title: Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda.
abstract: 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.
authors.affiliation: 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.
authors.forename: George W
authors.initials: GW
authors.lastname: Mbogo
authors.affiliation: 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.
authors.forename: Sheila
authors.initials: S
authors.lastname: Nankoberanyi
authors.affiliation: 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tukwasibwe
authors.affiliation: 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.
authors.forename: Frederick N
authors.initials: FN
authors.lastname: Baliraine
authors.affiliation: 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.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Nsobya
authors.affiliation: 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.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Conrad
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: 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.
authors.forename: Moses
authors.initials: M
authors.lastname: Kamya
authors.affiliation: 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.
authors.forename: Jordan
authors.initials: J
authors.lastname: Tappero
authors.affiliation: 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.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.affiliation: 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.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: 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.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: 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 prosenthal@medsfgh.ucsf.edu.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics*; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology* / Q000635:transmission; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014454:Uganda / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D002738:Chloroquine; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D005819:Genetic Markers; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011739:Pyrimethamine; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C001205:fanasil, pyrimethamine drug combination