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PRIMAQUINE DOSE AND THE RISK OF HAEMOLYSIS IN PATIENTS WITH UNCOMPLICATED PLASMODIUM VIVAX MALARIA: A SYSTEMATIC REVIEW AND INDIVIDUAL PATIENT DATA META-ANALYSIS
Author
Rajasekhar, Megha
Simpson, Julie A.
Ley, Benedikt
Edler, Peta
Chu, Cindy S.
Abreha, Tesfay
Awab, Ghulam R.
Baird, J. Kevin
Bancone, Germana
Barber, Bridget E.
Grigg, Matthew J.
Hwang, Jimee
Karunajeewa, Harin
Lacerda, Marcus Vinícius Guimarães de
Andrade, Simone Ladeia
Llanos Cuentas, Alejandro
Pukrittayakamee, Sasithon
Rijal, Komal R.
Saravu, Kavitha
Sutanto, Inge
Taylor, Walter R. J.
Thriemer, Kamala
Watson, James A.
Guerin, Philippe J.
White, Nicholas J.
Price, Ric N.
Commons, Robert J.
Simpson, Julie A.
Ley, Benedikt
Edler, Peta
Chu, Cindy S.
Abreha, Tesfay
Awab, Ghulam R.
Baird, J. Kevin
Bancone, Germana
Barber, Bridget E.
Grigg, Matthew J.
Hwang, Jimee
Karunajeewa, Harin
Lacerda, Marcus Vinícius Guimarães de
Andrade, Simone Ladeia
Llanos Cuentas, Alejandro
Pukrittayakamee, Sasithon
Rijal, Komal R.
Saravu, Kavitha
Sutanto, Inge
Taylor, Walter R. J.
Thriemer, Kamala
Watson, James A.
Guerin, Philippe J.
White, Nicholas J.
Price, Ric N.
Commons, Robert J.
Affilliation
The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, VIC, Australia.
The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, VIC, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Melbourne, VIC, Australia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.
The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, VIC, Australia / The University of Melbourne. Peter Doherty Institute for Infection and Immunity. Department of Infectious Diseases. Melbourne, VIC, Australia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Columbia University Mailman School of Public Health. International Center for AIDS Care and Treatment Programs (ICAP). Addis Ababa, Ethiopia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / Nangarhar University. Nangarhar Medical Faculty. Jalalabad, Afghanistan.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Universitas Indonesia. Faculty of Medicine. Oxford University Clinical Research Unit Indonesia. Jakarta, Indonesia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute. Brisbane, QLD, Australia / Menzies School of Health Research Clinical Research Unit. Infectious Diseases Society Sabah. Kota Kinabalu, Malaysia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / Menzies School of Health Research Clinical Research Unit. Infectious Diseases Society Sabah. Kota Kinabalu, Malaysia.
US Centers for Disease Control and Prevention. Malaria Branch. US President's Malaria Initiative. Atlanta, GA, USA / University of California San Francisco. Institute for Global Health Sciences. San Francisco, CA, USA.
The University of Melbourne. Melbourne Medical School. Department of Medicine-Western Health. St. Albans, VIC, Australia.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil / University of Texas Medical Branch. Galveston, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Doenças Parasitárias. Rio de Janeiro, RJ, Brasil / Nova University of Lisbon. Institute of Hygiene and Tropical Medicine. Global Health and Tropical Medicine. Lisbon, Portugal.
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Unit of Leishmaniasis and Malaria. Lima, Peru.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand.
Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine. Bangkok, Thailand / Tribhuvan University. Central Department of Microbiology. Kirtipur, Nepal.
Manipal Academy of Higher Education. Prasanna School of Public Health. Kasturba Medical College. Department of Infectious Diseases and Manipal Center for Infectious Diseases. Manipal, India.
University of Indonesia. Faculty of Medicine. Department of Parasitology. Jakarta, Indonesia.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Columbia University Mailman School of Public Health. International Center for AIDS Care and Treatment Programs (ICAP). Addis Ababa, Ethiopia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Hospital for Tropical Diseases. Oxford University Clinical Research Unit. Ho Chi Minh City, Viet Nam / The WorldWide Antimalarial Resistance Network (WWARN). Oxford, UK.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / The WorldWide Antimalarial Resistance Network (WWARN). Oxford, UK / Infectious Diseases Data Observatory (IDDO). Oxford, UK.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand.
The WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Melbourne, VIC, Australia / Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Darwin, NT, Australia / Grampians Health – Ballarat. General and Subspecialty Medicine. Ballarat, Australia.
The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, VIC, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Melbourne, VIC, Australia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.
The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, VIC, Australia / The University of Melbourne. Peter Doherty Institute for Infection and Immunity. Department of Infectious Diseases. Melbourne, VIC, Australia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Columbia University Mailman School of Public Health. International Center for AIDS Care and Treatment Programs (ICAP). Addis Ababa, Ethiopia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / Nangarhar University. Nangarhar Medical Faculty. Jalalabad, Afghanistan.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Universitas Indonesia. Faculty of Medicine. Oxford University Clinical Research Unit Indonesia. Jakarta, Indonesia.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Shoklo Malaria Research Unit. Mae Sot, Thailand / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute. Brisbane, QLD, Australia / Menzies School of Health Research Clinical Research Unit. Infectious Diseases Society Sabah. Kota Kinabalu, Malaysia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / Menzies School of Health Research Clinical Research Unit. Infectious Diseases Society Sabah. Kota Kinabalu, Malaysia.
US Centers for Disease Control and Prevention. Malaria Branch. US President's Malaria Initiative. Atlanta, GA, USA / University of California San Francisco. Institute for Global Health Sciences. San Francisco, CA, USA.
The University of Melbourne. Melbourne Medical School. Department of Medicine-Western Health. St. Albans, VIC, Australia.
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil / University of Texas Medical Branch. Galveston, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Doenças Parasitárias. Rio de Janeiro, RJ, Brasil / Nova University of Lisbon. Institute of Hygiene and Tropical Medicine. Global Health and Tropical Medicine. Lisbon, Portugal.
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Unit of Leishmaniasis and Malaria. Lima, Peru.
Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand.
Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine. Bangkok, Thailand / Tribhuvan University. Central Department of Microbiology. Kirtipur, Nepal.
Manipal Academy of Higher Education. Prasanna School of Public Health. Kasturba Medical College. Department of Infectious Diseases and Manipal Center for Infectious Diseases. Manipal, India.
University of Indonesia. Faculty of Medicine. Department of Parasitology. Jakarta, Indonesia.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Columbia University Mailman School of Public Health. International Center for AIDS Care and Treatment Programs (ICAP). Addis Ababa, Ethiopia.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Hospital for Tropical Diseases. Oxford University Clinical Research Unit. Ho Chi Minh City, Viet Nam / The WorldWide Antimalarial Resistance Network (WWARN). Oxford, UK.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / The WorldWide Antimalarial Resistance Network (WWARN). Oxford, UK / Infectious Diseases Data Observatory (IDDO). Oxford, UK.
University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand.
The WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Melbourne, VIC, Australia / Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / University of Oxford. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.
Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Darwin, NT, Australia / Grampians Health – Ballarat. General and Subspecialty Medicine. Ballarat, Australia.
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.
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