Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria

Abstract

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.).

Figure 1.. Location of Cruzeiro do Sul, Acre State, Brazil.

The trial was conducted at eight malaria diagnostic posts in Cruzeiro do Sul, a city with 85,000 residents and an annual parasite incidence of 147.5 malaria cases per 1000 residents.

Figure 2.. Enrollment and Outcomes.

All the patients received directly observed chloroquine for 3 days after being randomly assigned to one of three groups. The groups varied according to the primaquine regimen and whether receipt of the drug was observed or unobserved. G6PD denotes glucose-6-phosphate dehydrogenase.

Figure 3.. Freedom from Plasmodium vivax Recurrence at Day 168.

Panel A shows Kaplan–Meier curves indicating freedom from any recurrence of P. vivax infection among the 254 patients according to trial group. The shaded areas indicate 95% confidence intervals. In the calculation of the hazard ratios for between-group comparisons, a 97.5% confidence interval was used to account for multiple comparisons. Panel B shows freedom from homologous P. vivax recurrence (with homologous recurrence defined as no microsatellite difference between the baseline sample and the recurrence sample).