title: Amino acid substitutions in core and NS5A regions of the HCV genome can predict virological decrease with pegylated interferon plus ribavirin therapy.
abstract: BACKGROUND
  The current standard therapy for chronic hepatitis C is pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Recently, it has been reported that amino acid (aa) substitutions in the core region, as well as the IFN-sensitivity-determining region (ISDR), were predictive of non-virological response (NVR), sustained virological response (SVR) and early virological response. Despite the importance of these two predictive factors for combination therapy, their interaction is poorly understood.
  
  
  METHODS
  A total of 117 patients who were treated with PEG-IFN-α2b plus RBV combination therapy were selected for participation in this study. We determined the aa sequences in the core region and ISDR by direct sequencing and analysed them along with clinical data to identify predictive factors for therapeutic response.
  
  
  RESULTS
  The aa sequences in the core region and γ-glutamyl transpeptidase (GTP) levels were associated with SVR and NVR, but aa sequences in the ISDR were not. However, substitutions at both aa 70 and aa 91 in the core region without substitutions in the ISDR and higher levels of γ-GTP were independent predictive factors for NVR. Wild-type aa 70 and aa 91 in the core region, higher platelet counts and lower levels of γ-GTP were independent predictive factors for SVR.
  
  
  CONCLUSIONS
  These results indicate that analyses of aa substitutions in both the core region and the ISDR are useful for predicting the effectiveness of combination therapy, and could help to avoid therapy exposure for patients who have a low probability of SVR.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kitamura
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hatakeyama
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Nami
authors.initials: N
authors.lastname: Mori
authors.forename: Hiromi
authors.initials: H
authors.lastname: Saneto
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Kawaoka
authors.forename: Fukiko
authors.initials: F
authors.lastname: Mitsui
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Shintaro
authors.initials: S
authors.lastname: Takaki
authors.forename: Yoshiiku
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Waka
authors.initials: W
authors.lastname: Ohishi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016001:Confidence Intervals; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D011379:Prognosis; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D014758:Viral Core Proteins / Q000737:chemistry / Q000235:genetics*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C417083:peginterferon alfa-2b