title: Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment.
abstract: Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P <10(-3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.).
authors.affiliation: National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Rithea
authors.initials: R
authors.lastname: Leang
authors.affiliation: National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia Service de Médecine Tropicale et Humanitaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
authors.forename: Walter R J
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia World Health Organization, Phnom Penh, Cambodia.
authors.forename: Denis Mey
authors.initials: DM
authors.lastname: Bouth
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Song
authors.affiliation: Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joel
authors.identifier: http://orcid.org/0000-0003-4566-4030
authors.initials: J
authors.lastname: Tarning
authors.affiliation: National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Meng Chuor
authors.initials: MC
authors.lastname: Char
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Saorin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Valentine
authors.initials: V
authors.lastname: Duru
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Anais
authors.initials: A
authors.lastname: Domergue
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.affiliation: World Health Organization, Geneva, Switzerland dmenard@pasteur-kh.org ringwaldp@who.int.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia dmenard@pasteur-kh.org ringwaldp@who.int.
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
mesh_terms: D000293:Adolescent; D000328:Adult; D000942:Antigens, Bacterial / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002160:Cambodia; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D015767:Mefloquine / Q000627:therapeutic use; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000627:therapeutic use*; D017211:Treatment Failure; D055815:Young Adult; D010879:Piperazines
chemical_list: D000942:Antigens, Bacterial; D000954:Antigens, Surface; D000962:Antimalarials; D037621:Artemisinins; D015767:Mefloquine; D011804:Quinolines; C030659:K antigens; C039060:artenimol; C031327:artemisinin; C034759:piperaquine; D010879:Piperazines