Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Public Health
First Advisor
Parikh, Sunil
Abstract
Malaria is a leading cause of global morbidity and mortality with an estimated 249 million cases and 608,000 deaths in 2022, overwhelmingly in sub-Saharan Africa (SSA). 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 reduce the initial parasite burden, eliminate residual parasites, and provide post-treatment prophylaxis against new infections. Artemether-lumefantrine (AL) is the most widely prescribed ACT globally and in SSA. Unfortunately, ACT efficacy is threatened by widespread resistance in Southeast Asia, and by the emergence of partial artemisinin resistance in SSA. SSA also bears the highest burden of HIV worldwide, with over 2.4 million children and adolescents living with HIV and thus at risk for HIV-malaria coinfection. Understanding the influence of HIV-infection on antimalarial immunity and antimalarial-antiretroviral drug-drug interactions are necessary to optimize treatment in this vulnerable population. The purpose of this dissertation is to characterize the pathogenesis of malaria from the perspective of parasite dynamics, antimalarial drug exposure, and the host response to infection to better optimize antimalarial treatment regimens in the face of increasing drug resistance. Chapter 1 describes the development of the first population PK/PD model of lumefantrine in HIV-infected and HIV-uninfected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir/ritonavir-based antiretroviral regimens with daily trimethoprim-sulfamethoxazole prophylaxis. We found that efavirenz-based antiretroviral therapy was associated with significantly decreased lumefantrine exposure, and that HIV status and lumefantrine concentration were significant factors associated with recurrence risk. We further found significant selection for drug resistance associated mutations in recurrent infections, and that less sensitive parasites were able to tolerate lumefantrine concentrations ~3.5-fold higher than more sensitive parasites. Chapter 2 uses highly sensitive molecular markers and amplicon deep sequencing to characterize post-treatment stage-specific malaria parasite dynamics during a 42-day randomized trial of 3- versus 5-day artemether-lumefantrine in children with and without HIV. The prevalence of parasite-derived 18S rRNA was > 70% in children throughout follow-up, and the ring-stage marker SBP1 was detectable in over 15% of children on day 14 despite effective treatment. We found that the extended regimen significantly lowered the risk of recurrent ring-stage parasitemia compared to the standard 3-day regimen, and that higher day 7 lumefantrine concentrations decreased the probability of ring-stage parasites in the early post-treatment period. Longitudinal amplicon sequencing revealed dynamic patterns of multiclonal infections that included new and persistent clones in both the early post-treatment and later time periods, indicate that post-treatment parasite dynamics are highly complex despite efficacious therapy. Chapter 3 is a preliminary metabolomics study that incorporates different parasite markers to understand the host metabolic response to infection, treatment, and recurrence in HIV-infected and HIV-uninfected children. Malaria infection induces profound metabolic changes within the infected host, which can be studied using global untargeted metabolomics. We found that children without recurrent parasitemia had alterations in amino acid and fatty acid metabolism that resolved with treatment. In contrast, children with recurrent parasitemia had distinct metabolic changes that included fundamental amino acids involved in protein metabolism and the immune response to infection, whereas fatty acid metabolites did not significantly differ over time based on recurrence. Preliminary analysis further revealed a decreased difference in the metabolomes of HIV-infected and HIV-uninfected children during malaria infection compared to a healthy baseline, suggesting that the metabolic response to infection is similar between both groups.
Recommended Citation
Goodwin, Justin, "Malaria Parasite, Host, and Drug Dynamics in the Context of Artemether-Lumefantrine Treatment and HIV-Infection" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1267.
https://elischolar.library.yale.edu/gsas_dissertations/1267
