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, 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 BjörkmanSteffen 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, WWARN AL and ASAQ Molecular Marker Study Group

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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 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.

    Original languageEnglish
    Pages (from-to)833-843
    Number of pages11
    JournalAmerican Journal of Tropical Medicine and Hygiene
    Volume91
    Issue number4
    DOIs
    Publication statusPublished - 2014

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    Venkatesan, M., Gadalla, N. B., Stepniewska, K., Dahal, P., Nsanzabana, C., Moriera, C., Price, R. N., Ma˚rtensson, A., Rosenthal, P. J., Dorsey, G., Sutherland, C. J., Guérin, P., Davis, T. M. E., Ménard, D., Adam, I., Ademowo, G., Arze, C., Baliraine, F. N., Berens-Riha, N., ... WWARN AL and ASAQ Molecular Marker Study Group (2014). 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. American Journal of Tropical Medicine and Hygiene, 91(4), 833-843. https://doi.org/10.4269/ajtmh.14-0031