title: Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children.
abstract: BACKGROUND
  Artemisinin-based combination therapies, including artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), are recommended to treat uncomplicated falciparum malaria. Sensitivities to components of AL and DP are impacted by polymorphisms in pfmdr1 and pfcrt. We monitored changes in prevalences of polymorphisms in Tororo, Uganda, from 2008 to 2012.
  
  
  METHODS
  Polymorphic loci in pfmdr1 and pfcrt were characterized in samples from 312 children randomized to AL or DP for each episode of uncomplicated malaria (50 samples per arm for each 3-month interval) utilizing a fluorescent microsphere assay. Treatment outcomes and impacts of prior therapies were also characterized.
  
  
  RESULTS
  Prevalence increased significantly over time for pfmdr1 N86 (AL: odds ratio [OR], 2.08 [95% confidence interval {CI}, 1.83-2.38]; DP: 1.41 [95% CI, 1.25-1.57]), pfmdr1 D1246 (AL: 1.46 [95% CI, 1.29-1.64]; DP: 1.36 [95% CI, 1.23-1.50]), and pfcrt K76 (AL: 3.37 [95% CI, 1.85-6.16]; DP: 5.84 [95% CI, 1.94-17.53], and decreased for pfmdr1 Y184 (AL: 0.78 [95% CI, .70-.86]; DP: 0.84 [95% CI, .76-1.50]); changes were consistently greater in the AL arm. Recent AL treatment selected for pfmdr1 N86, D1246, and 184F in subsequent episodes; DP selected for the opposite alleles.
  
  
  CONCLUSIONS
  Genotypes with decreased sensitivity to AL components increased over time. This increase was greater in children receiving AL, suggesting that the choice of treatment regimen can profoundly influence parasite genetics and drug sensitivity.
  
  
  BACKGROUND
  NCT00527800.
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Conrad
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Norbert
authors.initials: N
authors.lastname: LeClair
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Wanzira
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Abel
authors.initials: A
authors.lastname: Kakuru
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Infectious Diseases Research Collaboration.
authors.forename: Mary
authors.initials: M
authors.lastname: Muhindo
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Tappero
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000483:Alleles; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D011110:Polymorphism, Genetic; D014454:Uganda / Q000453:epidemiology
chemical_list: D037621:Artemisinins; C031327:artemisinin
keywords: Plasmodium falciparum; artemether-lumefantrine; dihydroartemisinin-piperaquine; pfcrt; pfmdr1