PARASITE RESISTANCE

Selection of drug resistant malaria parasites by antimalarial and HIV therapies

Recent malaria control strategies include renewed interest in the use of drugs to prevent malaria. This program project includes three randomized clinical trials which will test whether long-term use of chemopreventive antimalarial therapies in children (Project 3) or of antiretroviral protease inhibitors (PIs) in children (Project 1) or pregnant women (Project 2) will decrease the incidence of malaria and related malarial morbidity. These interventions offer the exciting opportunity to significantly decrease the incidence and morbidity of malaria, the most important infectious disease in children and pregnant women in Africa. However, repeated or chronic therapy for infectious diseases routinely entails a risk of selection of drug-resistant parasites. This is a particular concern for malaria, as drug resistance already limits treatment options, and control efforts based of intermittent therapy have relied heavily on antifolates, against which resistance is increasing. Thus, as our 3 clinical trials test the preventive antimalarial efficacy of antimalarial and antiretroviral drugs, it is very important to characterize the impact of these interventions on the selection of drug-resistant malaria parasites.

We hypothesize that intermittent or chronic use of antimalarial and PI-based antiretroviral therapies will decrease the incidence of malaria, but that these therapies will select for drug resistant parasites that may become refractory to control efforts. Further, we hypothesize that different drugs will offer different selective pressures. Therefore, an appreciation of the selective pressures for resistance of different drugs can, in addition to the results of our clinical trials, guide public health policy for the management of HIV infection and malaria in Africa.

This project utilizes parasitology and molecular techniques to test our hypotheses, benefiting from a clinical laboratory with focused expertise in Tororo, a central laboratory in Kampala with extensive molecular and parasitological capabilities, and a laboratory with 20 years of experience studying malaria parasites at UCSF. These studies will complement our clinical trials to provide a balanced assessment of the costs and benefits of new chemopreventive measures to control malaria. Our specific aims are: 1) to characterize the selection of drug-resistant malaria parasites by antifolate chemopreventive regimens, 2) to characterize the selection of drug-resistant malaria parasites by chemoprevention with dihydroartemisinin/ piperaquine (DP), and 3) to characterize the selection of drug-resistant malaria parasites by antiretroviral protease inhibitors with antimalarial activity.