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.
© The American Society of Tropical Medicine and Hygiene.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antimalarials / therapeutic use
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Artemether, Lumefantrine Drug Combination
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Artemisinins / therapeutic use
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Child
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Child, Preschool
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Chloroquine / therapeutic use
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Clinical Trials as Topic
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Drug Combinations
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Drug Resistance / drug effects
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Drug Resistance / genetics*
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Ethanolamines / therapeutic use
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Female
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Fluorenes / therapeutic use
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Genetic Markers
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Humans
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Infant
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Malaria, Falciparum / drug therapy
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Malaria, Falciparum / epidemiology
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Malaria, Falciparum / parasitology*
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Malaria, Falciparum / transmission
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Male
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Membrane Transport Proteins / genetics*
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Membrane Transport Proteins / metabolism
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Multidrug Resistance-Associated Proteins / genetics*
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Multidrug Resistance-Associated Proteins / metabolism
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Mutation
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / genetics*
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Plasmodium falciparum / metabolism
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Polymorphism, Genetic
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Protozoan Proteins / genetics*
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Protozoan Proteins / metabolism
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Pyrimethamine / therapeutic use
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Sulfadoxine / therapeutic use
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Tetrahydrofolate Dehydrogenase / genetics*
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Tetrahydrofolate Dehydrogenase / metabolism
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Time Factors
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Uganda / epidemiology
Substances
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Antimalarials
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Artemether, Lumefantrine Drug Combination
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Artemisinins
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Drug Combinations
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Ethanolamines
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Fluorenes
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Genetic Markers
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Mdr1 protein, Plasmodium falciparum
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Membrane Transport Proteins
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Multidrug Resistance-Associated Proteins
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PfCRT protein, Plasmodium falciparum
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Protozoan Proteins
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fanasil, pyrimethamine drug combination
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Sulfadoxine
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Chloroquine
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Tetrahydrofolate Dehydrogenase
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Pyrimethamine