This program project includes three randomized clinical trials to test whether long-term use of chemopreventive antimalarial therapies in children or of antiretroviral protease inhibitors in children or pregnant women will decrease the incidence of malaria and related malarial morbidity. These interventions offer the 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 clinical trials test the preventive antimalarial efficacy of antiretroviral and antimalarial 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 protease inhibitor-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 policy for the management of HIV infection and malaria in Africa. Project 4 will utilize 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.
Our specific aims will be: 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, and 3) to characterize the selection of drug-resistant malaria parasites by antiretroviral protease inhibitors with antimalarial activity. These studies will complement our clinical trials to provide a balanced assessment of the costs and benefits of new chemopreventive measures to control malaria.
|Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna et al. (2018) Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. J Infect Dis 217:964-972|
|Odorizzi, Pamela M; Jagannathan, Prasanna; McIntyre, Tara I et al. (2018) In utero priming of highly functional effector T cell responses to human malaria. Sci Transl Med 10:|
|Savic, Rada M; Jagannathan, Prasanna; Kajubi, Richard et al. (2018) Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis 67:1079-1088|
|Jagannathan, Prasanna; Kakuru, Abel; Okiring, Jaffer et al. (2018) Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS Med 15:e1002606|
|Jagannathan, Prasanna; Kajubi, Richard; Aweeka, Francesca T (2018) Response to ""Antiretroviral Therapy With Efavirenz in HIV-Infected Pregnant Women: Understanding the Possible Mechanisms for Drug-Drug Interaction"". Clin Pharmacol Ther 103:571|
|Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2017) Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open Forum Infect Dis 4:ofx022|
|Sonoiki, Ebere; Nsanzabana, Christian; Legac, Jennifer et al. (2017) Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1. Antimicrob Agents Chemother 61:|
|Kajubi, R; Huang, L; Jagannathan, P et al. (2017) Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention. Clin Pharmacol Ther 102:520-528|
|Natureeba, Paul; Kakuru, Abel; Muhindo, Mary et al. (2017) Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine for the Prevention of Malaria Among HIV-Infected Pregnant Women. J Infect Dis 216:29-35|
|Roh, Michelle E; Shiboski, Stephen; Natureeba, Paul et al. (2017) Protective Effect of Indoor Residual Spraying of Insecticide on Preterm Birth Among Pregnant Women With HIV Infection in Uganda: A Secondary Data Analysis. J Infect Dis 216:1541-1549|
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