Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine

Worldwide Antimalarial Resistance Network (WWARN) DP Study Group

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Abstract

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Original languageEnglish
JournalAmerican Journal of Tropical Medicine and Hygiene
Volume91
Issue number4
Pages (from-to)833-843
Number of pages11
ISSN0002-9637
DOIs
Publication statusPublished - 2014

Keywords

  • Amino Acid Substitution
  • Amodiaquine/therapeutic use
  • Antimalarials/pharmacology
  • Artemether
  • Artemisinins/therapeutic use
  • Child
  • Child, Preschool
  • Chloroquine/pharmacology
  • Datasets as Topic
  • Drug Combinations
  • Drug Resistance/genetics
  • Drug Therapy, Combination
  • Ethanolamines/therapeutic use
  • Fluorenes/therapeutic use
  • Genetic Markers/genetics
  • Genotype
  • Humans
  • Infant
  • Kaplan-Meier Estimate
  • Lumefantrine
  • Malaria, Falciparum/drug therapy
  • Membrane Transport Proteins/genetics
  • Multidrug Resistance-Associated Proteins/genetics
  • Plasmodium falciparum/drug effects
  • Polymorphism, Genetic
  • Protozoan Proteins/genetics
  • Risk Factors

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