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

Meera Venkatesan(University of Maryland, Baltimore), Nahla B. Gadalla(National Institutes of Health), Kasia Stepniewska(University of Oxford), Prabin Dahal(Worldwide Veterinary Service), Christian Nsanzabana(University of Oxford), Clarissa Moriera(University of Oxford), Ric N. Price(University of Oxford), Andreas Mårtensson, Philip J. Rosenthal(University of California, San Francisco), Grant Dorsey(University of California, San Francisco), Colin J. Sutherland(University of London), Philippe J. Guérin(Université Sorbonne Nouvelle), Timothy M. E. Davis(University of Washington), Didier Ménard(Institut Pasteur), Ishag Adam(University of Khartoum), George Ademowo(University of Ibadan), Cesar Arze(University of Maryland, Baltimore), Frederick N. Baliraine(LeTourneau University), Nicole Berens‐Riha(Ludwig-Maximilians-Universität München), Anders Björkman(Karolinska Institutet), Steffen Borrmann(Wellcome Trust), Francesco Checchi(Hospital for Tropical Diseases), Meghna Desai(Centers for Disease Control and Prevention), Mehul Dhorda(University of Maryland, Baltimore), Abdoulaye Djimdé(Cheikh Anta Diop University), Badria El-Sayed(University of Washington), Teferi Eshetu(Jimma University), Frederick Eyase(Kenya Medical Research Institute), Catherine O. Falade(University of Ibadan), Jean‐François Faucher(Université de Limoges), Gabrielle Fröberg(Karolinska Institutet), Anastasia Grivoyannis(University of Washington), Sally Hamour(University College London), Sandrine Houzé(Université Paris Cité), Jacob D. Johnson(Kenya Medical Research Institute), Erasmus Kamugisha(Catholic University of Health and Allied Sciences), Simon Kariuki(Centers for Disease Control and Prevention), Jean‐René Kiechel(Drugs for Neglected Diseases Initiative), Fred Kironde(Makerere University), Poul‐Erik Kofoed(University of Southern Denmark), J Lebras(Université Paris Cité), Maja Malmberg(Karolinska Institutet), Leah Mwai(University of British Columbia), Billy Ngasala(Muhimbili University of Health and Allied Sciences), François Nosten(Shoklo Malaria Research Unit), Samuel L. Nsobya(Makerere University), Alexis Nzila(King Fahd University of Petroleum and Minerals), Mary C. Oguike(University of London), Sabina Dahlström Otienoburu(University of Washington), Bernhards Ogutu(Kenya Medical Research Institute), Jean‐Bosco Ouédraogo(Nazi Boni University), Patrice Piola(Institut Pasteur), Lars Rombo(Karolinska Institutet), Birgit Schramm(Médecins Sans Frontières), Anyirékun Fabrice Somé(University of Washington), Julie Thwing(Centers for Disease Control and Prevention), Johan Ursing, Rina P. M. Wong(University of Washington), Ahmed Zeynudin(Kenya Medical Research Institute), Issaka Zongo(University of Washington), Christopher V. Plowe(University of Maryland, Baltimore), Carol Hopkins Sibley(University of Washington), _ _
American Journal of Tropical Medicine and Hygiene
July 22, 2014
10.4269/ajtmh.14-0031
Cited by 301Open Access
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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.

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