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Title: The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis
Authors: Robert J. Commons
Julie A. Simpson
Kamala Thriemer
Georgina S. Humphreys
Tesfay Abreha
Sisay G. Alemu
Arletta Añez
Nicholas M. Anstey
Ghulam R. Awab
J. Kevin Baird
Bridget E. Barber
Isabelle Borghini-Fuhrer
Cindy S. Chu
Umberto D'Alessandro
Prabin Dahal
André Daher
Peter J. de Vries
Annette Erhart
Margarete S.M. Gomes
Lilia Gonzalez-Ceron
Matthew J. Grigg
Aliehsan Heidari
Jimee Hwang
Piet A. Kager
Tsige Ketema
Wasif A. Khan
Marcus V.G. Lacerda
Toby Leslie
Benedikt Ley
Kartini Lidia
Wuelton M. Monteiro
Francois Nosten
Dhelio B. Pereira
Giao T. Phan
Aung P. Phyo
Mark Rowland
Kavitha Saravu
Carol H. Sibley
André M. Siqueira
Kasia Stepniewska
Inge Sutanto
Walter R.J. Taylor
Guy Thwaites
Binh Q. Tran
Hien T. Tran
Neena Valecha
José Luiz F. Vieira
Sonam Wangchuk
Timothy William
Charles J. Woodrow
Lina Zuluaga-Idarraga
Philippe J. Guerin
Nicholas J. White
Ric N. Price
Melbourne School of Population and Global Health
Health Works, Amsterdam
Alborz University of Medical Sciences
Cho Ray Hospital
Jimma University
Armauer Hansen Research Institute
Addis Ababa University
Universitas Indonesia
Universidad de Antioquia
University of London
London School of Hygiene & Tropical Medicine
Prins Leopold Instituut voor Tropische Geneeskunde
Royal Brisbane and Women's Hospital
Fundacao Oswaldo Cruz
Menzies School of Health Research
Fundacao Universidade Federal de Rondonia
National Institute of Malaria Research India
University of California, San Francisco
Centers for Disease Control and Prevention
Liverpool School of Tropical Medicine
Universidade Federal do Amapa
Manipal Academy of Higher Education
Kasturba Medical College, Manipal
University of Washington, Seattle
Universiteit Antwerpen
Mahidol University
Nuffield Department of Clinical Medicine
Universidade do Estado do Amazonas
Universidade Federal do Para
Universitat de Barcelona
Amsterdam UMC - University of Amsterdam
Medicines for Malaria Venture
Nangarhar University
WorldWide Antimalarial Resistance Network
Nusa Cendana University
Queen Elizabeth Hospital
Medical Research Council Unit
National Institute for Public Health
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit
Organización Panamericana de Salud
WorldWide Antimalarial Resistance Network
Columbia University Mailman School of Public Health
International Centre for Diarrheal Diseases and Research
Eijkman-Oxford Clinical Research Unit
Ministry of Health
Secretaria de Saúde do Estado do Amapá
Oxford University Clinical Research Unit
Centro de Pesquisa em Medicina Tropical
Keywords: Medicine
Issue Date: 1-Sep-2018
Citation: The Lancet Infectious Diseases. Vol.18, No.9 (2018), 1025-1034
Abstract: © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001). Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.
ISSN: 14744457
Appears in Collections:Scopus 2018

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