A systematic review and individual patient data meta-analysis to determine the effect of primaquine dose on efficacy, tolerability and safety in uncomplicated Plasmodium vivax malaria in Latin America

Abstract

Background Primaquine is widely used to prevent relapses of Plasmodium vivax malaria, but the optimal dose in Latin America is unknown. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy, tolerability and safety of different primaquine dosing regimens for the prevention of P. vivax recurrences in Latin America. Methods MEDLINE, Web of Science, Embase, Scopus and Cochrane Central were systematically searched for prospective clinical efficacy studies of patients with uncomplicated P. vivax malaria in Latin America treated with daily primaquine within 28 days of schizontocidal treatment and published between January 1, 2000 and July 3, 2026. The efficacy of the total primaquine mg/kg dose on the rate of any P. vivax recurrence within 150 days of completing antimalarial treatment was assessed by Cox's proportional hazards regression. The effect of the daily primaquine mg/kg dose on gastrointestinal symptoms was assessed 5–7 days after starting primaquine and on the risk of haemolysis on days 1–14 after starting primaquine. The systematic review was registered at PROSPERO CRD42024598742. Findings Of 40 eligible studies, 1734 patients from 13 studies were included. The cumulative incidence of recurrence 150 days after the last dose of primaquine was 68.2% (95% CI 59.5–76.6) in 119 patients not treated with primaquine, 30.8% (27.0–35.0) in 1000 patients treated with low total dose (2 to <5 mg/kg) primaquine, and 8.7% (5.6–13.2) in 286 patients treated with high total dose (≥5 mg/kg) primaquine. The rate of recurrence within 150 days was lower in patients treated with high compared to low total dose primaquine (adjusted hazard ratio (AHR) 0.36, 95% CI 0.21–0.62; p < 0.0001). Gastrointestinal disturbance was reported in 1.1% (1/94) of patients administered a low daily primaquine dose (<0.375 mg/kg/day) and 2.6% (4/152) administered an intermediate daily dose (0.375 to <0.75 mg/kg/day). None of 501 patients with ≥30% G6PD activity had an acute haemoglobin drop by >25% to <7 g/dL within 14 days of starting primaquine, although only 7 patients received high daily dose primaquine (≥0.75 mg/kg/day). Interpretation Patients treated with high total dose primaquine had less than half the risk of P. vivax recurrence compared to those treated with low dose primaquine. The high dose regimen was well tolerated and no safety concerns were observed in patients with ≥30% G6PD activity. Funding Bill and Melinda Gates Foundation, Australian National Health and Medical Research Council and Royal Australasian College of Physicians.