Abstract Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy, is one of the most important drugs for the treatment of uncomplicated malaria, yet fundamental questions remain for assuring its optimal use in our most vulnerable populations, especially for children, and in the context of interacting antiretroviral therapies. Dolutegravir (DTG), now a first-line HIV treatment option per the updated HIV treatment guidelines, has never been studied in children in the setting of concomitant DP and its impact on DP pharmacokinetics is unknown, while lopinavir/ritonavir (LPV/r, another HIV treatment), is known to increase maximum piperaquine concentrations but the magnitude and associated risk of cardiotoxicity in children is still unclear. We plan to expand our current grant to allow us to study potential interactions between DTG and DP and to also more carefully, and safely, evaluate the potentially detrimental interaction between LPV/r and DP. This administrative supplement is requesting support to allow the study of DTG as one of three antiretrovirals that will be under evaluation. Specifically we are requesting support for the expansion of control children to include a broader age range which is necessary to age-match children who are managed on DTG. Additionally, this supplement is requesting support to permit a two phase study design that will allow us to complete a safe evaluation of the likely interaction between LPV/r / and DP (i.e. LPV/r is expected to increase piperaquine concentrations which has been associated with QTc prolongation). These two requests are to provide infrastructure support in Uganda. In summary, the results of our study has the potential to significantly impact treatment guidelines for HIV and malaria in children through this definitive study of pharmacokinetics and pharmacodynamics of DP in the setting of these antiretroviral therapies. Our overaching goal is to inform optimized DP dosing strategies for children.