Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax.

Alexandra G A Stewart,Peter A Zimmerman,James S Mccarthy

doi:10.3389/fphar.2021.784909

Abstract

Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of Plasmodium vivax and P. ovale malaria. Relapse, triggered by activation of dormant hypnozoites in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and P. vivax elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (CYP2D6) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate CYP2D6 genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for P. vivax elimination.

Highlights

Plasmodium vivax and P. ovale are unique human malaria species in their ability to develop into hypnozoites, a liver stage that can remain dormant until relapse occurs weeks to years later (Krotoski 1985)
Optimizing PQ dosing will be essential in glucose-6-phosphate dehydrogenase deficient (G6PDd) and impaired PQ metabolizers, as the total dose of PQ administered, influences efficacy for radical cure, while acute haemolytic anemia (AHA) occurs in a dose-dependent manner, with decreased dosing frequency used as a strategy to mitigate this risk in populations with milder variants (John et al, 2012)
Utilizing population knowledge of G6PDd and cytochrome P450 2D6 (CYP2D6) genotypes may facilitate dosing strategies that reduce the proportion of individuals currently deemed “ineligible” for radical cure and allow coverage thresholds for mass drug administration (MDA) to be reached

Summary

Introduction

Plasmodium vivax and P. ovale are unique human malaria species in their ability to develop into hypnozoites, a liver stage that can remain dormant until relapse occurs weeks to years later (Krotoski 1985). Pharmacogenetic testing for CYP2D6 diplotypes has the potential to play a significant role in patient management prior to use of PQ, for IM where alternative dosing strategies may be required. Optimizing PQ dosing will be essential in G6PDd and impaired PQ metabolizers, as the total dose of PQ administered, influences efficacy for radical cure, while AHA occurs in a dose-dependent manner, with decreased dosing frequency used as a strategy to mitigate this risk in populations with milder variants (John et al, 2012).

Results

Conclusion