Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria

The unusual sequential “radical cure” treatment regimen for P. vivax malaria reported by Chamma-Siqueira et al. from western Brazil complicates interpretation of the trial result. Usually chloroquine and primaquine are given together to treat P. vivax malaria. Both drugs have activities at the asexual stage of parasite development, but only primaquine kills the dormant liver-stage parasites (hypnozoites) that cause relapse. Although long-latency P. vivax malaria occurs in the Americas, most relapses emerge from the liver approximately 14 days after presentation of the initial illness. The slowly eliminated chloroquine suppresses the relapsing blood-stage infection for several weeks. Chamma-Siqueira et al. delayed administration of primaquine for a median of 17 days. Because each study group received the same dose of chloroquine, the authors were therefore comparing the asexual-stage antimalarial effects of primaquine against early relapse and the hypnozoitocidal effect against later relapses. Primaquine has relatively weak activity against asexual-stage parasites, so, unsurprisingly, the 2-week course was superior to the 1-week course. Clinical trials comparing radical curative activity in P. vivax and P. ovale malaria should assess concurrent — not sequential — treatment (i.e., hypnozoitocidal efficacy and not activities at the asexual stage of parasite development should be assessed).