Therapy for malaria in Africa has changed greatly in recent years, with adoption of new artemisinin-based combination therapy (ACT) as the standard treatment for uncomplicated malaria in most countries. However, our appreciation of the relative efficacies and safeties of leading ACTs remains ncomplete. In this study we continue to compare the efficacy and safety of the two leading ACTs, artesunate/amodiaquine and artemether/lumefantrine, using a novel longitudinal format.  In addition, added sample size will facilitate exploration of secondary clinical outcomes and molecular aims. We continue to test the hypotheses stated in our initial application, that longitudinal evaluation will identify important differences between the efficacies and selective pressures of leading antimalarial combination therapies and that identifiable parasite and host polymorphisms will help predict outcomes after antimalarial therapy. In addition, with our extension we will emphasize studies of safety, hypothesizing that longitudinal evaluation will identify important differences in the tolerability and safety of study regimens. Our project includes clinical studies at our established study site in Kampala, Uganda and related molecular studies in Kampala and San Francisco. Since initiation of our clinical trial in November, 2004 our project has been highly successful in working toward our aims, which will continue to be (1) to compare the efficacies of combination antimalarial therapies using a longitudinal design, (2) to follow plasmodial genetic polymorphisms as longitudinal markers of antimalarial drug resistance, and (3) to evaluate the roles of host genetic polymorphisms in antimalarial drug resistance and the incidence of clinical malaria. We anticipate that the experiments designed to achieve these aims will contribute to improved management of malaria and to a better understanding of the genetic factors that impact upon responses to therapy for this disease.