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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
Authors: Meera Venkatesan
Nahla B. Gadalla
Kasia Stepniewska
Prabin Dahal
Christian Nsanzabana
Clarissa Moriera
Ric N. Price
Andreas Ma˚rtensson
Philip J. Rosenthal
Grant Dorsey
Colin J. Sutherland
Philippe Guérin
Timothy M.E. Davis
Didier Ménard
Ishag Adam
George Ademowo
Cesar Arze
Frederick N. Baliraine
Nicole Berens-Riha
Anders Björkman
Steffen Borrmann
Francesco Checchi
Meghna Desai
Mehul Dhorda
Abdoulaye A. Djimdé
Badria B. El-Sayed
Teferi Eshetu
Frederick Eyase
Catherine Falade
Jean Franc¸ois Faucher
Gabrielle Fröberg
Anastasia Grivoyannis
Sally Hamour
Sandrine Houzé
Jacob Johnson
Erasmus Kamugisha
Simon Kariuki
Jean René Kiechel
Fred Kironde
Poul Erik Kofoed
Jacques LeBras
Maja Malmberg
Leah Mwai
Billy Ngasala
Francois Nosten
Samuel L. Nsobya
Alexis Nzila
Mary Oguike
Sabina Dahlström Otienoburu
Bernhards Ogutu
Jean Bosco Ouédraogo
Patrice Piola
Lars Rombo
Birgit Schramm
A. Fabrice Somé
Julie Thwing
Johan Ursing
Rina P.M. Wong
Ahmed Zeynudin
Issaka Zongo
Christopher V. Plowe
Carol Hopkins Sibley
University of Maryland School of Medicine
National Institute of Allergy and Infectious Diseases
Tropical Medicine Research Institute Sudan
Nuffield Department of Clinical Medicine
Menzies School of Health Research
Karolinska Institutet
University of California, San Francisco
London School of Hygiene & Tropical Medicine
University of Western Australia Faculty of Medicine and Dentistry
Institut Pasteur du Cambodge
University of Khartoum Faculty of Medicine
University of Ibadan
LeTourneau University
Ludwig-Maximilians-Universitat Munchen
Sveriges lantbruksuniversitet
Wellcome Trust Research Laboratories Nairobi
Magdeburg School of Medicine
Save the Children Fund
Centers for Disease Control and Prevention
University of Sciences
Jimma University
Kenya Medical Research Institute
Besançon University Medical Center
IRD Institut de Recherche pour le Developpement
University of Washington, Seattle
Hopital Bichat-Claude-Bernard AP-HP
Universite Paris Descartes
Catholic University of Health and Allied Sciences-Bugando
Drugs for Neglected Diseases Initiative
Makerere University
St. Augustine International University
Projecto de Saúde de Bandim
Kolding Sygehus
The University of British Columbia
Muhimbili University of Health and Allied Sciences
Mahidol University
King Fahd University of Petroleum and Minerals
-Bernard Hospital
Centre MURAZ
Institut Pasteur de Madagascar
Keywords: Immunology and Microbiology;Medicine
Issue Date: 1-Jan-2014
Citation: American Journal of Tropical Medicine and Hygiene. Vol.91, No.4 (2014), 833-843
Abstract: Copyright © 2014 by The American Society of Tropical Medicine and Hygiene. 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.
ISSN: 00029637
Appears in Collections:Scopus 2011-2015

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