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; WWARN AL & ASAQ Mol Marker Study

doi:10.4269/ajtmh.14-0031

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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

Journal article

Peer reviewed

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, …

The American journal of tropical medicine and hygiene, Vol.91(4), pp.833-843

01/10/2014

DOI: https://doi.org/10.4269/ajtmh.14-0031

PMCID: PMC4183414

PMID: 25048375

Abstract

Life Sciences & Biomedicine

Public, Environmental & Occupational Health

Science & Technology

Tropical Medicine

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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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
Creators - without role: Meera Venkatesan - Supreme Council Of Health
Nahla B. Gadalla - NIAID, NIH, Bethesda, MD 20892 USA
Kasia Stepniewska - University of Oxford
Prabin Dahal - University of Oxford
Christian Nsanzabana - University of Oxford
Clarissa Moriera - University of Oxford
Ric N. Price - University of Oxford
Andreas Martensson - College Station Medical Center
Philip J. Rosenthal - College Station Medical Center
Grant Dorsey - College Station Medical Center
Colin J. Sutherland - Supreme Council Of Health
Philippe Guerin - University of Oxford
Timothy M. E. Davis - University of Western Australia
Didier Menard - Inst Pasteur Cambodge, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia
Ishag Adam - University of Khartoum
George Ademowo - University of Ibadan
Cesar Arze - Supreme Council Of Health
Frederick N. Baliraine - LeTourneau University
Nicole Berens-Riha - College Station Medical Center
Anders Bjorkman - College Station Medical Center
Steffen Borrmann - Wellcome Trust
Francesco Checchi - Save Children, Paris, France
Meghna Desai - Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA
Mehul Dhorda - Supreme Council Of Health
Abdoulaye A. Djimde - Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Bamako, Mali
Badria B. El-Sayed - College Station Medical Center
Teferi Eshetu - Jimma University
Frederick Eyase - College Station Medical Center
Catherine Falade - University of Ibadan
Jean-Francois Faucher - College Station Medical Center
Gabrielle Froberg - College Station Medical Center
Anastasia Grivoyannis - University of Washington
Sally Hamour - The Royal Free Hospital
Sandrine Houze - Assistance Publique – Hôpitaux de Paris
Jacob Johnson - College Station Medical Center
Erasmus Kamugisha - Pontifícia Universidade Católica de São Paulo
Simon Kariuki - College Station Medical Center
Jean-Rene Kiechel - Drugs Neglected Dis Initiat, Geneva, Switzerland
Fred Kironde - Makerere University
Poul-Erik Kofoed - INDEPTH Network, Projecto Saude Bandim, Bissau, Guinea Bissau
Jacques LeBras - Assistance Publique – Hôpitaux de Paris
Maja Malmberg - College Station Medical Center
Leah Mwai - Wellcome Trust
Billy Ngasala - Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania
Francois Nosten - University of Oxford
Samuel L. Nsobya - Makerere University
Alexis Nzila - Wellcome Trust
Mary Oguike - Supreme Council Of Health
Sabina Dahlstrom Otienoburu - Bernard
Bernhards Ogutu - College Station Medical Center
Jean-Bosco Ouedraogo - Ctr Muraz, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso
Patrice Piola - University of Oxford
Lars Rombo - College Station Medical Center
Birgit Schramm - Epictr, Paris, France
A. Fabrice Some - Ctr Muraz, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso
Julie Thwing - Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA
Johan Ursing - College Station Medical Center
Rina P. M. Wong - University of Western Australia
Ahmed Zeynudin - Jimma University
Issaka Zongo - Ctr Muraz, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso
Christopher V. Plowe - Supreme Council Of Health
Carol Hopkins Sibley - University of Oxford
WWARN AL & ASAQ Mol Marker Study
Publication Details: The American journal of tropical medicine and hygiene, Vol.91(4), pp.833-843
Publisher: Amer Soc Trop Med & Hygiene
Number of pages: 11
Grant note: Bill and Melinda Gates Foundation; Bill & Melinda Gates Foundation
Identifiers: 9928405708331
Academic Unit: Qassim University
Language: English
Resource Type: Journal article