In the parent trial, over 70% of children developed recurrent microscopically detectable parasitemia within 6 weeks of initial treatment with AL. Recent studies using newer more sensitive molecular approaches have detected persistent submicroscopic parasitemia up to 14 days after AL treatment. Thus, although increasing AL exposure may improve efficacy, our understanding of the interplay of partner drug exposure, parasite dynamics, and drug resistance selection in high transmission settings with multiclonal infections is lacking. Malaria pathogenesis and ACT drug exposure are further influenced by HIV infection and antiretroviral therapy. The high rate of new infections following treatment in our study provides the opportunity to comprehensively study parasite dynamics in children, and the impact that HIV infection has on those dynamics. Using state of the art molecular and genetic studies conducted in a randomized clinical trial, I propose to assess the relationship of persistent parasite detection to treatment outcomes, transmission dynamics, and drug resistance after AL treatment. I will further characterize the influence of sub-therapeutic partner drug levels on the selection of drug resistance. The combination of detailed parasite strain dynamics, drug pharmacokinetics, and drug resistance analysis has not been conducted to date. My overarching hypothesis is that a more detailed understanding of the influence of drug exposure and parasite dynamics on drug resistance selection will enable the optimization of current and future antimalarial regimens. This fellowship will provide me with an advanced experimental and statistical background in molecular biology and pharmacology, and will further my development as a physician-scientist with a career at the forefront of infectious disease treatment and prevention in a global health context.