Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia

Abstract

Hyperbilirubinemia is frequently seen in patients treated with atazanavir (ATV). Polymorphisms at the uridin-glucoronosyl-transferase 1A1 (UGT1A1) and multidrug resistance 1 (MDR1) genes may influence, respectively, bilirubin and ATV plasma concentrations. HIV-infected individuals receiving ATV 300 mg daily plus ritonavir 100 mg daily at one clinic were examined. ATV plasma concentrations were measured at steady state. MDR1-3435C>T and UGT1A1 polymorphisms were examined in DNA extracted from blood mononuclear cells. A total of 118 patients (all Caucasian) were analysed. The median ATV plasma concentration was 465 ng/ml [interquartile range (IQR), 233-958]. MDR1-3435 genotypes were as follows: CC (32%), CT (47%) and TT (21%). CC patients showed higher ATV minimum concentration than those with CT/TT genotypes: 939 ng/ml (IQR, 492-1266) versus 376 ng/ml (IQR, 221-722) (P = 0.001). In multivariate analyses, having at least one T allele at MDR1-3435 was independently associated with lower ATV plasma concentrations (beta: -427 [95% confidence interval (CI), -633 to -223]; P < 0.001). The proportion of patients with grade 3-4 hyperbilirubinemia varied with distinct UGT1A1 genotypes: 80% for 7/7, 29% for 6/7 and 18% for 6/6 (P = 0.012). In the multivariate analysis, having at least one 7 allele at UGT1A1 was independently associated with severe hyperbilirubinemia (odds ratio, 2.96; 95% CI, 1.29-6.78; P = 0.01). Polymorphisms at MDR1-3435 significantly influence ATV plasma concentrations, as does being Caucasian patients with CT/TT genotypes, having lower ATV levels, even using ritonavir boosting. On the other hand, although ATV plasma concentrations directly correlate with bilirubin levels, the risk of severe hyperbilirubinemia is further increased in the presence of the UGT1A1-TA7 allele.