Affiliations 

  • 1 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
  • 2 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; WorldWide Antimalarial Resistance Network (WWARN), Asia-Pacific Regional Centre, Melbourne, VIC, Australia
  • 3 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • 4 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  • 5 Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • 6 ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
  • 7 MORU, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nangarhar Medical Faculty, Nangarhar University, Jalalabad, Afghanistan
  • 8 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit Indonesia, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
  • 9 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Malaysia
  • 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, Malaysia
  • 11 US President's Malaria Initiative, Malaria Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA; Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA
  • 12 Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, St Albans, VIC, Australia
  • 13 Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil; Instituto Leônidas e Maria Deane, Fiocruz, Manaus, Brazil; University of Texas Medical Branch, Galveston, TX, USA
  • 14 Laboratory of Parasitic Diseases, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil; Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, NOVA University of Lisbon, Lisbon, Portugal
  • 15 Unit of Leishmaniasis and Malaria, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru
  • 16 MORU, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 17 Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Central Department of Microbiology, Tribhuvan University, Kirtipur, Nepal
  • 18 Department of Infectious Diseases, Kasturba Medical College, and Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India
  • 19 Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
  • 20 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
  • 21 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam; WWARN, Oxford, UK
  • 22 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; WWARN, Oxford, UK; Infectious Diseases Data Observatory (IDDO), Oxford, UK
  • 23 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; MORU, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 24 WorldWide Antimalarial Resistance Network (WWARN), Asia-Pacific Regional Centre, Melbourne, VIC, Australia; Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • 25 WorldWide Antimalarial Resistance Network (WWARN), Asia-Pacific Regional Centre, Melbourne, VIC, Australia; Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia; General and Subspecialty Medicine, Grampians Health-Ballarat, Ballarat, VIC, Australia. Electronic address: robert.commons@gmail.com
Lancet Infect Dis, 2024 Feb;24(2):184-195.
PMID: 37748497 DOI: 10.1016/S1473-3099(23)00431-0

Abstract

BACKGROUND: Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.

METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680.

FINDINGS: Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias.

INTERPRETATION: Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.

FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

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

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