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.
