Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis
1
Issued Date
2023-01-01
Resource Type
ISSN
14733099
eISSN
14744457
Scopus ID
2-s2.0-85173156283
Pubmed ID
37748496
Journal Title
The Lancet Infectious Diseases
Rights Holder(s)
SCOPUS
Bibliographic Citation
The Lancet Infectious Diseases (2023)
Suggested Citation
Commons R.J., Rajasekhar M., Edler P., Abreha T., Awab G.R., Baird J.K., Barber B.E., Chu C.S., Cui L., Daher A., Gonzalez-Ceron L., Grigg M.J., Hwang J., Karunajeewa H., Lacerda M.V.G., Ladeia-Andrade S., Lidia K., Llanos-Cuentas A., Longley R.J., Pereira D.B., Pasaribu A.P., Pukrittayakamee S., Rijal K.R., Sutanto I., Taylor W.R.J., Thanh P.V., Thriemer K., Vieira J.L.F., Watson J.A., Zuluaga-Idarraga L.M., White N.J., Guerin P.J., Simpson J.A., Price R.N., Adhikari B., Anstey N.M., Assefa A., Boyd S.C., Chau N.H., Day N.P., Degaga T.S., Dondorp A.M., Erhart A., Ferreira M.U., Ghimire P., Green J.A., Koh G.C., Mekuria A.H., Mueller I., Naadim M.N., Nelwan E.J., Nosten F., Price D.J., Sattabongkot J., Stepniewska K., von Seidlein L., William T., Woodrow C.J., Woyessa A. Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis. The Lancet Infectious Diseases (2023). doi:10.1016/S1473-3099(23)00430-9 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/90393
Title
Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis
Author(s)
Commons R.J.
Rajasekhar M.
Edler P.
Abreha T.
Awab G.R.
Baird J.K.
Barber B.E.
Chu C.S.
Cui L.
Daher A.
Gonzalez-Ceron L.
Grigg M.J.
Hwang J.
Karunajeewa H.
Lacerda M.V.G.
Ladeia-Andrade S.
Lidia K.
Llanos-Cuentas A.
Longley R.J.
Pereira D.B.
Pasaribu A.P.
Pukrittayakamee S.
Rijal K.R.
Sutanto I.
Taylor W.R.J.
Thanh P.V.
Thriemer K.
Vieira J.L.F.
Watson J.A.
Zuluaga-Idarraga L.M.
White N.J.
Guerin P.J.
Simpson J.A.
Price R.N.
Adhikari B.
Anstey N.M.
Assefa A.
Boyd S.C.
Chau N.H.
Day N.P.
Degaga T.S.
Dondorp A.M.
Erhart A.
Ferreira M.U.
Ghimire P.
Green J.A.
Koh G.C.
Mekuria A.H.
Mueller I.
Naadim M.N.
Nelwan E.J.
Nosten F.
Price D.J.
Sattabongkot J.
Stepniewska K.
von Seidlein L.
William T.
Woodrow C.J.
Woyessa A.
Rajasekhar M.
Edler P.
Abreha T.
Awab G.R.
Baird J.K.
Barber B.E.
Chu C.S.
Cui L.
Daher A.
Gonzalez-Ceron L.
Grigg M.J.
Hwang J.
Karunajeewa H.
Lacerda M.V.G.
Ladeia-Andrade S.
Lidia K.
Llanos-Cuentas A.
Longley R.J.
Pereira D.B.
Pasaribu A.P.
Pukrittayakamee S.
Rijal K.R.
Sutanto I.
Taylor W.R.J.
Thanh P.V.
Thriemer K.
Vieira J.L.F.
Watson J.A.
Zuluaga-Idarraga L.M.
White N.J.
Guerin P.J.
Simpson J.A.
Price R.N.
Adhikari B.
Anstey N.M.
Assefa A.
Boyd S.C.
Chau N.H.
Day N.P.
Degaga T.S.
Dondorp A.M.
Erhart A.
Ferreira M.U.
Ghimire P.
Green J.A.
Koh G.C.
Mekuria A.H.
Mueller I.
Naadim M.N.
Nelwan E.J.
Nosten F.
Price D.J.
Sattabongkot J.
Stepniewska K.
von Seidlein L.
William T.
Woodrow C.J.
Woyessa A.
Author's Affiliation
Infectious Diseases Data Observatory
WorldWide Antimalarial Resistance Network
Faculty of Tropical Medicine, Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
Oxford University Clinical Research Unit
Melbourne Medical School
Melbourne School of Population and Global Health
The Peter Doherty Institute for Infection and Immunity
Universidad Peruana Cayetano Heredia, Instituto de Medicina Tropical Alexander von Humboldt
Tribhuvan University
National Institute of Malariology, Parasitology and Entomology Hanoi
Universitas Nusa Cendana
Universitas Sumatera Utara
Universitas Indonesia
Instituto de Higiene e Medicina Tropical
Universidad de Antioquia
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Fundacao Oswaldo Cruz
Menzies School of Health Research
QIMR Berghofer Medical Research Institute
Fundacao Universidade Federal de Rondonia
University of California, San Francisco
Instituto Nacional de Salud Pública. México
Centers for Disease Control and Prevention
Fiocruz Amazônia
UT Medical Branch at Galveston
Mailman School of Public Health
Morsani College of Medicine
Nuffield Department of Medicine
Universidade Federal do Pará
Grampians Health
Nangarhar University
Dart Centre Asia Pacific
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Centro de Pesquisa em Medicina Tropical de Rondônia
WorldWide Antimalarial Resistance Network
Faculty of Tropical Medicine, Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
Oxford University Clinical Research Unit
Melbourne Medical School
Melbourne School of Population and Global Health
The Peter Doherty Institute for Infection and Immunity
Universidad Peruana Cayetano Heredia, Instituto de Medicina Tropical Alexander von Humboldt
Tribhuvan University
National Institute of Malariology, Parasitology and Entomology Hanoi
Universitas Nusa Cendana
Universitas Sumatera Utara
Universitas Indonesia
Instituto de Higiene e Medicina Tropical
Universidad de Antioquia
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Fundacao Oswaldo Cruz
Menzies School of Health Research
QIMR Berghofer Medical Research Institute
Fundacao Universidade Federal de Rondonia
University of California, San Francisco
Instituto Nacional de Salud Pública. México
Centers for Disease Control and Prevention
Fiocruz Amazônia
UT Medical Branch at Galveston
Mailman School of Public Health
Morsani College of Medicine
Nuffield Department of Medicine
Universidade Federal do Pará
Grampians Health
Nangarhar University
Dart Centre Asia Pacific
Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Centro de Pesquisa em Medicina Tropical de Rondônia
Other Contributor(s)
Abstract
Background: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. 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, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 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). 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. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5–7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. Findings: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2–53·9) in 1470 patients treated without primaquine, 19·3% (16·9–21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0–9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17–0·27; p<0·0001) and high-dose primaquine (0·10, 0·08–0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5–7 were reported by 4·0% (95% CI 0·0–8·7) of 893 patients treated without primaquine, 6·2% (0·5–12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8–10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7–16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. Interpretation: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. Funding: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.