Analysis of the effect of primaquine dose on efficacy, safety, and tolerability in patients with Plasmodium vivax malaria in Ethiopia: a systematic review and individual patient data meta-analysis

Background The 8-aminoquinoline antimalarials are used to prevent P. vivax relapses. Recent evidence suggests high-dose primaquine (7mg/kg total dose) provides optimal efficacy, however, many countries, including Ethiopia, use low-dose primaquine (3.5mg/kg total dose). To understand the risks and benefits of different primaquine dosing regimens for P. vivax malaria in Ethiopia, we undertook a systematic review and individual patient data meta-analysis. Methods We searched for antimalarial efficacy studies in patients with uncomplicated P. vivax mono-infections conducted in Ethiopia, published between January 1, 2000, and March 8, 2024. Studies were included if they had at least 28 days of follow-up and included a treatment arm with daily primaquine, commenced within seven days of starting antimalarial treatment. Study investigators were approached to share individual patient data, which were standardised and pooled. We performed a one-stage meta-analysis to estimate the cumulative incidence of P. vivax recurrence by day 180 after different primaquine total dose regimens. The number and proportion of gastrointestinal symptoms on days 5-7 and clinically significant haemolysis within 14 days were described and stratified by daily primaquine dose. PROSPERO CRD42023491851. Results Of 297 identified studies, 5 were eligible for inclusion. Data from 1,378 patients from all 5 studies were obtained. The cumulative incidence of P. vivax recurrence by day 180 was 61.0% (95%CI: 55.3–66.8) in patients who were not treated with primaquine, 16.6% (12.0–22.7) following low total dose and 8.9% (6.4–12.4) following high total dose primaquine. High total dose primaquine (7mg/kg) was associated with a reduced rate of recurrence compared with low total dose (3.5mg/kg) (Adjusted Hazard Ratio 0.40; 95% CI 0.24-0.68, p=0.001). Gastrointestinal disturbance on days 5–7 was recorded in 20/104 (19.1%) patients without primaquine, 36/225 (16.0%) patients treated with 0.5mg/kg/day primaquine and 54/224 (24.1%) patients treated with 1mg/kg/day primaquine. In patients with normal G6PD activity (≥30%), one patient had a ≥25% fall in haemoglobin to <7g/dL following 0.5mg/kg/day primaquine and two patients had a >5g/dL fall, one following 0.5mg/kg/day and one following 1mg/kg/day. Conclusions Low and high total dose primaquine reduced the risk of recurrence substantially in Ethiopia compared with no primaquine, with high-dose regimens conferring greater protection. All doses were tolerated similarly among G6PD normal patients, with few significant haemolytic events observed.