Title: RESISTANCE OF MALARIA PARASITES TO ARTEMISININ-BASED COMBINATION THERAPIES Project summary The control of malaria in Africa is challenged by increasing drug resistance. New artemisinin- based combination therapy (ACT) regimens are generally very effective, and have recently been adopted as standard therapy for uncomplicated malaria by nearly every country in Africa. However, heavy and repeated use of ACTs, as is now occuring, will lead to strong selective pressure for resistance to components of these regimens. Our understanding of mechanisms of resistance to ACTs is incomplete. We suggest that the best means of identifying resistance- mediating mutations before they are widespread will be to evaluate parasites that emerge soon after therapy, while they are under the selective pressure of long-acting ACT partner drugs. We hypothesize that treatment failures and the emergence of new infections soon after treatment with ACTs will be associated with known and unknown mutations in malaria parasites that alter responses to artemisinin partner drugs. To test this hypothesis, we will systematically evaluate parasites from recent and ongoing clinical trials in Uganda and Burkina Faso to identify associations between candidate mutations and clinical responses to ACTs. We further hypothesize that increasing use of ACTs will select for parasites with decreasing drug sensitivity, but also decreased fitness. To test this hypothesis, we will search for associations between treatment outcomes and in vitro measures of drug sensitivity and fitness. We will also study parasites with introduced mutations to test the impact of these alterations on in vitro measures of drug sensitivity and fitness.
Our specific aims will be (1) to identify genotypes associated with decreased responses to ACTs in Africa, (2) to assess molecular mechanisms and parasitological consequences of increasing resistance to ACTs, and (3) to characterize the specific impacts of parasite polymorphisms on drug sensitivity and fitness. Our studies will offer important insights into mechanisms of resistance to the most important new antimalarial regimens. They will also have direct practical relevance, as they will identify molecular markers of resistance to key regimens, offer an """"""""early warning system"""""""" for resistance by studying genotypes of parasites that emerge soon after treatment, and provide insight into the fitness consequences of increasing resistance.

Public Health Relevance

New combination therapies have recently become standard for the treatment of malaria, one of the greatest infectious disease problems in the world, due to increasing resistance to older drugs. This project involves studies of mechanisms of resistance of malaria parasites to new combination antimalarial therapies. These studies will have important public health benefits, as they will identify simple markers to identify resistance to new drugs before this problem is widespread, and they will offer insight into choices of the best new therapies for malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075045-05
Application #
8493975
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Rogers, Martin J
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$468,401
Indirect Cost
$123,076
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tukwasibwe, Stephen; Tumwebaze, Patrick; Conrad, Melissa et al. (2017) Drug resistance mediating Plasmodium falciparum polymorphisms and clinical presentations of parasitaemic children in Uganda. Malar J 16:125
Taylor, Aimee R; Flegg, Jennifer A; Holmes, Chris C et al. (2017) Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium Falciparum Drug Sensitivity-Associated Haplotypes in Uganda. Open Forum Infect Dis 4:ofw229
Walakira, Andrew; Tukwasibwe, Stephen; Kiggundu, Moses et al. (2017) Marked variation in prevalence of malaria-protective human genetic polymorphisms across Uganda. Infect Genet Evol 55:281-287
Yeka, Adoke; Kigozi, Ruth; Conrad, Melissa D et al. (2016) Artesunate/Amodiaquine Versus Artemether/Lumefantrine for the Treatment of Uncomplicated Malaria in Uganda: A Randomized Trial. J Infect Dis 213:1134-42
Nankabirwa, Joaniter I; Conrad, Melissa D; Legac, Jennifer et al. (2016) Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity. Antimicrob Agents Chemother 60:5649-54
Rosenthal, Philip J (2016) Artefenomel: a promising new antimalarial drug. Lancet Infect Dis 16:6-8
Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda et al. (2015) Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network. Am J Trop Med Hyg 93:57-68
Taylor, Steve M; Parobek, Christian M; DeConti, Derrick K et al. (2015) Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis 211:680-8
Cooper, Roland A; Conrad, Melissa D; Watson, Quentin D et al. (2015) Lack of Artemisinin Resistance in Plasmodium falciparum in Uganda Based on Parasitological and Molecular Assays. Antimicrob Agents Chemother 59:5061-4
Tumwebaze, Patrick; Conrad, Melissa D; Walakira, Andrew et al. (2015) Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from ugandan children. Antimicrob Agents Chemother 59:3018-30

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