title: Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi.
abstract: BACKGROUND
  In 2007, Malawi replaced sulfadoxine-pyrimethamine (SP) with an artemisinin-based combination therapy as the first-line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy. Here we estimate the effect of reduced SP pressure on the prevalence of SP-resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci.
  
  
  METHODS
  Samples obtained from individuals with clinical malaria during a period of high SP use (1999-2001), a transitional period (2007-2008), and a period of low SP use (2012) were genotyped for resistance markers at pfdhfr-ts codons 51, 59, and 108 and pfdhps codons 437, 540, and 581. Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr-ts and pfdhps.
  
  
  RESULTS
  An increase in the prevalence of the resistance haplotypes DHFR 51I/59R/108N and DHPS 437G/540E occurred under sustained drug pressure, with no change in haplotype prevalence 5 years after reduction in SP pressure. The DHPS 437G/540E/581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure. Changes to the sweep characteristics flanking pfdhfr-ts and pfdhps were minimal.
  
  
  CONCLUSIONS
  In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future.
authors: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors: Elena
authors: E
authors: Artimovich
authors: Department of Fakultät Mathematik/Naturwissenschaften/Informatik, University of Applied Sciences Mittweida, Germany.
authors: Kristan
authors: K
authors: Schneider
authors: Blantyre Malaria Project.
authors: Terrie E
authors: TE
authors: Taylor
authors: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: James G
authors: JG
authors: Kublin
authors: Department of Pharmacy, University of Malawi College of Medicine, Blantyre.
authors: Fraction K
authors: FK
authors: Dzinjalamala
authors: School of Life Sciences, Arizona State University, Tempe.
authors: Ananias A
authors: AA
authors: Escalante
authors: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors: Christopher V
authors: CV
authors: Plowe
authors: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors: Miriam K
authors: MK
authors: Laufer
authors: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors: Shannon
authors: S
authors: Takala-Harrison
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use*; D016054:DNA, Protozoan / Q000235:genetics; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008295:Malawi; D020125:Mutation, Missense; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use*; D012641:Selection, Genetic; D013413:Sulfadoxine / Q000494:pharmacology* / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D004338:Drug Combinations; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine
keywords: DHFR; DHPS; malaria; pyrosequencing; resistance; selective sweeps; sulfadoxine-pyrimethamine