Journal of Gastroenterology

, Volume 45, Issue 6, pp 656–665

Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection

  • Mina Nakagawa
  • Naoya Sakamoto
  • Mayumi Ueyama
  • Kaoru Mogushi
  • Satoshi Nagaie
  • Yasuhiro Itsui
  • Seishin Azuma
  • Sei Kakinuma
  • Hiroshi Tanaka
  • Nobuyuki Enomoto
  • Mamoru Watanabe
Original Article—Liver, Pancreas, and Biliary Tract

DOI: 10.1007/s00535-009-0195-7

Cite this article as:
Nakagawa, M., Sakamoto, N., Ueyama, M. et al. J Gastroenterol (2010) 45: 656. doi:10.1007/s00535-009-0195-7

Abstract

Background

Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy.

Methods

We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses.

Results

On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P < 0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181).

Conclusions

The number of mutations in the ISDR sequence of HCV-1b (≥2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.

Keywords

Hepatitis C virus (HCV)Chronic hepatitis CPEG-IFN plus RBV therapyCombination therapyInterferon sensitivity determining region (ISDR)

Abbreviations

HCV

Hepatitis C virus

IFN

Interferon

PEG

Polyethylene glycol

PEG-IFN

Pegylated-interferon-alpha 2b

RBV

Ribavirin

ISDR

Interferon sensitivity determining region

BMI

Body mass index

ALT

Alanine transaminase

dM

Double mutant

ITT analysis

Intention-to-treat analysis

PP analysis

Per protocol analysis

SVR

Sustained virological response

ETR

End of treatment response

PKR

Double stranded RNA-dependent protein kinase

TLR

Toll-like receptor

MyD88

Myeloid differentiation primary response gene 88

Copyright information

© Springer 2010

Authors and Affiliations

  • Mina Nakagawa
    • 1
    • 2
  • Naoya Sakamoto
    • 1
    • 2
  • Mayumi Ueyama
    • 1
  • Kaoru Mogushi
    • 3
  • Satoshi Nagaie
    • 3
  • Yasuhiro Itsui
    • 1
    • 4
  • Seishin Azuma
    • 1
  • Sei Kakinuma
    • 1
    • 2
  • Hiroshi Tanaka
    • 3
  • Nobuyuki Enomoto
    • 5
  • Mamoru Watanabe
    • 1
  1. 1.Department of Gastroenterology and HepatologyTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department for Hepatitis ControlTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Information Center for Medical ScienceTokyo Medical and Dental UniversityTokyoJapan
  4. 4.Department of Internal MedicineSoka Municipal HospitalSaitamaJapan
  5. 5.First Department of Internal MedicineUniversity of YamanashiYamanashiJapan