Safety and efficacy of primaquine in patients withPlasmodium vivaxmalaria from South Asia: a systematic review and individual patient data meta-analysis

Abstract

BackgroundThe optimal dosing of primaquine to prevent relapsingPlasmodium vivaxmalaria in South Asia remains unclear. We investigated the efficacy and safety of different primaquine regimens to preventP. vivaxrelapse.MethodsA systematic review identifiedP. vivaxefficacy studies from South Asia published between 1 January 2000 and 23 August 2021. In a one-stage meta-analysis of available individual patient data, the cumulative risks ofP. vivaxrecurrence at day 42 and 180 were assessed by primaquine total mg/kg dose and duration. The risk of recurrence by day 180 was also determined in a two-stage meta-analysis. Patients with a >25% drop in haemoglobin to <70 g/L, or an absolute drop of >50 g/L between days 1 and 14 were categorised by daily mg/kg primaquine dose.ResultsIn 791 patients from 7 studies in the one-stage meta-analysis, the day 180 cumulative risk of recurrence was 61.1% (95% CI 42.2% to 80.4%; 201 patients; 25 recurrences) after treatment without primaquine, 28.8% (95% CI 8.2% to 74.1%; 398 patients; 4 recurrences) following low total (2 to <5 mg/kg) and 0% (96 patients; 0 recurrences) following high total dose primaquine (≥5 mg/kg). In the subsequent two-stage meta-analysis of nine studies (3529 patients), the pooled proportions ofP. vivaxrecurrences by day 180 were 12.1% (95% CI 7.7% to 17.2%), 2.3% (95% CI 0.3% to 5.4%) and 0.7% (95% CI 0% to 6.1%), respectively. No patients had a >25% drop in haemoglobin to <70 g/L.ConclusionsPrimaquine treatment led to a marked decrease inP. vivaxrecurrences following low (~3.5 mg/kg) and high (~7 mg/kg) total doses, with no reported severe haemolytic events.PROSPERO registration numberCRD42022313730.