title: Polymorphisms of NS5B protein relates to early clearance of hepatitis C virus by interferon plus ribavirin: a pilot study.
abstract: Although randomized trials have shown enhancement of efficacy for combination therapy with interferon (IFN) alpha-2b and ribavirin compared with IFN monotherapy as first-line treatment for chronic hepatitis C, infection with genotype 1b and high viremia are still associated with significantly low response rates compared with non-1 genotypes and low viremia. We analysed amino acid sequences of the viral RNA-dependent RNA polymerase (RdRP) or nonstructural protein 5B (NS5B), responsible for ribavirin misincorporation into RNA products in patients with genotype 1b-related chronic hepatitis C and high viremia, and examined the relationship between such RdRp polymorphisms, and the initial decline in viral load induced by combination therapy with IFN-alpha and ribavirin. Substitution of glutamic acid to lysine at the 124th position (E124K) and of isoleucine to valine at the 85th position (I85V) were found to be closely associated with a potent decline of viral load and viral clearance at 8 weeks of treatment (five of five patients, coincidence rate 100%). In conclusion, our results suggest that the polymorphisms of E124K and I85V identified in NS5B protein are crucial for early viral clearance in patients with genotype 1b and high viremia by combination therapy with IFN and ribavirin, and that detection of amino acid sequence motifs might enable prediction of clinical efficacy.
authors.affiliation: Research Center for Liver Diseases, the Kitasato Institute, Minato-ku, Tokyo, Japan. kumagai-n@kitasato.or.jp
authors.forename: N
authors.initials: N
authors.lastname: Kumagai
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Kinoshita
authors.forename: S
authors.initials: S
authors.lastname: Tsunematsu
authors.forename: K
authors.initials: K
authors.lastname: Tsuchimoto
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Ishii
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000008:administration & dosage; D001483:Base Sequence; D004279:DNA, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage*; D017386:Sequence Homology, Amino Acid; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase