title: Directional selection at the pfmdr1, pfcrt, pfubp1, and pfap2mu loci of Plasmodium falciparum in Kenyan children treated with ACT.
abstract: BACKGROUND
  The efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria may be threatened by parasites with reduced responsiveness to artemisinins. Among 298 ACT-treated children from Mbita, Kenya, submicroscopic persistence of P. falciparum on day 3 posttreatment was associated with subsequent microscopically detected parasitemia at days 28 or 42.
  
  
  METHODS
  DNA sequences of resistance-associated parasite loci pfcrt, pfmdr1, pfubp1, and pfap2mu were determined in the Mbita cohort before treatment, on days 2 and 3 after initiation of treatment, and on the day of treatment failure.
  
  
  RESULTS
  Parasites surviving ACT on day 2 or day 3 posttreatment were significantly more likely than the baseline population to carry the wild-type haplotypes of pfcrt (CVMNK at codons 72-76; P < .001) and pfmdr1 (NFD at codons 86, 184, 1246; P < .001). In contrast, variant alleles of the novel candidate resistance genes pfap2mu (S160N/T; P = .006) and pfubp-1 (E1528D; P < .001) were significantly more prevalent posttreatment. No genetic similarities were found to artemisinin-tolerant parasites recently described in Cambodia.
  
  
  CONCLUSIONS
  Among treated children in western Kenya, certain P. falciparum genotypes defined at pfcrt, pfmdr1, pfap2mu, and pfubp1 more often survive ACT at the submicroscopic level, and contribute to onward transmission and subsequent patent recrudescence.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Gisela
authors.initials: G
authors.lastname: Henriques
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Hallett
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Khalid B
authors.initials: KB
authors.lastname: Beshir
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Nahla B
authors.initials: NB
authors.lastname: Gadalla
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Johnson
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Burrow
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Donelly A
authors.initials: DA
authors.lastname: van Schalkwyk
authors.affiliation: Human Health Division, International Centre for Insect Physiology and Ecology, Mbita Point.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sawa
authors.affiliation: Kenya Medical Research Institute, Nairobi.
authors.forename: Sabah A
authors.initials: SA
authors.lastname: Omar
authors.affiliation: Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Sutherland
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002160:Cambodia; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C031327:artemisinin
keywords: artemisinin; drug resistance; genetics; malaria