Higher dose primaquine prevents relapse of P. vivax malaria, study finds
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A higher dose of primaquine was significantly more effective at preventing relapse of Plasmodium vivax malaria than a smaller dose, according to study findings published in The New England Journal of Medicine.
The study was conducted in 2018 during malaria season in a city in the western Brazilian Amazon with a high prevalence of infection. It compared a primaquine dose of 7 mg per kg of body weight with a dose of 3.5 mg/kg, which is widely recommended in the Americas, according to Nathália N. Chamma-Siqueira, MSc, from the Evandro Chagas Institute, and colleagues.
Chamma-Siqueira and colleagues noted that P. vivax caused close to 84% of the more than 144,000 cases of malaria recorded in 2020 in the Brazilian Amazon.
“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,” Chamma-Siqueira and colleagues wrote. “P. vivax blood-stage parasites are sensitive to chloroquine in most of the world, except in Southeast Asia and Oceania, but hypnozoite eradication requires the use of primaquine or tafenoquine.”
“The efficacy of primaquine therapy depends on the total dose given during a round of therapy (either 3.5 mg or 7 mg), because of variable drug susceptibility worldwide,” they wrote. “In Brazil, and in most of the Americas, the recommended P. vivax treatment consists of a combination of chloroquine (total dose, 25 mg/kg) and primaquine at a total dose of 3.5 mg/kg, despite the only moderate efficacy of this regimen (60% to 70%) in preventing recurrence within 6 months.”
The researchers enrolled 254 participants aged between 5 and 80 years. After all participants received chloroquine for 3 days at a total dose of 25 mg/kg, they were randomly assigned to one of three groups: the first, comprising 63 patients, received a total primaquine dose of 3.5 mg/kg over an unobserved 7 days; the second, comprising 96 patients, received the same dosage but over an observed 7 days; and the third, comprising 95 patients, received a total primaquine dose of 7 mg/kg over an observed 14 days. The researchers monitored participants for 168 days.
“By day 28, three P. vivax recurrences were observed: two in group 1 and one in group 2,” Chamma-Siqueira and colleagues reported. “By day 168, a total of 70 recurrences had occurred: 24 in group 1, 34 in group 2, and 12 in group 3.”
The authors noted that no serious adverse events were noted throughout the trial.
On day 168, the percentage of patients without recurrence was 58% (95% CI, 44%-70%) in group 1, 59% (95% CI, 47%-69%) in group 2, and 86% (95% CI, 76%-92%) in group 3.
“Because all the patients received the same dose of chloroquine and no significant between-group difference was observed for the day 28 response to treatment, our findings suggest that a higher total dose of primaquine prevented P. vivax recurrence, which generally occurs more than 28 days after the initiation of treatment,” the researchers wrote.
They said effective relapse prevention is essential for management of P. vivax infection.
“Alternatives to current treatment include higher total doses of primaquine over 14 days or single-dose tafenoquine with a clear understanding of the benefits (eg, potentially higher efficacy of higher dose primaquine) and limitations of each option,” they wrote. “A side-by-side comparison of these options would allow for a better evaluation of the response to antirelapse treatment and would help to clarify uncertainties concerning P. vivax treatment.”
Perspective
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Philip J. Rosenthal, MD
Treatments for malaria kill erythrocytic parasites that are responsible for the clinical manifestations of the disease. However, standard therapies do not eliminate hypnozoites, dormant liver stages of P. vivax (and the uncommon species Plasmodium ovale), for which therapy will typically elicit a full clinical recovery but will commonly be followed weeks to months later by relapse because of eventual development of hypnozoites into recurrent bloodstream parasites.
The standard therapy to eliminate dormant hypnozoites is primaquine. The efficacy of primaquine appears dependent on the total dose given rather than the length of therapy. Standard therapy in the Americas with a 3.5 mg/kg total dose has been suboptimal, with a 60% to 70% rate of relapse. This study in Brazil compared regimens providing 3.5 and 7 mg/kg total dose, each following standard therapy, against bloodstream infection with chloroquine. The greater dose was achieved by extending daily therapy from 7 to 14 days. Comparing groups with observed therapy, the higher primaquine dosage had significantly better efficacy, with only 14% of subjects compared with 41% in the lower (shorter) dosage group experiencing relapse within 168 days.
Although multiple caveats apply — it is hard to distinguish relapse from reinfection, so some outcomes may have been misclassified; these results may not be relevant for other areas with P. vivax malaria, as drug susceptibilities vary; a longer dosing course may lead to decreased compliance with the full regimen; only patients with normal G6PD activity were studied, avoiding the challenge of treating deficient individuals who are at risk for primaquine-induced hemolysis; the study did not consider tafenoquine, a new related drug with simpler dosing that might replace primaquine — this study argues that the new standard of care to treat P. vivax malaria in the Americas should include a 14-day 7 mg/kg total dose regimen for primaquine.
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