This program project includes three randomized clinical trials to test whether long-term use ofchemopreventive antimalarial therapies in children or of antiretroviral protease inhibitors in children orpregnant women will decrease the incidence of malaria and related malarial morbidity. These interventionsoffer the opportunity to significantly decrease the incidence and morbidity of malaria, the most importantinfectious disease in children and pregnant women in Africa. However, repeated or chronic therapy forinfectious diseases routinely entails a risk of selection of drug-resistant parasites. This is a particular concernfor malaria, as drug resistance already limits treatment options, and control efforts based of intermittenttherapy have relied heavily on antifolates, against which resistance is increasing. Thus, as our clinical trialstest the preventive antimalarial efficacy of antiretroviral and antimalarial drugs, it is very important tocharacterize the impact of these interventions on the selection of drug-resistant malaria parasites. Wehypothesize that intermittent or chronic use of antimalarial and protease inhibitor-based antiretroviraltherapies will decrease the incidence of malaria, but that these therapies will select for drug resistantparasites that may become refractory to control efforts. Further, we hypothesize that different drugs will offerdifferent selective pressures. Therefore, an appreciation of the selective pressures for resistance of differentdrugs can, in addition to the results of our clinical trials, guide public policy for the management of HIVinfection and malaria in Africa. Project 4 will utilize parasitology and molecular techniques to test ourhypotheses, benefiting from a clinical laboratory with focused expertise in Tororo, a central laboratory inKampala with extensive molecular and parasitological capabilities, and a laboratory with 20 years ofexperience studying malaria parasites at UCSF.
Our specific aims will be: 1) to characterize the selection ofdrug-resistant malaria parasites by antifolate chemopreventive regimens, 2) to characterize the selection ofdrug-resistant malaria parasites by chemoprevention with dihydroartemisinin/piperaquine, and 3) tocharacterize the selection of drug-resistant malaria parasites by antiretroviral protease inhibitors withantimalarial activity. These studies will complement our clinical trials to provide a balanced assessment ofthe costs and benefits of new chemopreventive measures to control malaria.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-AARR-C (40))
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University of California San Francisco
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