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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.

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dc.contributor.author Rajasekhar, Megha
dc.contributor.author Simpson, Julie A.
dc.contributor.author Ley, Benedikt
dc.contributor.author Edler, Peta
dc.contributor.author Chu, Cindy S.
dc.contributor.author Abreha, Tesfay
dc.contributor.author Awab, Ghulam R.
dc.contributor.author Baird, J. Kevin
dc.contributor.author Bancone, Germana
dc.contributor.author Barber, Bridget E.
dc.contributor.author Grigg, Matthew J.
dc.contributor.author Hwang, Jimee
dc.contributor.author Karunajeewa, Harin
dc.contributor.author Lacerda, Marcus V. G.
dc.contributor.author Ladeia-Andrade, Simone
dc.contributor.author Llanos Cuentas, Elmer Alejandro
dc.contributor.author Pukrittayakamee, Sasithon
dc.contributor.author Rijal, Komal R.
dc.contributor.author Saravu, Kavitha
dc.contributor.author Sutanto, Inge
dc.contributor.author Taylor, Walter R. J.
dc.contributor.author Thriemer, Kamala
dc.contributor.author Watson, James A.
dc.contributor.author Guerin, Philippe J.
dc.contributor.author White, Nicholas J.
dc.contributor.author Price, Ric N.
dc.contributor.author Commons, Robert J.
dc.date.accessioned 2023-10-12T15:30:09Z
dc.date.available 2023-10-12T15:30:09Z
dc.date.issued 2023
dc.identifier.uri https://hdl.handle.net/20.500.12866/14293
dc.description.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. en_US
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartofseries Lancet Infectious Diseases
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Primaquine en_US
dc.subject Risk en_US
dc.subject Haemolysis en_US
dc.subject Patients en_US
dc.subject Plasmodium vivax en_US
dc.subject Malaria en_US
dc.subject Systematic review en_US
dc.subject Patient data meta-analysis en_US
dc.subject.mesh Primaquina
dc.subject.mesh Riesgo
dc.subject.mesh Hemólisis
dc.subject.mesh Pacientes
dc.subject.mesh Plasmodium vivax
dc.subject.mesh Malaria
dc.subject.mesh Revisión Sistemática
dc.subject.mesh Metaanálisis como Asunto
dc.title Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis. en_US
dc.type info:eu-repo/semantics/review
dc.identifier.doi https://doi.org/10.1016/S1473-3099(23)00431-0
dc.relation.issn 1474-4457


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