Resposta terapêutica da primaquina em malária vivax - influência de variantes genéticas de G6PD, CYP2C19, CYP2D6 e CYP3A4

Abstract

In the Amazon, Plasmodium vivax (P. vivax) infection is more prevalent, and its treatment includes primaquine (PQ), a hypnozoiticide drug. However, its use is limited by the risk of acute hemolytic anemia (AHA) in glucose-6-phosphate dehydrogenase (dG6PD) deficient individuals, with a frequency of 4.5% to 10% in the Amazon region. Interaction with cytochrome P450 (CYP) liver enzymes, some pharmacogenes such as CYP2C19, CYP2D6 and CYP3A4 associated with PQ metabolism can significantly enhance or reduce its biotransformation. This study aims to evaluate the influence of CYP2C19, CYP2D6 and CYP3A4 variants on hemolysis in G6PD-deficient and non-G6PD-deficient individuals treated with primaquine for P. vivax. We included 18 patients of both sexes, > 6 months of age treated with PQ, diagnosed with vivax malaria and hemolysis. Phenotyping for G6PD was performed using the SD Biosensor and genotyping for G6PD and CYPs using the real-time PCR technique. Of these, 55.6% had the African A- variant (G202A/A376G ), 11.1% the African A+ (A376G), 5.6% the Mediterranean (C563T) and 27.8% were wild type. Genotyping of CYP2C19, CYP2D6 and CYP3A4 did not show statistical significance in the frequency of star alleles between groups (p >0.05). Elevated levels of hepatic and renal markers were observed in normal (gNM), rapid (gRM) and ultra-rapid (gUM) metabolizers of CYP2C19 and CYP2D6 in dG6PD (p < 0.05). CYP3A4 *1/*1B genotype had greater clinical impact in both groups, although not significant (p >0.05). These findings reinforce the importance of studies on the mapping of G6PD deficiency and genetic variants of CYP2C19, CYP2D6 and CYP3A4, which will allow validating the prevalence and determining the influence of CYPs on the hemolytic process of individuals with vivax malaria, and will contribute to a more adequate, avoiding complications caused by the metabolism of PQ in CYP