Effect of higher dose primaquine for the radical cure of Plasmodium vivax malaria in Indonesia: a systematic review and individual patient data meta-analysis

Abstract

Background: Plasmodium vivax malaria has diverse transmission and relapse patterns in Indonesia. The optimal dose of primaquine to prevent relapses across the country is unknown. We evaluated the anti-relapse efficacy, gastrointestinal tolerability, and haematological safety (G6PD activity ≥30%) of different primaquine regimens in varied endemic settings in Indonesia. Methods: We systematically searched for studies published between 1 January 2000 and 23 July 2024 prospectively enrolling patients with acute uncomplicated P. vivax malaria where some patients were treated with primaquine. Individual patient data (IPD) from eligible studies were pooled and harmonised. We fitted one-stage IPD multivariable regression models to estimate the causal relationship between the body weight-adjusted primaquine dose with three separate primary outcomes: (i) the time to first P. vivax recurrence (days 7–180), (ii) any gastrointestinal discomfort (days 5–7), and (iii) ≥25% reduction relative to baseline haemoglobin and a reduction to <7 g/dL (days 1–14). Findings: Of ten eligible studies, seven were available for inclusion. Compared with a total dose of 3.5 mg/kg primaquine, patients treated with a total dose of 7 mg/kg had a lower rate of recurrence over 6 months (adjusted hazard ratio 0.53; 95% confidence interval [CI] 0.45–0.63; n = 1797); the relative efficacy was consistent across regions, but the absolute benefit varied. Gastrointestinal discomfort was more frequent with higher doses (adjusted risk ratio 1.32 per 0.25 mg/kg daily dose; 95% CI 1.15–1.51; n = 952). In 822 patients available to be assessed for haematological safety (788 [96%] with G6PD activity ≥70% and 34 [4%] with activity 30% to <70%), only one patient developed clinically relevant haemolysis. Interpretation: Across all transmission settings in Indonesia, a total dose of 7 mg/kg halved the rate of recurrent P. vivax malaria over a 6-month period compared with the low dose of 3.5 mg/kg. However, increased daily doses slightly increased risks of gastrointestinal discomfort and haemolysis. Funding: NDM Tropical Network Fund, Bill and Melinda Gates Foundation.