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

Abstract

Background: The 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.

Methods: Quantitative 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.

Findings: Independent 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.

Conclusion: If tafenoquine is deployed for radical cure, primaquine will still be needed to obtain high population coverage. Better radical cure antimalarial regimens are needed.

Fig 1. Distribution of G6PD activities in wild type males (determined from phenotype) and wild type females (only those determined from genotype to avoid bias from heterozygotes).

Each activity has been scaled by 10/(Study median activity) to obtain a global median of 10. The units are relative to the corresponding study median. The 70% of population median threshold is shown by the vertical dashed red line.

Fig 2. Comparison of prescribing restrictions for primaquine and tafenoquine under three different scenarios broken down by gender.

This assumes that 10% of heterozygous females would test deficient at screens with a 30% activity threshold, and 70% of heterozygous females and 5% of all wild type individuals at a 70% threshold. Top left: current proportions of individuals ineligible for radical cure for vivax malaria following G6PD deficiency testing; top right: proportions of individuals ineligible for radical cure if primaquine and tafenoquine could be given to females breast-feeding infants older than 1 month; bottom left: proportions of individuals ineligible for radical cure if primaquine could be given to G6PD deficient persons.

Fig 3. Proportions of individuals who would not be treated with tafenoquine if 10% of males were found to be G6PD deficient.

Assumptions as in Fig 2.

Fig 4. Comparison of estimated treatment coverage for primaquine (blue) and tafenoquine (red) under the three main scenarios considered in this paper.

i) current prescribing restrictions (thick lines); ii) 8-aminoquinolines given to G6PD normal lactating women with infants older than 1 month (dashed lines); iii) alternative primaquine regimen for G6PD deficient individuals (dotted line).