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

Background: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. Patients and methods: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. Results: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 (β: –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). Conclusions: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.

[1]  Cheng Cheng,et al.  MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype , 2006, Clinical pharmacology and therapeutics.

[2]  V. Soriano,et al.  Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  Amalio Telenti,et al.  Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. , 2005, The Journal of infectious diseases.

[4]  S. Rutella,et al.  Atazanavir inhibits P-glycoprotein and multidrug resistance-associated protein efflux activity. , 2005, Journal of acquired immune deficiency syndromes.

[5]  S. Spector,et al.  An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children , 2005, AIDS.

[6]  C. Goujard,et al.  Clinical Pharmacokinetics and Summary of Efficacy and Tolerability of Atazanavir , 2005, Clinical pharmacokinetics.

[7]  V. Soriano,et al.  Predictors of Virological Response to Atazanavir in Protease Inhibitor-Experienced Patients , 2004, HIV clinical trials.

[8]  V. Calvez,et al.  Interactions between Atazanavir-Ritonavir and Tenofovir in Heavily Pretreated Human Immunodeficiency Virus-Infected Patients , 2004, Antimicrobial Agents and Chemotherapy.

[9]  V. Natarajan,et al.  Ritonavir Decreases the Nonrenal Clearance of Digoxin in Healthy Volunteers with Known MDR1 Genotypes , 2004, Therapeutic drug monitoring.

[10]  M. Sulkowski Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  M. Bray New data in a 200-year investigation. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  J. Schubert,et al.  No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment. , 2003, European journal of medical research.

[13]  Conrad C. Huang,et al.  Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. , 2003, Pharmacogenetics.

[14]  C. Bellodi,et al.  MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients , 2003, AIDS.

[15]  S. Chaillou,et al.  Intracellular Concentration of Protease Inhibitors in HIV-1--Infected Patients: Correlation with MDR-1 Gene Expression and Low Dose of Ritonavir , 2002, HIV clinical trials.

[16]  C. Michelet,et al.  Simultaneous Quantitative Assay of Six HIV Protease Inhibitors, One Metabolite, And Two Non-Nucleoside Reverse Transcriptase Inhibitors in Human Plasma by Isocratic Reversed-Phase Liquid Chromatography , 2002, Therapeutic drug monitoring.

[17]  Jacques Fellay,et al.  Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study , 2002, The Lancet.

[18]  R. Green,et al.  Mechanism of indinavir-induced hyperbilirubinemia. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[19]  W. März,et al.  Rapid detection of the C3435T polymorphism of multidrug resistance gene 1 using fluorogenic hybridization probes. , 2000, Clinical chemistry.

[20]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. Beglinger,et al.  HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. , 1999, Biochemical pharmacology.

[22]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.

[23]  E. Beutler,et al.  Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D W Nebert,et al.  The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. , 1997, Pharmacogenetics.

[25]  B. Burchell,et al.  Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome , 1996, The Lancet.

[26]  D Lindhout,et al.  The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. , 1995, The New England journal of medicine.

[27]  B. Burchell,et al.  Specificity of human UDP-glucuronosyltransferases and xenobiotic glucuronidation. , 1995, Life sciences.

[28]  K Ueda,et al.  Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. , 1990, The Journal of biological chemistry.

[29]  K. Skubitz P-glycoprotein and multidrug resistance. , 1990, American journal of clinical pathology.

[30]  I. Pastan,et al.  The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. , 1987, The Journal of biological chemistry.