title: Influence of a single nucleotide polymorphism at the main ribavirin transporter gene on the rapid virological response to pegylated interferon-ribavirin therapy in patients with chronic hepatitis C virus infection.
abstract: The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 μg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.
authors.affiliation: Laboratory of Pharmacology, Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Morello
authors.forename: Lorena
authors.initials: L
authors.lastname: Cuenca
authors.forename: Vincent
authors.initials: V
authors.lastname: Soriano
authors.forename: José
authors.initials: J
authors.lastname: Medrano
authors.forename: Antonio
authors.initials: A
authors.lastname: Madejón
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vispo
authors.forename: Pablo
authors.initials: P
authors.lastname: Barreiro
authors.forename: Pablo
authors.initials: P
authors.lastname: Labarga
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Jiménez-Nácher
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodríguez-Nóvoa
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications*; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D033721:Equilibrative Nucleoside Transporter 1; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a