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 total dose primaquine (7 mg/kg) provides optimal efficacy, however, many countries, including Ethiopia, use low total dose primaquine (3.5 mg/kg). 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 with 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 (7 mg/kg) was associated with a reduced rate of recurrence compared with low total dose (3.5 mg/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 0.5 mg/kg primaquine daily and 54/224 (24.1%) patients treated with 1 mg/kg primaquine daily. In patients with normal G6PD activity (≥ 30%), one patient had a ≥ 25% fall in haemoglobin to < 7 g/dL following 0.5 mg/kg primaquine daily and two patients had a > 5 g/dL fall, one following 0.5 mg/kg daily and one following 1 mg/kg daily. Conclusions: Low and high total dose primaquine reduced the risk of recurrence of P. vivax malaria substantially in Ethiopia compared with no primaquine, with high total dose regimens conferring greater protection. All doses demonstrated acceptable tolerability and clinically significant haemolytic events were uncommon in patients with ≥ 30% G6PD activity.