Fulltext

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis

Commons RJ 1 , Simpson JA 2 , Thriemer K 3 , Humphreys GS 4 , Abreha T 5 , Alemu SG 6 Show all authors , Añez A 7 , Anstey NM 3 , Awab GR 8 , Baird JK 9 , Barber BE 10 , Borghini-Fuhrer I 11 , Chu CS 12 , D'Alessandro U 13 , Dahal P 4 , Daher A 14 , de Vries PJ 15 , Erhart A 16 , Gomes MSM 17 , Gonzalez-Ceron L 18 , Grigg MJ 10 , Heidari A 19 , Hwang J 20 , Kager PA 21 , Ketema T 22 , Khan WA 23 , Lacerda MVG 24 , Leslie T 25 , Ley B 3 , Lidia K 26 , Monteiro WM 27 , Nosten F 12 , Pereira DB 28 , Phan GT 29 , Phyo AP 30 , Rowland M 31 , Saravu K 32 , Sibley CH 33 , Siqueira AM 34 , Stepniewska K 35 , Sutanto I 36 , Taylor WRJ 37 , Thwaites G 38 , Tran BQ 39 , Tran HT 40 , Valecha N 41 , Vieira JLF 42 , Wangchuk S 43 , William T 44 , Woodrow CJ 45 , Zuluaga-Idarraga L 46 , Guerin PJ 4 , White NJ 47 , Price RN 48

Affiliations 

  • 1 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; WorldWide Antimalarial Resistance Network, Clinical module, Darwin, NT, Australia; Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
  • 2 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
  • 3 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • 4 WorldWide Antimalarial Resistance Network, Oxford, UK; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
  • 5 ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
  • 6 College of Natural Sciences, Addis Ababa University, Addis Ababa, Ethiopia; Armauer Hansen Research Institute, Addis Ababa, Ethiopia
  • 7 Departamento de Salud Pública, Universidad de Barcelona, Barcelona, Spain; Organización Panamericana de Salud, Oficina de país Bolivia, La Paz, Bolivia
  • 8 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nangarhar Medical Faculty, Nangarhar University, Jalalabad Afghanistan
  • 9 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia
  • 10 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
  • 11 Medicines for Malaria Venture, Geneva, Switzerland
  • 12 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
  • 13 Unit of Malariology, Institute of Tropical Medicine, Antwerp, Belgium; Medical Research Council Unit, Fajara, The Gambia
  • 14 Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Vice-Presidency of Research and Reference Laboratories, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Liverpool School of Tropical Medicine, Liverpool, UK
  • 15 Department of Internal Medicine, Tergooi Hospital, Hilversum, Netherlands
  • 16 Unit of Malariology, Institute of Tropical Medicine, Antwerp, Belgium; Medical Research Council Unit, Fajara, The Gambia; Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium
  • 17 Superintendência de Vigilância em Saúde do Estado do Amapá -SVS/AP, Macapá, Amapá, Brazil; Federal University of Amapá, Macapá, Amapá, Brazil
  • 18 Regional Centre for Public Health Research, National Institute for Public Health, Tapachula, Chiapas, Mexico
  • 19 Department of Medical Parasitology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
  • 20 US President's Malaria Initiative, Malaria Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA; Global Health Group, University of California San Francisco, San Francisco, CA, USA
  • 21 Centre for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, Netherlands
  • 22 Department of Biology, Addis Ababa University, Addis Ababa, Ethiopia; Department of Biology, Jimma University, Jimma, Ethiopia
  • 23 International Centre for Diarrheal Diseases and Research, Dhaka, Bangladesh
  • 24 Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil; Fundação Oswaldo Cruz, Instituto Leônidas e Maria Deane (FIOCRUZ-Amazonas), Manaus, Brazil
  • 25 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; HealthNet-TPO, Kabul, Afghanistan
  • 26 Department of Pharmacology and Therapy, Faculty of Medicine, Nusa Cendana University, Kupang, Indonesia
  • 27 Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil; Programa de Pós-graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil
  • 28 Centro de Pesquisa em Medicina Tropical de Rondônia, Porto Velho, Rondônia, Brazil; Universidade Federal de Rondônia, Porto Velho, Rondônia, Brazil
  • 29 Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, Netherlands; Tropical Diseases Clinical Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam
  • 30 Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
  • 31 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
  • 32 Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India; Manipal McGill Center for Infectious Diseases, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • 33 WorldWide Antimalarial Resistance Network, Oxford, UK; Department of Genome Sciences, University of Washington, Seattle, WA, USA
  • 34 Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil; Programa de Pós-graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil; Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
  • 35 WorldWide Antimalarial Resistance Network, Oxford, UK
  • 36 Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
  • 37 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 38 Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
  • 39 Tropical Diseases Clinical Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam
  • 40 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
  • 41 Malaria Research Centre, Delhi, India
  • 42 Federal University of Pará, Belém, Pará, Brazil
  • 43 Public Health Laboratory, Department of Public Health, Ministry of Health, Thimphu, Bhutan
  • 44 Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia; Infectious Diseases Unit, Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
  • 45 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Division of Clinical Sciences, St George's, University of London, London, UK
  • 46 Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
  • 47 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 48 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; WorldWide Antimalarial Resistance Network, Clinical module, Darwin, NT, Australia; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Electronic address: rprice@menzies.edu.au
Lancet Infect Dis, 2018 Sep;18(9):1025-1034.
PMID: 30033231 DOI: 10.1016/S1473-3099(18)30348-7

Abstract

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.

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

MeSH terms
Similar publications