High-dose, short-course primaquine after point-of-care G6PD testing for the radical cure of Plasmodium vivax malaria: a safety study in Papua New Guinea and Indonesia

Abstract

Background: High total dose primaquine (PQ 7 mg/kg) over 7 days can improve treatment adherence and reduce Plasmodium vivax malaria recurrences. We evaluated the safety of pre-treatment glucose-6-phosphate dehydrogenase (G6PD) testing followed by high-dose primaquine for P. vivax malaria in Indonesia and Papua New Guinea. Methods: Patients with P. vivax malaria presenting to four community health clinics were screened for G6PD deficiency using the STANDARD G6PD (SD Biosensor, Republic of Korea) and treated with PQ7 (1 mg/kg/day, 7 days) if G6PD normal, PQ14 (0.5 mg/kg/day, 14 days) if G6PD intermediate, and PQ8W (0.75 mg/kg/week, 8 weeks) if G6PD deficient. Safety and tolerability were assessed through community-based follow-up by study teams on days 3 and 7. Findings: Between October 2023 and September 2024, 800 patients were enrolled: 626 (78.3%) received PQ7, 148 (18.5%) PQ14, and 26 (3.3%) PQ8W. Of those patients who did not withdraw, 97.8% (773/790) were followed up on day 3 and 97.7% (765/783) on day 7. A total of 27 adverse events of special interest (AESIs) were reported in 26 patients; the risk of an AESI was 2.7% (17/626) of patients treated with PQ7, 4.1% (6/148) of patients treated with PQ14 and 11.5% (3/26) of patients treated with PQ8W. Overall, 24 AESIs (88.9%) were related to haemolysis, with the majority (n = 21) due to a fall in haemoglobin >3 g/dL, all without clinical compromise. Serious adverse events (SAEs) occurred in 16 (2.0%) patients, mostly gastrointestinal intolerance (68.8%; 11/16) in patients receiving PQ7. Of the 626 patients treated with PQ7, 9 (1.4%) experienced SAEs that were probably or possibly related to primaquine. Interpretation: The implementation of G6PD testing to guide primaquine treatment of patients with P. vivax malaria was feasible and the primaquine regimens had acceptable safety profiles. The study paves the way for large scale implementation studies of the intervention. Funding: UNITAID and Australian National Health and Medical Research Council.