Publications & Reports

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 Martensson, Philip J Rosenthal, Grant Dorsey, Colin J Sutherland, Philippe Guerin, Timothy M E Davis, Didier Menard, Ishag Adam, George Ademowo, Cesar Arze, Frederick N Baliraine, Nicole Berens-Riha, Anders Bjorkman, Steffen Borrmann, Francesco Checchi, Meghna Desai Mehul Dhorda, Abdoulaye A Djimde, Badria B El-Sayed, Teferi Eshetu, Frederick Eyase, Catherine Falade, Jean-Francois Faucher, Gabrielle Froberg, Anastasia Grivoyannis, Sally Hamour, Sandrine Houze, Jacob Johnson, Erasmus Kamugisha, Simon Kariuki, Jean-Rene Kiechel, Fred Kironde, Poul-Erik Kofoed Jacques LeBras, Maja Malmberg, Leah Mwai, Billy Ngasala, Francois Nosten, Samuel L Nsobya, Alexis Nzila Mary Oguike, Sabina Dahlstrom Otienoburu, Bernhards Ogutu, Jean-Bosco Ouedraogo, Patrice Piola, Lars Rombo, Birgit Schramm, A Fabrice Some, Julie Thwing, Johan Ursing, Rina P M Wong, Ahmed Zeynudin, Issaka Zongo, Christopher V Plowe, Carol Hopkins Sibley
WorldWide Antimalarial Resistance Network Molecular Module, Howard Hughes Medical Institute/Center for Vaccine Development, and Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland; National Institute of Allergy an


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.


  • Journal: The American Journal of Tropical Medicine and Hygiene
  • Published: 21/07/2014
  • Volume: Epub ahead of print


Health Issue