Clinical Pearls & Morning Reports

By Carla Rothaus

Published March 30, 2022


In the trial by Chamma-Siqueira et al., was the higher dose of primaquine more effective than the lower dose in preventing relapse of P. vivax malaria? 

Chamma-Siqueira et al. conducted a randomized trial that compared three primaquine regimens to treat and prevent relapse of Plasmodium vivax malaria in Brazil: group 1 received a dose of 0.5 mg per kilogram per day for 7 days (total primaquine dose of 3.5 mg per kilogram) without observed administration; group 2 received the same dose with observed administration; and group 3 received a dose of 0.5 mg per kilogram per day for 14 days (total primaquine dose of 7.0 mg per kilogram) with observed administration. Read the NEJM Original Article here.

Clinical Pearls

Q: Are hypnozoites a feature of P. vivax malaria?

A: Malaria remains a public health concern in the Americas. In 2020, a total of 144,887 cases were reported in the Brazilian Amazon; of these cases, 83.6% were caused by P. vivax. Treatment for P. vivax malaria presents additional challenges for the control and elimination of malaria because the infection involves both blood-stage parasites and hypnozoites, dormant parasite forms in the liver that can cause relapse weeks after an acute infection. Hypnozoite eradication requires the use of primaquine or tafenoquine.

Q: What is the current recommended treatment for P. vivax malaria in Brazil?

A: In Brazil, and in most of the Americas, the recommended P. vivax treatment consists of a combination of chloroquine (total dose, 25 mg per kilogram) and primaquine at a total dose of 3.5 mg per kilogram, despite the only moderate efficacy of this regimen (60 to 70%) in preventing recurrence within 6 months.

Morning Report Questions

Q: In the trial by Chamma-Siqueira et al., was the higher dose of primaquine more effective than the lower dose in preventing relapse of P. vivax malaria?

A: Among the patients in the trial who received directly observed therapy, the recurrence-free percentage by day 168 was higher among those who had received a higher total dose of primaquine (86%) than among those who had received a lower total dose (59%). By day 168, the percentage of patients who were recurrence-free 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. The between-group difference among patients who were recurrence-free by day 168 was 27 percentage points (97.5% CI, 10 to 44; P<0.001) between group 1 and group 3 and 27 percentage points (97.5% CI, 12 to 42; P<0.001) between group 2 and group 3. 

Q: Did the trial by Chamma-Siqueira et al. enroll patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency?

A: No serious adverse events were observed in the trial, but the authors enrolled only patients with normal G6PD activity. Clinicians in the Americas often administer lower-dose primaquine without previous G6PD testing on the basis of the historically low incidence of adverse events. However, since such events have been reported during malaria treatment, efforts should be made to implement regular G6PD testing before primaquine use, especially if higher doses are considered. A recent study evaluated daily primaquine doses of 1 mg per kilogram administered during a 7-day period as compared with the same total dose (7 mg per kilogram) given over a 14-day period. Although the two regimens had similar efficacy, three cases of severely reduced hemoglobin levels occurred in the 7-day group as compared with one case in the 14-day group, mostly among female G6PD heterozygotes. Therefore, overcoming barriers to broad implementation of robust G6PD testing programs is needed for clinicians in countries where the intensification of antirelapse treatment is being considered for P. vivax malaria.

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