Safety and efficacy of three alternative regimens against relapsing Plasmodium vivax malaria in glucose 6-phosphate dehydrogenase deficient patients in the Brazilian Amazon (ALTPRIM)

Background Daily primaquine-induced hemolysis is a common cause of complications during Plasmodium vivax malaria treatment in individuals with glucose 6-phosphate dehydrogenase deficiency (G6PDd). Alternative regimens balancing safety and efficacy are needed. Methods G6PDd participants with P. vivax malaria from two sites in Brazilian Amazon between 2018 and 2022 were randomly allocated to three study arms, which received chloroquine (CQ) from day 1 to day 3 plus: (arm-1) seven-day course of primaquine (PQ) (0.5mg/kg/day), beginning at day 5; (arm-2) weekly PQ over eight weeks (0.75mg/kg/week) or; (arm-3) weekly CQ over 12 weeks (5mg/kg/week). A normal G6PD participants group was also enrolled in parallel using CQ for three days plus PQ for seven days. Primary focus was the safety profile, and the secondary was the number of patients free from the first recurrence until day 180. Results Fifty-four G6PDd participants were enrolled. Two participants in arm-1, but the arm was halted due to safety concerns. Weekly PQ group presented higher hemoglobin falls in D3 after the first dose (ΔHb = -1.61) than weekly CQ (ΔHb = -0.99), but efficacy was superior over the six-month follow-up. Conclusions Postponing the beginning of daily PQ to day 5, when less oxidative stress related to malaria itself would, in theory, decrease hemolytic effects of the drug in G6PDd patients, did not show to be safe. Weekly CQ avoiding the first relapse was not able to stop further relapses. Weekly PQ, as already demonstrated in Southeast Asia, was equally safe and efficacious in patients from Latin America.