title: Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis.
abstract: BACKGROUND
  Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance.
  
  
  METHODS
  We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria.
  
  
  RESULTS
  We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity.
  
  
  CONCLUSIONS
  Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions.
  
  
  BACKGROUND
  Wellcome Trust (UK).
authors.affiliation: Worldwide Anti-malarial Resistance Network, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia. Electronic address: rprice@menzies.edu.au.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
authors.forename: Lorenz
authors.initials: L
authors.lastname: von Seidlein
authors.affiliation: National Institute of Malaria Research, Dwarka, New Delhi, India.
authors.forename: Neena
authors.initials: N
authors.lastname: Valecha
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Baird
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D014943:Global Health; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy / Q000453:epidemiology* / Q000469:parasitology; D010966:Plasmodium vivax / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D002738:Chloroquine