A shorter course for anti-relapse therapy against vivax malaria
Authors: Philip J Rosenthal
Journal: The Lancet (2019)

Although Plasmodium falciparum causes the greatest number of global malaria infections and deaths, the impact of infection with Plasmodium vivax, the dominant human malaria parasite outside of Africa, is large, with an estimated 7·4 million cases in 2017.1WHOWorld malaria report 2018. World Health Organization, Geneva2018Google Scholar, 2Howes RE Battle KE Mendis KN et al.Global epidemiology of Plasmodium vivax.Am J Trop Med Hyg. 2016; 95: 15-34Crossref PubMed Scopus (219) Google Scholar A particular challenge with P vivax infection is hypnozoites: dormant liver-stage parasites that are not eliminated by standard antimalarial treatments. Hypnozoites do not cause clinical illness, but without therapy that targets them, P vivax infections will commonly relapse, with recurrent symptomatic blood-stage infections weeks to months after the primary infection. By enabling recurrent episodes of malaria and ongoing transmission, P vivax relapses contribute substantially to the burden of malaria and make malaria eradication more difficult. Standard therapy to eliminate P vivax hypnozoites is primaquine administered daily for 2 weeks, beginning soon after initiation of primary therapy to eliminate asexual parasites. Primaquine is generally well tolerated, but achieving compliance with a 2-week regimen is difficult. Furthermore, primaquine has dose-dependent toxicity in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy, with the potential for lethal haemolysis.3Luzzatto L Arese P Favism and glucose-6-phosphate dehydrogenase deficiency.New Engl J Med. 2018; 378: 60-71Crossref PubMed Scopus (108) Google Scholar Recommendations for primaquine to treat P vivax infection with or without prior G6PD testing vary around the world, but because of low expectations for full compliance, cost concerns, high risks of reinfection, and the difficulty of testing for G6PD deficiency prior to therapy, most patients presenting with P vivax infection do not receive anti-relapse therapy.4Recht J Ashley EA White NJ Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: divergent policies and practices in malaria endemic countries.PLoS Negl Trop Dis. 2018; 12e0006230Crossref PubMed Scopus (72) Google Scholar In The Lancet, Walter Taylor and colleagues5Taylor 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; (published online July 18.)http://dx.doi.org/10.1016/S0140-6736(19)31285-1Summary Full Text Full Text PDF Scopus (62) Google Scholar present the results of a randomised, double-blind, placebo-controlled trial in four countries (Afghanistan, Ethiopia, Indonesia, and Vietnam). The trial compared a standard 14-day course of primaquine (0·5 mg/kg per day), a 7-day course of primaquine at a higher dose (1·0 mg/kg per day), and placebo, all following standard therapy for asexual infection, for the treatment of uncomplicated vivax malaria. Of the 2336 enrolled patients (62·8% men, median age 16 years [IQR 10 to 26]), 935 were randomly allocated to the 7-day primaquine regimen, 937 to the 14-day primaquine regimen, and 464 to placebo. Patients were followed up for 1 year after therapy. The incidence of recurrent malaria in the placebo group was 0·96 episodes per person-year. Both primaquine regimens were effective, with recurrent malaria subsequently causing 0·18 episodes per person-year in the 7-day primaquine group and 0·16 episodes per person-year in the 14-day treatment group. The 7-day treatment course was non-inferior to the standard 14-day regimen (absolute incidence rate difference 0·02 [95% CI −0·02 to 0·05], within the pre-defined non-inferiority margin of 0·07; p=0·34). This result is important. Halving the length of an anti-relapse treatment course for vivax malaria has the potential to markedly increase the number of patients who receive a full course of anti-relapse therapy, thus decreasing recurrent episodes of malaria and transmission of malaria to others. Despite the potential benefits of 7-day primaquine therapy, two important caveats apply. First, the study excluded those with G6PD deficiency, and thus did not provide information regarding potential risks in this group. The use of primaquine is facilitated by available point-of-care tests for G6PD deficiency,6Roca-Feltrer A Khim N Kim S et al.Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia.PLoS One. 2014; 9e116143Crossref PubMed Scopus (43) Google Scholar but these tests might not identify all patients at risk of haemolysis, and safety concerns continue to challenge efforts to roll out anti-relapse therapy. Second, the 7-day regimen comprised a remarkably high daily dose of primaquine, four times higher than the original daily dose in a 14-day regimen, and twice the daily dose in a 14-day regimen that is recommended for areas with high rates of relapse (and was administered to the 14-day group of this trial).7WHOGuidelines for the treatment of malaria. World Health Organization, Geneva2015Google Scholar The higher daily dose might have been needed to yield adequate 7-day efficacy, but it would be expected to increase toxicity. In fact, although the incidence of adverse events was low, five patients, all in the 7-day arm, needed to temporarily discontinue therapy because of gastrointestinal symptoms, and three of four patients with significant haemolysis (including one patient requiring transfusion, who was G6PD-deficient but had been enrolled because of misdiagnosis as G6PD-normal) were in the 7-day group. We could reasonably ask whether, with the short-course regimen, the presumed benefit of compliance will be balanced out by missed doses due to toxic effects. Tafenoquine became the second drug available for anti-relapse therapy in 2018. The extended half-life of tafenoquine allows single-dose anti-relapse therapy, a marked improvement over 7-day or 14-day courses. 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. Demonstration of safety with tafenoquine might allow it to eventually replace primaquine as a single-dose anti-relapse therapy. For now, the report by Taylor and colleagues5Taylor 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; (published online July 18.)http://dx.doi.org/10.1016/S0140-6736(19)31285-1Summary Full Text Full Text PDF Scopus (62) Google Scholar 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. I declare no competing interests. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trialIn patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria. Full-Text PDF Open Access