Project Summary Malaria and HIV remain major challenges in sub-Saharan Africa (SSA), and the risk of co-infection remains high; complicated by drug-drug interactions, the potential for overlapping adverse events, as well as bidirectional negative clinical impacts. For HIV, a near universal transition to dolutegravir (DTG)-based regimens is occurring across the lifespan in SSA. While an improvement over existing regimens, emerging data clearly link DTG with increases in body mass index and metabolic derangements. Prospective studies of such changes in SSA pediatric settings are scarce and must be conducted to ensure that early life exposure to DTG does not lead to potential longer-term negative health impacts in HIV-infected children. SSA also bears the majority of the world's malaria burden. Treatment relies on artemisinin-based combination therapies (ACTs), of which artemether-lumefantrine (AL) and amodiaquine-artesunate (AS-AQ) are most utilized in SSA. ACTs combine a potent short-acting artemisinin derivative with a long-acting partner drug, an approach that has improved efficacy for the immediate episode, but also provides some protection against new exposures to infectious bites after treatment is completed. We have demonstrated reductions in piperaquine, another important ACT partner drug when given with DTG, and anticipate reductions will occur with AL and AS-AQ. Such bidirectional interactions must be urgently assessed in children to avoid any unintended negative consequences on malaria and HIV outcomes. Unfortunately, resistance to artemisinin, the critical backbone of all ACTs, has now been detected in multiple African countries, including Uganda, further emphasizing the need to optimize treatment regimens. For the partner drug lumefantrine, our group has demonstrated that pharmacokinetic (PK) exposure is a strong predictor of the risk of re-infection, and that less susceptible parasites are able to tolerate higher concentrations of drug. Similar studies are necessary for the artemisinin derivatives, which vary in PK for each ACT regimen, and for amodiaquine, a component of AS-AQ. Our group has led critical PK and pharmacodynamic (PD) studies aimed at informing the optimized use of ACTs in the most vulnerable populations for malaria, especially young children and those with HIV living in high transmission settings. To ensure that antimalarial and antiretroviral therapy remain optimized in the current shifting landscape, we propose to establish four longitudinal pediatric cohorts with the goal of 1) assessing the impact of HIV/DTG and repeated malaria infection on weight gain and the development of metabolic abnormalities in Ugandan children, 2) determining the PK of DTG and/or ACTs in HIV-uninfected children and HIV-infected children and their bidirectional clinical impacts, and 3) determining whether ACT PK is a driver of drug resistance selection. Our studies aim to ultimately inform guidelines on the appropriate management of both HI...