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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).

Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria. BACKGROUND: In most of the Americas, the recommended treatment to prevent relapse of Plasmodium vivax malaria is primaquine at a total dose of 3.5 mg per kilogram of body weight, despite evidence of only moderate efficacy. METHODS: In this trial conducted in Brazil, we evaluated three primaquine regimens to prevent relapse of P. vivax malaria in children at least 5 years of age and in adults with microscopy-confirmed P. vivax monoinfection. All the patients received directly observed chloroquine for 3 days (total dose, 25 mg per kilogram). Group 1 received a total primaquine dose of 3.5 mg per kilogram (0.5 mg per kilogram per day) over 7 days with unobserved administration; group 2 received the same regimen as group 1 but with observed administration; and group 3 received a total primaquine dose of 7.0 mg per kilogram over 14 days (also 0.5 mg per kilogram per day) with observed administration. We monitored the patients for 168 days. RESULTS: We enrolled 63 patients in group 1, 96 in group 2, and 95 in group 3. The median age of the patients was 22.4 years (range, 5.4 to 79.8). By day 28, three P. vivax recurrences were observed: 2 in group 1 and 1 in group 2. By day 168, a total of 70 recurrences had occurred: 24 in group 1, 34 in group 2, and 12 in group 3. No serious adverse events were noted. On day 168, the percentage of patients without recurrence was 58% (95% confidence interval [CI], 44 to 70) in group 1, 59% (95% CI, 47 to 69) in group 2, and 86% (95% CI, 76 to 92) in group 3. Survival analysis showed a difference in the day 168 recurrence-free percentage of 27 percentage points (97.5% CI, 10 to 44; P<0.001) between group 1 and group 3 and a difference of 27 percentage points (97.5% CI, 12 to 42; P<0.001) between group 2 and group 3. CONCLUSIONS: The administration of primaquine at a total dose of 7.0 mg per kilogram had higher efficacy in preventing relapse of P. vivax malaria than a total dose of 3.5 mg per kilogram through day 168. (Supported by the U.S. Agency for International Development; ClinicalTrials.gov number, NCT03610399.).