Efficacy of delayed tafenoquine administration for radical cure of Plasmodium vivax Malaria: A systematic review.

Malaria remains a significant global public health challenge. Among the causative species, Plasmodium vivax and Plasmodium ovale can form dormant liver stages known as hypnozoites, which require additional treatment to prevent relapse of the disease. Currently in the U.S., the only available anti-relapse therapies are single-dose tafenoquine (TQ) and a 14-day course of primaquine. Both medications carry the risk of hemolysis in patients with glucose-6-phosphate-dehydrogenase (G6PD) deficiency, necessitating G6PD testing before administering. Moreover, TQ is approved only for coadministration with chloroquine, limiting its use when G6PD testing is delayed or unavailable. We conducted a systematic review assessing the efficacy of a single dose of TQ (≥300 mg) administered three or more days (delayed) after initiation of chloroquine/hydroxychloroquine for blood stage malaria in patients with confirmed infection. Five databases (Medline, Embase, Cochrane, CINAHL, and Scopus) and one register (Clinicaltrials.gov) were searched through January 2026 yielding 394 unique articles. Two randomized, open-label trials (conducted 1996-1999) met inclusion criteria; both evaluated single-dose TQ (500 or 600 mg) administered on Day 4 or Day 6 following a 3-day chloroquine course. Based on limited data from trials that used higher than currently recommended TQ doses, we conclude that there is insufficient evidence to definitively recommend for or against delayed TQ administration. However, the data does suggest that delayed TQ is likely better than treatment with chloroquine alone and could be a preferable option to the 14-day primaquine regimen in situations where adherence is unlikely. Clinicians should weigh risks and benefits of each regimen in collaborations with their patients to determine the most appropriate treatment approach.