Advancing Plasmodium vivax malaria treatment in India: The vital role of glucose 6-phosphate dehydrogenase point-of-care tests

For India to achieve elimination by 2030, the challenges posed by Plasmodium (P.) vivax cannot be overlooked owing to its burden and unique biology. In 2023, in India, about 224000 malaria cases were reported, and a significant proportion (40%) were P. vivax cases. In P. vivax infection, the persistence of dormant liver stage of parasite, i.e, hypnozoites, leading to relapses weeks or months later poses challenge in its elimination. For obviating further transmission chain and achieve elimination, it is imperative to get rid of the hypnozoites. The mainstay of treatment for eliminating hypnozoites is currently primaquine in India, and is given as 0.5 mg/kg/day for 14 days. Recently, tafenoquine, another 8-aminoquinoline, has been approved by FDA[1]. Compared to primaquine, it has a long halflife of 16 days, and thus it is suitable for single dose administration for radical cure of P. vivax. Both primaquine and tafenoquine acts as a hypnozoitocidal (targets hypnozoites in the liver). Importantly, if recommended doses of primaquine are not consumed and metabolized by the patients, it can lead to relapse months/years following the initial infection. Evidence suggests that the relapse rate of P. vivax in India varies from 8.1% to 38% following unsupervised radical cure[2]. Also, the recommended lower dose (0.25 mg/kg/day) of primaquine for 14 days is challenged with low compliance among the patients, and higher daily dose of primaquine (0.5 mg/kg/day) requires mandatory ruling out glucose 6-phosphate dehydrogenase (G6PD) deficiency owing to increased risk of hemolysis[3]. G6PD deficiency is among the most common X-linked enzymopathies globally, with prevalence in the Indian subcontinent ranging from 2.3% to 27%[4]. Deficient red blood cells are highly susceptible to oxidative stress, leading to potentially life-threatening hemolysis upon exposure to 8-aminoquinolines. Thus to prevent hemolysis in patients during anti-malarial treatment for P. vivax (both high-dose primaquine or tafenoquine), it is important to test for G6PD enzyme activity before initiating treatment. Further, if G6PD status is known, higher daily doses of primaquine, for example, 0.5-1 mg/kg can be safely dispensed[5]. Higher dose has been tested in various studies for efficacy, and recent systematic review and meta-analysis points towards the limited evidence from India on the topic[3]. Studies have reported drop in hemoglobin and hemolytic episodes among G6PD deficient patients during treatment with primaquine. Brita-Sousa et al. have reported primaquine induced hemolytic anemia in G6PD deficient patients[6]. Majority of patients developed signs of hemolysis after their 3rd dose of primaquine, and required 6 days of in-hospital management with the requirement of blood transfusion in half (48.9%) of the patients. Moreover, one-fourth of the patients also developed acute kidney injury resulting from hemolysis. Since it is X-linked recessive disorder, in a population, males could be either deficient or normal, and females could have a spectrum of G6PD enzyme activity: >70% - normal activity (homozygous for normal allele),