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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD059454-05
Application #
8382588
Study Section
Special Emphasis Panel (ZRG1-AARR-C)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$271,842
Indirect Cost
$82,269
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation. Malar J 15:497
Jagannathan, Prasanna; Bowen, Katherine; Nankya, Felistas et al. (2016) Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4+ T Cells and Limits Their Production of Immunoregulatory Interleukin 10. J Infect Dis 214:329-38
Boivin, Michael J; Sikorskii, Alla; Familiar-Lopez, Itziar et al. (2016) Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children. Malar J 15:210
Kakuru, Abel; Natureeba, Paul; Muhindo, Mary K et al. (2016) Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting. Malar J 15:500
Achan, Jane; Kakuru, Abel; Ikilezi, Gloria et al. (2016) Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy. Pediatr Infect Dis J 35:1329-1332
Kakuru, Abel; Jagannathan, Prasanna; Muhindo, Mary K et al. (2016) Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med 374:928-39
Farrington, Lila A; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Frequent Malaria Drives Progressive Vδ2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood. J Infect Dis 213:1483-90
Marquez, Carina; Chamie, Gabriel; Achan, Jane et al. (2016) Tuberculosis Infection in Early Childhood and the Association with HIV-exposure in HIV-uninfected Children in Rural Uganda. Pediatr Infect Dis J 35:524-9
Odorizzi, Pamela M; Feeney, Margaret E (2016) Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity. Trends Mol Med 22:877-888
Muhindo, Mary K; Kakuru, Abel; Natureeba, Paul et al. (2016) Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda. Malar J 15:437

Showing the most recent 10 out of 44 publications