Polymorphisms of the CYP2D6 gene and its relationship with Plasmodium vivax relapses after chloroquine-primaquine treatment in Turbo, Colombia

• Published in: Diagnostic microbiology and infectious disease Vol. 113; no. 3; p. 117013
• Main Authors: Sierra-Cifuentes, Veronica, Zuluaga-Idárraga, Lina, Aguirre-Acevedo, Daniel, Silva de Barros Puça, Maria Carolina, Nobrega de Sousa, Tais, Lopera-Mesa, Tatiana M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2025
• Subjects: Adolescent; Adult; Aged; Antimalarials - blood; Antimalarials - therapeutic use; Chloroquine - therapeutic use; Colombia; CYP2D6 polymorphisms; Cytochrome P-450; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Female; Genotype; Humans; Malaria; Malaria, Vivax - drug therapy; Malaria, Vivax - genetics; Malaria, Vivax - parasitology; Male; Middle Aged; Phenotype; Plasmodium vivax; Plasmodium vivax - drug effects; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Primaquine; Primaquine - blood; Primaquine - therapeutic use; Recurrence; Relapse; Young Adult; Colombia; Plasmodium vivax; Relapse; CYP2D6 polymorphisms; Malaria; Primaquine; Cytochrome P-450
• DOI: 10.1016/j.diagmicrobio.2025.117013
• ISSN: 0732-8893; 1879-0070

•CYP2D6 enzyme metabolizes primaquine, an anti-malarial drug that prevents relapses by P. vivax hypnozoites.•CYP2D6 gene polymorphisms were identified in 71 participants with P. vivax infection, from a malaria endemic region in Colombia.•Diplotypes associated with poor (gPM) and intermediate (gIM and gNM-S) CYP2D6 metabolizers were present in 18.3 % of participants.•No conclusive association was found between CYP2D6 phenotypes and the risk of P. vivax relapses, neither plasma primaquine levels in the study participants. Plasmodium vivax relapse due to hypnozoites represents a significant mechanism for parasite persistence in the population. Primaquine (PQ), the drug of choice for eliminating hypnozoites, requires metabolic activation by Cytochrome P450-2D6 (CYP2D6). Genetic variations in CYP2D6 can alter PQ metabolism, potentially increasing the risk of relapses. This study aimed to determine CYP2D6 polymorphisms in subjects with Plasmodium vivax under supervised chloroquine-primaquine treatment and explore their association with relapses and PQ plasma levels. CYP2D6 phenotypes and genotypes were successfully determined for 71 out of 78 patients included in the study. Nine polymorphisms (SNPs and indels) and gene copy number variation were analyzed. The association between the CYP2D6 phenotype, P. vivax relapse over six months follow-up, and PQ plasma levels were explored. Most diplotypes (81.7 %) were associated with normal (gNM-F) and ultrarapid (gUM) CYP2D6 metabolizers, while 18.3 % were associated with poor (gPM) and intermediate (gIM and gNM-S) metabolizers. The median plasma PQ concentration on day 2 was higher in impaired CYP2D6 activity group (poor/intermediate) compared normal metabolizers (normal/ultrarapid) (660.4 ng/ml vs 313.5 ng/ml; effect size r -0.51, 95 % CI -0.82 to 0.03). No significant difference was found in the hazard ratio (HR) of relapse between impaired and normal CYP2D6 activity (adjusted HR: 1.45; 95 % CI: 0.39–5.39). Impaired CYP2D6 activity phenotypes were frequent in individuals infected with P. vivax from an endemic region of Colombia. Further research is essential to elucidate the relationship between these phenotypes and P. vivax relapses, as suggested by this exploratory study. [Display omitted]