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      Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study

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          Abstract

          Background

          Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin–piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia.

          Methods

          In this prospective cohort study, we enrolled patients aged 2–65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin–piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319.

          Findings

          Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory concentration (IC 50) values, and lower mefloquine IC 50 values; none had multiple pfmdr1 copies, a genetic marker of mefloquine resistance.

          Interpretation

          Dihydroartemisinin–piperaquine failures are caused by both artemisinin and piperaquine resistance, and commonly occur in places where dihydroartemisinin–piperaquine has been used in the private sector. In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin–piperaquine failures, and a more effective first-line ACT in areas where dihydroartemisinin–piperaquine failures are common. The use of single low-dose primaquine to eliminate circulating gametocytes is needed in areas where artemisinin and ACT resistance is prevalent.

          Funding

          National Institute of Allergy and Infectious Diseases.

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          Author and article information

          Journal
          101130150
          27022
          Lancet Infect Dis
          Lancet Infect Dis
          The Lancet. Infectious diseases
          1473-3099
          1474-4457
          21 January 2016
          08 January 2016
          March 2016
          01 March 2017
          : 16
          : 3
          : 357-365
          Affiliations
          Laboratory of Malaria and Vector Research (C Amaratunga PhD, P Lim PhD, G S Tullo BS, J M Anderson PhD, R M Fairhurst PhD), and Biostatistics Research Branch (M P Fay PhD), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA; National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia (P Lim, S Suon MD, S Sreng, D Dek BA, V Try BA); Sampov Meas Referral Hospital, Pursat, Cambodia (S Mao MD); Makara 16 Referral Hospital, Preah Vihear, Cambodia (C Sopha MD); Ratanakiri Referral Hospital, Ratanakiri, Cambodia (B Sam MD); Wellcome Trust Sanger Institute, Hinxton, UK (R Amato PhD); Medical Research Council Centre for Genomics and Global Health (R Amato), Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine (D Blessborn PhD, L Song PhD, J Tarning PhD), University of Oxford, Oxford, UK; and Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (D Blessborn, L Song, J Tarning)
          Author notes
          Correspondence to: Dr Rick M Fairhurst, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Room 3E-10A, Rockville, MD 20852, USA, rfairhurst@ 123456niaid.nih.gov
          [*]

          Contributed equally

          Article
          PMC4792715 PMC4792715 4792715 nihpa752673
          10.1016/S1473-3099(15)00487-9
          4792715
          26774243
          d5b3b137-5f1f-4620-97b3-ca473db7ccef
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