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Title: The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: A WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis
Authors: Robert J. Commons
Julie A. Simpson
Kamala Thriemer
Cindy S. Chu
Nicholas M. Douglas
Tesfay Abreha
Sisay G. Alemu
Arletta Añez
Nicholas M. Anstey
Abraham Aseffa
Ashenafi Assefa
Ghulam R. Awab
J. Kevin Baird
Bridget E. Barber
Isabelle Borghini-Fuhrer
Umberto D'Alessandro
Prabin Dahal
André Daher
Peter J. De Vries
Annette Erhart
Margarete S.M. Gomes
Matthew J. Grigg
Jimee Hwang
Piet A. Kager
Tsige Ketema
Wasif A. Khan
Marcus V.G. Lacerda
Toby Leslie
Benedikt Ley
Kartini Lidia
Wuelton M. Monteiro
Dhelio B. Pereira
Giao T. Phan
Aung P. Phyo
Mark Rowland
Kavitha Saravu
Carol H. Sibley
André M. Siqueira
Kasia Stepniewska
Walter R.J. Taylor
Guy Thwaites
Binh Q. Tran
Tran T. Hien
José Luiz F. Vieira
Sonam Wangchuk
James Watson
Timothy William
Charles J. Woodrow
Francois Nosten
Philippe J. Guerin
Nicholas J. White
Ric N. Price
Melbourne School of Population and Global Health
Health Works, Amsterdam
Cho Ray Hospital
Jimma University
Armauer Hansen Research Institute
Addis Ababa University
London School of Hygiene & Tropical Medicine
Columbia University Irving Medical Center
Fundacao Oswaldo Cruz
Menzies School of Health Research
Fundacao Universidade Federal de Rondonia
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
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
Gleneagles Hospital
Ethiopian Public Health Institute
Nangarhar University
WorldWide Antimalarial Resistance Network (WWARN)
Nusa Cendana University
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit
Organización Panamericana de Salud
Eijkman-Oxford Clinical Research Unit
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
WorldWide Antimalarial Resistance Network (WWARN)
International Centre for Diarrheal Diseases and Research
Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM)
Ministry of Health
Secretaria de Saúde do Estado do Amapá
Oxford University Clinical Research Unit
Keywords: Medicine
Issue Date: 1-Aug-2019
Citation: BMC Medicine. Vol.17, No.1 (2019)
Abstract: © 2019 The Author(s). Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.
ISSN: 17417015
Appears in Collections:Scopus 2019

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