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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD059454-01
Application #
7574840
Study Section
Special Emphasis Panel (ZRG1-AARR-C (40))
Project Start
2008-09-15
Project End
2013-07-31
Budget Start
2008-09-15
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$234,582
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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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:
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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
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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
Koss, Catherine A; Natureeba, Paul; Kwarisiima, Dalsone et al. (2017) Viral Suppression and Retention in Care up to 5 Years After Initiation of Lifelong ART During Pregnancy (Option B+) in Rural Uganda. J Acquir Immune Defic Syndr 74:279-284
Conroy, Andrea L; McDonald, Chloe R; Gamble, Joel L et al. (2017) Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV. Am J Obstet Gynecol 217:684.e1-684.e17

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