title: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy.
abstract: OBJECTIVE
  Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs.
  
  
  METHODS
  We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1-191 of the core region and amino acids 2209-2248 of NS5A, and early viral kinetics.
  
  
  RESULTS
  Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions.
  
  
  CONCLUSIONS
  Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.
authors: Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. akuta-gi@umin.ac.jp
authors: Norio
authors: N
authors: Akuta
authors: Fumitaka
authors: F
authors: Suzuki
authors: Hitomi
authors: H
authors: Sezaki
authors: Yoshiyuki
authors: Y
authors: Suzuki
authors: Tetsuya
authors: T
authors: Hosaka
authors: Takashi
authors: T
authors: Someya
authors: Masahiro
authors: M
authors: Kobayashi
authors: Satoshi
authors: S
authors: Saitoh
authors: Sachiyo
authors: S
authors: Watahiki
authors: Junko
authors: J
authors: Sato
authors: Marie
authors: M
authors: Matsuda
authors: Mariko
authors: M
authors: Kobayashi
authors: Yasuji
authors: Y
authors: Arase
authors: Kenji
authors: K
authors: Ikeda
authors: Hiromitsu
authors: H
authors: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D012709:Serum Albumin / Q000032:analysis; D014758:Viral Core Proteins / Q000737:chemistry* / Q000235:genetics; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D012367:RNA, Viral; D012254:Ribavirin; D012709:Serum Albumin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase