Implications of current therapeutic restrictions for primaquine and tafenoquine in the radical cure of vivax malaria

Abstract

BackgroundThe 8-aminoquinoline antimalarials, the only drugs which prevent relapse of vivax and ovale malaria (radical cure), cause dose-dependent oxidant haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Patients with <30% and <70% of normal G6PD activity are not given standard regimens of primaquine and tafenoquine, respectively. Both drugs are currently considered contraindicated in pregnant and lactating women.MethodsQuantitative G6PD enzyme activity data from 5198 individuals were used to estimate the proportions of heterozygous females who would be ineligible for treatment at the 30% and 70% activity thresholds, and the relationship with the severity of the deficiency. This was used to construct a simple model relating allele frequency in males to the potential population coverage of tafenoquine and primaquine under current prescribing restrictions.FindingsIndependent of G6PD deficiency, the current pregnancy and lactation restrictions will exclude ~13% of females from radical cure treatment. This could be reduced to ~4% if 8-aminoquinolines can be prescribed to women breast-feeding infants older than 1 month. At a 30% activity threshold, approximately 8–19% of G6PD heterozygous women are ineligible for primaquine treatment; at a 70% threshold, 50–70% of heterozygous women and approximately 5% of G6PD wild type individuals are ineligible for tafenoquine treatment. Thus, overall in areas where the G6PDd allele frequency is >10% more than 15% of men and more than 25% of women would be unable to receive tafenoquine. In vivax malaria infected patients these proportions will be lowered by any protective effect against P. vivax conferred by G6PD deficiency.ConclusionIf tafenoquine is deployed for radical cure, primaquine will still be needed to obtain high population coverage. Better radical cure antimalarial regimens are needed.

Targeting liver stage malaria with metformin

“…For example, primaquine and tafenoquine, 8-aminoquinolines that target malaria liver stages, are the only drugs approved to treat P. vivax hypnozoites -the long-lived, dormant, hepatic forms that cause malaria relapses. However, their short half-life, long dosage regimens, and incompatibility with glucose-6-phosphate dehydrogenase deficiency (which requires prescreening of recipients) makes them unsuitable for widespread use (5). Despite recent advances in novel parasite-directed antimalarials, which hold much promise and are currently in the clinical pipeline, there is still a need for alternative approaches (6).…”

Vivax malaria in pregnancy and lactation: a long way to health equity

“…The second layer of a gender-specific morbidity results from the ineligibility of many females for radical cure due to their reproductive stage. It is estimated that about 13% of females with P. vivax are temporarily ineligible for radical cure due to pregnancy or lactation [6], and the proportion who eventually receive 8-aminoquinolones postpartum as recommended by the WHO is unknown. Relapse is the main source of P. vivax infection in areas of low endemicity and contributes to chronic anaemia.…”

“…The World Health Organization (WHO) estimated the global incidence of Plasmodium vivax to be 7.5 million cases in 2017, and it is the most prevalent malaria species in Southeast Asia [3]. Women and their fetuses uniquely suffer from the complications of malaria in pregnancy [4,5], including those associated with P. vivax infection [6].…”

“…On the Thailand-Myanmar border the strongest risk factor for P. vivax in the first 12 weeks postpartum was a history of P. vivax infection during the previous 9 months [22]. Exclusion of pregnant and lactating females from radical cure potentially affects about 13% of females in malaria-endemic areas [6]. Providing PMQ postpartum for radical cure of P. vivax is essential in Southeast Asia because the majority of P. vivax infections are attributed to relapse [23,24].…”

Malaria in the 21st century - still a threatening problem

“…Tafenoquine, an 8-aminoquinoline, is used as a single-dose treatment for Plasmodium vivax relapse prevention. Administration of this drug, as well as primaquine, follow the same restriction and adverse events (glucose-6-phosphate dehydrogenase deficiency) [26].…”