Impact of CYP2D6 Genetic Variation on Radical Cure of Plasmodium vivax Malaria

Plasmodium vivax (P. vivax) is the most widespread human malaria parasite, with 2.5 billion people at risk of infection worldwide. P. vivax forms liver hypnozoites, which trigger further symptomatic episodes (relapses) weeks or months after the initial episode. Radical cure of vivax malaria requires hypnozoitocide therapy to prevent relapses. The two US Food and Drug Administration (FDA)-approved hypnozoiticides for human use, primaquine, and tafenoquine, are pro-drugs, that require in vivo conversion into metabolites with redox activity. This mini-review focuses on the association between CYP2D6-mediated hydroxylation and hypnozoitocide efficacy of primaquine and tafenoquine. Studies in murine models show that the antimalarial activity of primaquine and tafenoquine is abolished by CYP2D knock-out and partially restored by knock-in of humanized CYP2D6. Human studies explored the impact of CYP2D6 genetic variation and genotype-inferred CYP2D6 phenotype on anti-relapse efficacy. Most, but not all, studies with primaquine report higher rates of relapse in patients with decreased CYP2D6 activity (activity scores (AS) <= 1) compared to normal activity (AS >= 1.5). Potential factors for discordance among studies include risk of reinfection in endemic areas, adherence to primaquine-treatment, assignment of CYP2D6 phenotypes based on CYP2D6 polymorphism and choice of AS values for dichotomizing the study cohorts. Tafenoquine anti-relapse efficacy did not differ between patients with AS < 1 vs. AS >= 1.5 in 2 studies. Absence/small number of poor CYP2D6 metabolizers in AS <= 1 groups, combined with lesser dependence of tafenoquine on CYP2D6-mediated conversion into active redox metabolites may account for this result. Additional tafenoquine studies with larger representation of poor CYP2D6 metabolizers are warranted.

Automated summary

Plasmodium vivax is the most widespread human malaria parasite requiring hypnozoiticide therapy for radical cure. Studies have shown the crucial role of CYP2D6 in the efficacy of primaquine and tafenoquine. Patients with decreased CYP2D6 activity may have higher relapse rates with primaquine, while tafenoquine shows less dependence on CYP2D6 activity. Additional studies with more representation of poor CYP2D6 metabolizers are needed for tafenoquine efficacy evaluation.