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Higher-Dose Primaquine to Prevent Relapse of Plasmodium vivax Malaria

A higher dose of a primaquine-based regimen was more effective at preventing relapses of Plasmodium vivax malaria than the currently recommended regimen, a randomized trial found.

More patients randomized to receive a higher dose of the antiparasitic primaquine (7.0 mg/kg over 14 days) did not experience a relapse in P. vivax malaria after 168 days (86%, 95% CI 76-92) compared to either unobserved (58%, 95% CI 44-70) or observed (59%, 95% CI 47-69) groups who received the currently recommended total 3.5 mg/kg dose over 7 days, reported Nathália Chamma-Siqueira, MSc, of Instituto Evandro Chagas in Brazil, and colleagues.

These differences translated to a 27 percentage point difference between the high-dose and lower dose groups for recurrence (97.5% CI 10-44 and 97.5% CI 12-42, respectively, P<0.0001), they stated in the New England Journal of Medicine.

Vivax malaria relapse can be especially insidious, the authors noted, as it involves “both blood-stage parasites and hypnozoites,” dormant parasites that can cause relapse weeks after infection. In most of the Americas, P. vivax malaria is treated with 25 mg/kg of chloroquine and a dose of 3.5 mg/kg of primaquine, “despite the only moderate efficacy of this regimen,” which is 60%-70% effective at preventing malaria recurrence within 6 months, they said.

From April to October 2018, Chamma-Siqueira’s group evaluated three primaquine-based regimens among 254 children and adults, ages 5 and up, with confirmed P. vivax malaria monoinfection at eight malaria diagnostic posts in the western Brazilian Amazon.

All participants were given directly-observed chloroquine for 3 days, and then randomized into three treatment groups. All patients then received 0.5 mg/kg of primaquine per day, either for 14 days (7.0 mg/kg total dose; n=95 with observed administration) or 7 days (3.5 mg/kg in total; n=63 for the unobserved group and 96 for the observed group).

Patients’ median age was 22, more than half were male, and 71% lived in urban areas. They had a median duration of fever of 2 days.

At day 28, there were three recurrences among the 3.5 mg/kg groups, though the authors noted that “a total of 97% or more of the patients in each trial group had an adequate clinical and parasitologic response by day 28.”

Chamma-Siqueira’s group added that adverse events (AEs) were “not systematically assessed,” but there were no serious AEs related to either primaquine or chloroquine, and median hemoglobin levels were similar between groups on days 0, 14, and 28.

In an accompanying editorial, Brian Greenwood, MD, and Chris Drakeley, PhD, both of the London School of Tropical Medicine and Hygiene, said that the study provided “convincing evidence” that a higher-dose primaquine regimen was more effective than the current recommended treatment, but also cited some potential difficulties in widescale implementation.

“Adoption of the 14-day course of treatment would benefit patients in Brazil, but the administration of 14 days of treatment under direct observation could be difficult to achieve, especially in remote communities in Amazonia where the incidence of malaria can be high,” they wrote.

Greenwood and Drakeley also pointed out how there may not be resources for glucose-6-phosphate dehydrogenase (G6PD) testing, because the drug is not recommended for pregnant patients with G6PD deficiency, as it may induce severe hemolytic anemia.

“Increasing the availability of reliable, rapid point-of-care tests for G6PD deficiency would allow for the use of the higher dose of primaquine or the use of tafenoquine [Krintafel] in mass or targeted drug administration campaigns conducted as part of an elimination program,” they said.

Chamma-Siqueira’s group also cited single-dose tafenoquine as another treatment option in these patients. The agent was approved by the FDA to treat P. vivax malaria in 2018 and was the first malaria drug to be approved in 60 years. However, in 2019, the drug was not able to prove non-inferiority to primaquine for P. vivax malaria relapse.

The authors added that while there has been no side-by-side comparison of tafenoquine and higher-dose primaquine in the Americas, their results still show better response in preventing malaria recurrence with primaquine.

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