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Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda
George W. Mbogo
George W. Mbogo
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Sheila Nankoberanyi
Sheila Nankoberanyi
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Stephen Tukwasibwe
Stephen Tukwasibwe
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Frederick N. Baliraine
Frederick N. Baliraine
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Samuel L. Nsobya
Samuel L. Nsobya
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Melissa D. Conrad
Melissa D. Conrad
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Emmanuel Arinaitwe
Emmanuel Arinaitwe
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Moses Kamya
Moses Kamya
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Jordan Tappero
Jordan Tappero
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Sarah G. Staedke
Sarah G. Staedke
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Grant Dorsey
Grant Dorsey
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Bryan Greenhouse
Bryan Greenhouse
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Philip J. Rosenthal
Philip J. Rosenthal
Infectious Diseases Research Collaboration, Kampala, Uganda; Le Tourneau University, Longview, Texas; Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, Georgia; London School of Hygiene and Tropical Medicine, United Kingdom; University of California, San Francisco, California
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Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistance-mediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003–2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008–2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.
Author Notes
Financial support: This study was funded by an International Center of Excellence in Malaria Research grant (AI089674) and a Fogarty International Center training grant (TW007375), both from the National Institutes of Health. Some study samples were from a trial supported by the Doris Duke Charitable Foundation; the U.S. President's Emergency Plan for AIDS Relief; and Cooperative Agreement U62P024421 from the Centers for Disease Control and Prevention (CDC); the National Center for HIV, Viral Hepatitis, STD, and TB Prevention; and the Global AIDS Program. The funders were not involved with study design, data analysis, or manuscript preparation.
Authors' addresses: George W. Mbogo, Sheila Nankoberanyi, Stephen Tukwasibwe, Samuel L. Nsobya, Emmanuel Arinaitwe, and Moses Kamya, Infectious Diseases Research Collaboration, Kampala, Uganda, E-mails: mbggeorge@yahoo.co.uk, nankshila@yahoo.com, stephentukwasibwe@yahoo.com, samnsobya@yahoo.co.uk, earinaitwe@idrc-uganda.org, and mkamya@infocom.co.ug. Frederick N. Baliraine, Le Tourneau University, Longview, TX, E-mail: FredBaliraine@letu.edu. Melissa D. Conrad, Grant Dorsey, Bryan Greenhouse, and Philip J. Rosenthal, Department of Medicine, University of California, San Francisco, CA, E-mails: ConradM@medsfgh.ucsf.edu, gdorsey@medsfgh.ucsf.edu, bgreenhouse@medsfgh.ucsf.edu, and prosenthal@medsfgh.ucsf.edu. Jordan Tappero, Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, GA, E-mail: jtappero@cdc.gov. Sarah G. Staedke, London School of Hygiene and Tropical Medicine, UK, E-mail: sarah.staedke@lshtm.ac.uk.
Reprints requests: Philip J. Rosenthal, Department of Medicine, Box 0811, University of California, San Francisco, CA 94143-0811. E-mail: prosenthal@medsfgh.ucsf.edu.
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1.
Yeka A, Gasasira A, Mpimbaza A, Achan J, Nankabirwa J, Nsobya S, Staedke SG, Donnelly MJ, Wabwire-Mangen F, Talisuna A, Dorsey G, Kamya MR, Rosenthal PJ, 2012. Malaria in Uganda: challenges to control on the long road to elimination: I. Epidemiology and current control efforts. Acta Trop 121: 184–195.
-
2.
Nanyunja M, Nabyonga Orem J, Kato F, Kaggwa M, Katureebe C, Saweka J, 2011. Malaria treatment policy change and implementation: the case of Uganda. Malar Res Treat 2011: 683167.
-
3.
Nosten F, White NJ, 2007. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 77: 181–192.
-
4.
Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Dokomajilar C, Kamya MR, Rosenthal PJ, 2007. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA 297: 2210–2219.
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5.
Yeka A, Dorsey G, Kamya MR, Talisuna A, Lugemwa M, Rwakimari JB, Staedke SG, Rosenthal PJ, Wabwire-Mangen F, Bukirwa H, 2008. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda. PLoS ONE 3: e2390.
-
6.
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Rosenthal PJ, 2013. The interplay between drug resistance and fitness in malaria parasites. Mol Microbiol 89: 1025–1038.
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8.
Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, Sidhu AB, Naude B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE, 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6: 861–871.
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