Selection of known Plasmodium falciparum resistance-mediating polymorphisms by artemether-lumefantrine and amodiaquine-sulfadoxine-pyrimethamine but not dihydroartemisinin-piperaquine in Burkina Faso

Antimicrob Agents Chemother. 2010 May;54(5):1949-54. doi: 10.1128/AAC.01413-09. Epub 2010 Mar 15.

Abstract

Artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DP), and amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) offer excellent antimalarial efficacy but may select for parasite polymorphisms that decrease drug sensitivity. We evaluated the selection of known polymorphisms in genes encoding putative transporters (pfcrt and pfmdr1) and SP targets (pfdhfr and pfdhps) in parasites that caused new infections within 42 days of therapy for uncomplicated falciparum malaria in Burkina Faso. In 559 children in 2006, 42-day genotype-uncorrected failures were seen in 31.2% with AL, 11.8% with AQ-SP, and 7.6% with DP. After prior AL therapy, selection of wild-type sequences was seen for K76T in pfcrt (72.7% mixed or mutant results pretreatment versus 52.1% in new infections; P = 0.008) and N86Y (36.0% versus 18.7%; P = 0.025) and Y184F (66.7% versus 45.8%; P = 0.009) in pfmdr1. After prior AQ-SP therapy, selection of mutant sequences was seen for N51I (30.8% versus 61.5%; P = 0.05), C59R (28.2% versus 76.9%; P = 0.002), and S108N (30.8% versus 76.9%; P = 0.005) in pfdhfr. After prior DP therapy, selection was not seen for K76T (72.7% versus 77.8%; P = 0.96) in pfcrt or N86Y (36.0% versus 33.3%; P = 0.84), Y184F (66.7% versus 77.8%; P = 0.39), or D1246Y (9.3% versus 0%; P = 0.42) in pfmdr1. In 378 additional treatments with DP in 2007, 42-day uncorrected failure was seen in 10.9%. After prior DP, selection was again not seen for K76T (66.7% mixed or mutant results versus 59.5%; P = 0.43) in pfcrt or N86Y (38.7% versus 40.5%; P = 0.85), Y184F (67.6% versus 73.0%; P = 0.54), or D1246Y (3.6% versus 8.1%; P = 0.50) in pfmdr1. Despite its chemical similarity, piperaquine did not select for the same polymorphisms as chloroquine or AQ, suggesting different mechanisms of resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amodiaquine / therapeutic use
  • Antimalarials / therapeutic use*
  • Artemether
  • Artemisinins / therapeutic use*
  • Burkina Faso
  • Drug Combinations
  • Drug Resistance, Bacterial / genetics
  • Ethanolamines / therapeutic use*
  • Fluorenes / therapeutic use*
  • Genotype
  • Humans
  • Infant
  • Lumefantrine
  • Malaria, Falciparum / drug therapy*
  • Membrane Transport Proteins / genetics
  • Multidrug Resistance-Associated Proteins / genetics
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics*
  • Polymorphism, Single Nucleotide
  • Protozoan Proteins / genetics
  • Pyrimethamine / therapeutic use
  • Quinolines / therapeutic use
  • Randomized Controlled Trials as Topic
  • Recurrence
  • Sulfadoxine / therapeutic use

Substances

  • Antimalarials
  • Artemisinins
  • Drug Combinations
  • Ethanolamines
  • Fluorenes
  • Mdr1 protein, Plasmodium falciparum
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • PfCRT protein, Plasmodium falciparum
  • Protozoan Proteins
  • Quinolines
  • Amodiaquine
  • fanasil, pyrimethamine drug combination
  • dihydroartemisinin
  • Sulfadoxine
  • piperaquine
  • Artemether
  • Lumefantrine
  • Pyrimethamine