Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

Abstract

Background In the Amazon, Plasmodium vivax is the prevalent malaria parasite, and the standard treatment is chloroquine combined with primaquine. However, this regimen is limited because of the risk of acute hemolytic anemia (AHA) in glucose-6-phosphate dehydrogenase deficient individuals (G6PDd). CYP2D6 is a key enzyme that is involved in the metabolism of a large number of drugs. Primaquine is a prodrug that requires conversion by the CYP2D6 enzyme in order to be effective against malaria. Furthermore, interaction with cytochrome P450 (CYP) liver enzymes of some pharmacogenes, such as CYP2C19, CYP2D6 and CYP3A4 associated with PQ metabolism, may enhance, or reduce its biotransformation. Methods A series of cases were followed-up at an infectious diseases reference hospital in the Western Brazilian Amazon. The inclusion criteria were patients of either sex, > 6 months of age, diagnosed with vivax malaria, treated with PQ and presence of hemolysis after treatment. The STANDARD G6PD (SD Biosensor®) assay was used to test G6PD status, and real-time PCR was used to genotype G6PD, CYP2C19, CYP2D6 and CYP3A4. Results Eighteen patients were included, of which 55.6% had the African A- variant (G202A/A376G), 11.1% the African A + variant (A376G), 5.6% the Mediterranean variant (C563T) and 27.8% were the wild type. CYP2C19, CYP2D6 and CYP3A4 genotyping showed no statistically significant differences in the frequency of star alleles between the groups (p > 0.05). Elevated levels of liver and kidney markers in the G6PDd patients were observed in gNM, gRM and gUM of CYP2C19 and CYP2D6 (p < 0.05). Conclusions These findings reinforce the importance of studies on the mapping of G6PD deficiency and CYP2C19, CYP2D6 and CYP3A4 genetic variations. This mapping will allow us to validate the prevalence of CYPs and determining their influence on the hemolytic process in vivax malaria patients, and will aid in decisions regarding the appropriate treatment regimen, thereby avoiding complications caused by the breakdown of PQ by CYP.