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

ALISA P. ALKER Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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PHARATH LIM Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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RITHY SEM Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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NAMAN K. SHAH Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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PORAVUTH YI Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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DENIS MEY BOUTH Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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REIKO TSUYUOKA Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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JASON D. MAGUIRE Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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THIERRY FANDEUR Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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FREDERIC ARIEY Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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CHANSUDA WONGSRICHANALAI Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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STEVEN R. MESHNICK Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina; Pasteur Institute of Cambodia, Phnom Penh, Cambodia; National Center for Parasitology, Entomology and Malaria Control (CNM), Phnom Penh, Cambodia; World Health Organization, Phnom Penh, Cambodia; US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia; NIPH/NAMRU-2 Laboratory, National Institute of Public Health (NIPH), Phnom Penh, Cambodia

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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.

Author Notes

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