@article{e34ed2c57c2a459886042a7337c02aa7,
title = "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",
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 resistance1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemetherlumefantrine (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.",
keywords = "amodiaquine plus artesunate, artemether plus benflumetol, chloroquine, molecular marker, amodiaquine, amodiaquine, artesunate drug combination, antimalarial agent, artemether, artemisinin derivative, benflumetol, carrier protein, drug combination, ethanolamine derivative, fluorene derivative, genetic marker, Mdr1 protein, Plasmodium falciparum, multidrug resistance protein, PfCRT protein, Plasmodium falciparum, protozoal protein, allele, antimalarial drug resistance, Article, child, clinical trial, copy number variation, directional selection, drug dosage form comparison, drug efficacy, drug sensitivity, drug treatment failure, follow up, gene, genetic code, genotype, haplotype, human, infant, infection risk, major clinical study, malaria falciparum, mixed infection, multidrug resistance, nonhuman, parasite isolation, parasitemia, patient coding, Plasmodium falciparum, Plasmodium falciparum chloroquine resistance transporter gene, Plasmodium falciparum multidrug resistance transporter 1 gene, recurrent infection, reinfection, single nucleotide polymorphism, Tanzania, therapy effect, treatment response, amino acid substitution, drug effects, drug resistance, genetic polymorphism, genetics, information processing, Kaplan Meier method, Malaria, Falciparum, parasitology, preschool child, risk factor, Amino Acid Substitution, Amodiaquine, Antimalarials, Artemisinins, Child, Child, Preschool, Chloroquine, Datasets as Topic, Drug Combinations, Drug Resistance, Drug Therapy, Combination, Ethanolamines, Fluorenes, Genetic Markers, Genotype, Humans, Infant, Kaplan-Meier Estimate, Membrane Transport Proteins, Multidrug Resistance-Associated Proteins, Polymorphism, Genetic, Protozoan Proteins, Risk Factors",
author = "Meera Venkatesan and Gadalla, {Nahla B.} and Kasia Stepniewska and Prabin Dahal and Christian Nsanzabana and Clarissa Moriera and Price, {Ric N.} and Andreas Ma˚rtensson and Rosenthal, {Philip J.} and Grant Dorsey and Sutherland, {Colin J.} and Philippe Gu{\'e}rin and Davis, {Timothy M.E.} and Didier M{\'e}nard and Ishag Adam and George Ademowo and Cesar Arze and Baliraine, {Frederick N.} and Nicole Berens-Riha and Anders Bj{\"o}rkman and Steffen Borrmann and Francesco Checchi and Meghna Desai and Mehul Dhorda and Djimd{\'e}, {Abdoulaye A.} and El-Sayed, {Badria B.} and Teferi Eshetu and Frederick Eyase and Catherine Falade and Faucher, {Jean Franc¸ois} and Gabrielle Fr{\"o}berg and Anastasia Grivoyannis and Sally Hamour and Sandrine Houz{\'e} and Jacob Johnson and Erasmus Kamugisha and Simon Kariuki and Kiechel, {Jean Ren{\'e}} and Fred Kironde and Kofoed, {Poul Erik} and Jacques LeBras and Maja Malmberg and Leah Mwai and Billy Ngasala and Francois Nosten and Nsobya, {Samuel L.} and Alexis Nzila and Mary Oguike and Otienoburu, {Sabina Dahlstr{\"o}m} and Bernhards Ogutu and Ou{\'e}draogo, {Jean Bosco} and Patrice Piola and Lars Rombo and Birgit Schramm and Som{\'e}, {A. Fabrice} and Julie Thwing and Johan Ursing and Wong, {Rina P.M.} and Ahmed Zeynudin and Issaka Zongo and Plowe, {Christopher V.} and Sibley, {Carol Hopkins} and {WWARN AL and ASAQ Molecular Marker Study Group}",
year = "2014",
doi = "10.4269/ajtmh.14-0031",
language = "English",
volume = "91",
pages = "833--843",
journal = "American Journal of Tropical Medicine and Hygiene",
issn = "0002-9637",
publisher = "American Society of Tropical Medicine and Hygiene",
number = "4",
}
