Short-Course, High-Dose Primaquine Effective for Radical Cure of P vivax Malaria

For patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity in malaria-endemic areas where frequent relapsing strains of Plasmodium vivax are prevalent, a 7-day high-dose course of primaquine was noninferior to a 14-day course, according to study results published in the Lancet.¹

This double-blind, multinational, placebo-controlled, noninferiority trial (ClinicalTrials.gov identifier: NCT01814683) included 2 healthcare clinics in each of the following 4 countries: Afghanistan, Ethiopia, Indonesia, and Vietnam. Patients with normal G6PD and uncomplicated P vivax malaria, were randomly assigned in a 2:2:1 ratio to a standard 14-day course of primaquine (0.5 mg/kg per day), a 7-day high-dose course of primaquine (1.0 mg/kg per day), or placebo. Treatment was fully supervised and was dosed according to body weight.

The primary end point was the incidence rate of symptomatic P vivax parasitemia (mono-infection or mixed infection) over 12 months, assessed in the intention-to-treat population. Noninferiority was set to a margin of 0.07 recurrences per person-year of the 7-day regimen compared with the 14-day regimen.

Of the 2336 patients enrolled in the study (62.8% men; median age, 16 years [interquartile range, 10-26]), 935 were assigned to the 7-day primaquine regimen, 937 to the 14-day primaquine regimen, and 464 to placebo. Both primaquine regimens were effective, with recurrent malaria subsequently causing 0.18 episodes per person-year (95% CI, 0.15-0.21) in the 7-day primaquine group and 0.16 episodes per person-year (95% CI, 0.13-0.18) in the 14-day treatment group. The 7-day treatment course was noninferior to the standard 14-day regimen (absolute incidence rate difference 0.02; 95% CI, −0.02 to 0.05; P =.34). The incidence of recurrent malaria in the placebo group was 0.96 episodes per person-year (95% CI, 0.83-1.08).

Although the incidence of adverse events was low, 5 patients in the 7-day group needed to temporarily discontinue therapy because of gastrointestinal symptoms. Researchers noted that gastrointestinal symptoms might have contributed to a greater number of patients with incomplete treatment in the 7-day primaquine group compared with the 14-day primaquine and placebo group (5.7% vs 3.9% and 3.0%, respectively). In addition, 3 of 4 patients with significant hemolysis were in the 7-day primaquine group.

Tafenoquine, which was licensed in the United States and Australia in 2018, offers a single dose option for P vivax radical cure with its extended half-life. However, “G6PD deficiency is also a contraindication for use of tafenoquine, and because of its prolonged action, it might require more stringent restriction in those with relatively low G6PD levels,” noted Philip J. Rosenthal, MD, from the department of medicine at the University of California, San Francisco in an editorial commentary.²

While tafenoquine may eventually replace primaquine as a single-dose anti-relapse therapy with safety demonstration, this study “offers a potential strategy for halving the length of therapy for eliminating hypnozoites, which is an incremental yet important advance in the treatment of vivax malaria,” concluded Dr Rosenthal.

References

1. Taylor WRJ, Thriemer K, von Seidlein L, et al. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial. Lancet. 2019;394:929-938.

2. Rosenthal PJ. A shorter course for anti-relapse therapy against vivax malaria. Lancet. 2019;394:898-900.