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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

Commons RJ 1 , Simpson JA 2 , Thriemer K 3 , Chu CS 4 , Douglas NM 3 , Abreha T 5 Show all authors , Alemu SG 6 , Añez A 7 , Anstey NM 3 , Aseffa A 8 , Assefa A 9 , Awab GR 10 , Baird JK 4 , Barber BE 3 , Borghini-Fuhrer I 11 , D'Alessandro U 12 , Dahal P 4 , Daher A 13 , de Vries PJ 14 , Erhart A 12 , Gomes MSM 15 , Grigg MJ 3 , Hwang J 16 , Kager PA 17 , Ketema T 18 , Khan WA 19 , Lacerda MVG 20 , Leslie T 21 , Ley B 3 , Lidia K 22 , Monteiro WM 20 , Pereira DB 23 , Phan GT 24 , Phyo AP 25 , Rowland M 21 , Saravu K 26 , Sibley CH 27 , Siqueira AM 20 , Stepniewska K 4 , Taylor WRJ 4 , Thwaites G 4 , Tran BQ 28 , Hien TT 4 , Vieira JLF 29 , Wangchuk S 30 , Watson J 4 , William T 31 , Woodrow CJ 10 , Nosten F 4 , Guerin PJ 4 , White NJ 4 , Price RN 32

Affiliations 

  • 1 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia. rob.commons@wwarn.org
  • 2 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 3 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
  • 4 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
  • 5 ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
  • 6 Addis Ababa University, Addis Ababa, Ethiopia
  • 7 Departamento de Salud Pública, Universidad de Barcelona, Barcelona, Spain
  • 8 Armauer Hansen Research Institute, Addis Ababa, Ethiopia
  • 9 Malaria and Neglected Tropical Diseases Research Team, Bacterial, Parasitic, Zoonotic Diseases Research Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia
  • 10 Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 11 Medicines for Malaria Venture, Geneva, Switzerland
  • 12 Medical Research Council Unit The Gambia at LSTMH, Fajara, The Gambia
  • 13 Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
  • 14 Department of Internal Medicine, Tergooi Hospital, Hilversum, the Netherlands
  • 15 Superintendência de Vigilância em Saúde do Estado do Amapá - SVS/AP, Macapá, Amapá, Brazil
  • 16 U.S. President's Malaria Initiative, Malaria Branch, U.S. Centers for Disease Control and Prevention, Atlanta, USA
  • 17 Centre for Infection and Immunity Amsterdam (CINEMA), Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, the Netherlands
  • 18 Department of Biology, Addis Ababa University, Addis Ababa, Ethiopia
  • 19 International Centre for Diarrheal Diseases and Research, Dhaka, Bangladesh
  • 20 Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil
  • 21 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
  • 22 The Department of Pharmacology and Therapy, Faculty of Medicine, Nusa Cendana University, Kupang, Indonesia
  • 23 Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia, Brazil
  • 24 Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, the Netherlands
  • 25 Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
  • 26 Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Madhav Nagar, Manipal, Karnataka, India
  • 27 WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK
  • 28 Tropical Diseases Clinical Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam
  • 29 Federal University of Pará (Universidade Federal do Pará - UFPA), Belém, Pará, Brazil
  • 30 Public Health Laboratory, Department of Public Health, Ministry of Health, Thimphu, Bhutan
  • 31 Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
  • 32 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia. ric.price@wwarn.org
BMC Med, 2019 08 01;17(1):151.
PMID: 31366382 DOI: 10.1186/s12916-019-1386-6

Abstract

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  25% to  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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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