Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data
Issued Date
2022-12-01
Resource Type
eISSN
17417015
Scopus ID
2-s2.0-85137936051
Pubmed ID
36109733
Journal Title
BMC Medicine
Volume
20
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
BMC Medicine Vol.20 No.1 (2022)
Suggested Citation
Stepniewska K., Allen E.N., Humphreys G.S., Poirot E., Craig E., Kennon K., Yilma D., Bousema T., Guerin P.J., White N.J., Price R.N., Raman J., Martensson A., Mwaiswelo R.O., Bancone G., Bastiaens G.J.H., Bjorkman A., Brown J.M., D’Alessandro U., Dicko A.A., El-Sayed B., Elzaki S.E., Eziefula A.C., Gonçalves B.P., Hamid M.M.A., Kaneko A., Kariuki S., Khan W., Kwambai T.K., Ley B., Ngasala B.E., Nosten F., Okebe J., Samuels A.M., Smit M.R., Stone W.J.R., Sutanto I., Ter Kuile F., Tine R.C., Tiono A.B., Drakeley C.J., Gosling R., Stergachis A., Barnes K.I., Chen I. Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data. BMC Medicine Vol.20 No.1 (2022). doi:10.1186/s12916-022-02504-z Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/87178
Title
Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data
Author(s)
Stepniewska K.
Allen E.N.
Humphreys G.S.
Poirot E.
Craig E.
Kennon K.
Yilma D.
Bousema T.
Guerin P.J.
White N.J.
Price R.N.
Raman J.
Martensson A.
Mwaiswelo R.O.
Bancone G.
Bastiaens G.J.H.
Bjorkman A.
Brown J.M.
D’Alessandro U.
Dicko A.A.
El-Sayed B.
Elzaki S.E.
Eziefula A.C.
Gonçalves B.P.
Hamid M.M.A.
Kaneko A.
Kariuki S.
Khan W.
Kwambai T.K.
Ley B.
Ngasala B.E.
Nosten F.
Okebe J.
Samuels A.M.
Smit M.R.
Stone W.J.R.
Sutanto I.
Ter Kuile F.
Tine R.C.
Tiono A.B.
Drakeley C.J.
Gosling R.
Stergachis A.
Barnes K.I.
Chen I.
Allen E.N.
Humphreys G.S.
Poirot E.
Craig E.
Kennon K.
Yilma D.
Bousema T.
Guerin P.J.
White N.J.
Price R.N.
Raman J.
Martensson A.
Mwaiswelo R.O.
Bancone G.
Bastiaens G.J.H.
Bjorkman A.
Brown J.M.
D’Alessandro U.
Dicko A.A.
El-Sayed B.
Elzaki S.E.
Eziefula A.C.
Gonçalves B.P.
Hamid M.M.A.
Kaneko A.
Kariuki S.
Khan W.
Kwambai T.K.
Ley B.
Ngasala B.E.
Nosten F.
Okebe J.
Samuels A.M.
Smit M.R.
Stone W.J.R.
Sutanto I.
Ter Kuile F.
Tine R.C.
Tiono A.B.
Drakeley C.J.
Gosling R.
Stergachis A.
Barnes K.I.
Chen I.
Author's Affiliation
WorldWide Antimalarial Resistance Network
Centre National de Recherche et de Formation sur le Paludisme
Faculty of Tropical Medicine, Mahidol University
Muhimbili University of Health and Allied Sciences
University of the Witwatersrand Faculty of Health Sciences
University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology
Tropical Medicine Research Institute Sudan
Institute of Endemic Diseases Sudan
Hubert Kairuki Memorial University
Universite Cheikh Anta Diop
Jimma University
Kenya Medical Research Institute
Universitas Indonesia
National Institute for Communicable Diseases
London School of Hygiene & Tropical Medicine
Green Templeton College
Menzies School of Health Research
University of California, San Francisco
Centers for Disease Control and Prevention
Liverpool School of Tropical Medicine
University of Sussex
University of Washington
Rijnstate Hospital
Karolinska Institutet
International Centre for Diarrhoeal Disease Research Bangladesh
Nuffield Department of Medicine
Uppsala Universitet
Radboud University Medical Center
University of Cape Town
Disease Control and Elimination Theme
Centre National de Recherche et de Formation sur le Paludisme
Faculty of Tropical Medicine, Mahidol University
Muhimbili University of Health and Allied Sciences
University of the Witwatersrand Faculty of Health Sciences
University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology
Tropical Medicine Research Institute Sudan
Institute of Endemic Diseases Sudan
Hubert Kairuki Memorial University
Universite Cheikh Anta Diop
Jimma University
Kenya Medical Research Institute
Universitas Indonesia
National Institute for Communicable Diseases
London School of Hygiene & Tropical Medicine
Green Templeton College
Menzies School of Health Research
University of California, San Francisco
Centers for Disease Control and Prevention
Liverpool School of Tropical Medicine
University of Sussex
University of Washington
Rijnstate Hospital
Karolinska Institutet
International Centre for Diarrhoeal Disease Research Bangladesh
Nuffield Department of Medicine
Uppsala Universitet
Radboud University Medical Center
University of Cape Town
Disease Control and Elimination Theme
Other Contributor(s)
Abstract
Background: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. Methods: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. Results: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17–0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19–0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. Conclusions: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. Trial registration: PROSPERO, CRD42019128185.