Selection of Known Plasmodium falciparum Resistance-Mediating Polymorphisms by Artemether-Lumefantrine and Amodiaquine- Sulfadoxine-Pyrimethamine but Not Dihydroartemisinin- Piperaquine in Burkina Faso

Abstract

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.