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

James Watson,Podjanee Jittamala,Germana Bancone,Nicholas J White,Walter R J Taylor,Cindy S Chu

doi:10.1371/journal.pntd.0006440

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.

Highlights

Plasmodium vivax is an important cause of malaria outside Sub-Saharan Africa
If tafenoquine is deployed for radical cure, primaquine will still be needed to obtain high population coverage
We examined the effect of these restrictions on the potential coverage of radical cure with primaquine today and tafenoquine in the future

Summary

Introduction

The WHO estimates that P. vivax comprises 41% of the malaria burden outside of Africa. This translates into 6–11 million cases/year with an estimated 1800–4900 deaths. South East Asia and Oceania have the highest incidence with relapse rates exceeding 50% [2]. In this context relapse from liver hypnozoites is the main cause of P. vivax malaria illness and asymptomatic carriage [3]. Patients with

Methods

Results

Conclusion