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PFMDR1 AND IN VIVO RESISTANCE TO ARTESUNATE-MEFLOQUINE IN FALCIPARUM MALARIA ON THE CAMBODIAN–THAI BORDER

Artemisinin combination therapies (ACTs) have recently been adopted as first-line therapy for Plasmodium falciparum infections in most malaria-endemic countries. In this study, we estimated the association between artesunate-mefloquine therapy failure and genetic changes in the putative transporter, pfmdr1. Blood samples were acquired from 80 patients enrolled in an 2004 in vivo efficacy study in Pailin, Cambodia, and genotyped for pfmdr1 copy number and haplotype. Having parasites with three or more copies of pfmdr1 before treatment was strongly associated with recrudescence (hazard ratio [HR] = 8.30; 95% CI: 2.60–26.43). This relationship was maintained when controlling for initial parasite density and hematocrit (HR = 7.91; 95% CI: 2.38–26.29). Artesunate-mefloquine treatment selected for increased pfmdr1 copy number, because isolates from recurrent episodes had higher copy numbers than the paired enrollment samples (Wilcoxon rank test, P = 0.040). pfmdr1 copy number should be evaluated further as a surveillance tool for artesunate-mefloquine resistance in Cambodia.

Received September 12, 2006. Accepted for publication January 1, 2007.

Acknowledgments: We thank the study subjects for their participation. We appreciate the assistance and support provided by Dr. Socheat Duong, Augustina Ika Susanti, Jesse Kwiek, William Miller, Anne Purfield, Paul Wilson, Nareth Kong, Wini Kania, and Dr. J. Kevin Baird. We thank MR4 for providing us with malaria DNA.

Financial support: This work was funded by the United States Navy Medical (NHRC/NMRC) ILIR Program.

Disclaimer: The views and opinions are those of the authors and do not purport to represent those of the US Navy or Department of Defense.

^* Address correspondence to Steven R. Meshnick, Department of Epidemiology, UNC Chapel Hill School of Public Health, CB # 7435, Chapel Hill, NC 27599. E-mail: meshnick{at}email.unc.edu

Authors’ addresses: Alisa P. Alker, Naman K. Shah, and Steven R. Meshnick, Department of Epidemiology, UNC Chapel Hill School of Public Health, CB # 7435, Chapel Hill, NC 27599, E-mails: alker{at}unc.edu, naman{at}email.unc.edu, and meshnick{at}email.unc.edu. Pharath Lim, Rithy Sem, and Frederic Ariey, Institut Pasteur du Cambodge, 5 Monivong Boulevard, BP 983, Phnom Penh, Cambodia, E-mails: pharath{at}pasteur-kh.org, srithy{at}pasteur-kh.org, and fariey{at}pasteur-kh.org. Poravuth Yi, National Center for Parasitology, Entomology and Malaria Control (CNM), 372 Boulevard Monivong/Rue 322, Phnom Penh, Cambodia, E-mail: yiporavuth{at}yahoo.com. Denis Mey Bouth, World Health Organization, PO Box 1217, Phnom Penh, Cambodia, E-mail: denism{at}cam.wpro.who.int. Reiko Tsuyuoka, WHO Office in the Lao People’s Democratic Republic, PO Box 343, Vientiane, Laos, E-mail: Tsuyuokar{at}lao.wpro.who.int. Jason D. Maguire, United States Naval Medical Research Unit No.2, U.S. Embassy, Jakarta, Indonesia, E-mail: JDMaguire{at}mar.med.navy.mil. Thierry Fandeur, Unité d’Immunologie Moléculaire des Parasites CNRS URA 2581, Institut Pasteur, 28 rue du Dr ROUX, 75724 Paris Cedex 15, France, E-mail: tfandeur{at}pasteur.fr. Chansuda Wongsrichanalai, National Institute of Public Health/Naval Medical Research Unit No. 2 Laboratory, Phnom Penh, Cambodia, E-mail: chansuda{at}namru2.med.navy.mil.

Reprint requests: Steven R. Meshnick, Department of Epidemiology, UNC Chapel Hill School of Public Health, CB # 7435, Chapel Hill, NC 27599. E-mail: meshnick{at}email.unc.edu.

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