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

Abstract

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.

Cytochrome P450 2D6 profiles and anti-relapse efficacy of tafenoquine against Plasmodium vivax in Australian Defence Force personnel

“…PQ metabolism in humans utilizes two pathways for metabolite conversion: the MAO-A pathway converting PQ to inactive carboxyprimaquine and the CYP2D6 pathway where hydroxylation generates phenolic metabolites with redox activity. The latter is believed to be responsible for the hypnozoiticide efficacy and hemolytic activity of PQ when there is a deficiency in the G6PD enzyme ( 23 ). There has been substantial evidence that CYP2D6 phenotype or genotype-predicted activity score is a significant factor in PQ metabolism and an IM or PM is at increased risk of PQ failure with P. vivax relapse ( 24 – 26 ).…”

Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips

“…Thus, the global burden of this species is certainly underestimated. Moreover, experts agree that P. vivax will be the last human malaria parasite species to be eliminated due to its unique biology, including (i) the presence of hypnozoites, a latent (dormant) form of the parasite that develops in the liver ( Krotoski, 1985 ) which can reactivate weeks or months after the primary infection causing clinical relapses ( White, 2011 ); (ii) the limitation of using primaquine and tafenoquine to kill hypnozoites in pregnant women and G6PD-defficient individuals due to the risk of acute hemolytic anemia ( Baird, 2019 ); (iii) the risk of primaquine treatment failure in patients with particular cytochrome P450 isozyme 2D6 (CYP2D6) polymorphisms ( Suarez-Kurtz, 2021 ); (iv) the recent findings that invasion of merozoites into reticulocytes is not limited to the Duffy binding protein ( Ménard et al., 2010 ) and the detection of P. vivax in sub-Saharan Africa, where this blood group is nearly absent ( Zimmerman, 2017 ); (v) the outdoor biting behaviour of vectors transmitting P. vivax , that results on low efficacy control measures when impregnated bed nets are used. All together, these unique aspects of the biology of P. vivax strongly support the generalized view that this species will be the last human malaria parasite to be eliminated ( Mueller et al., 2009 ).…”