Journal of Gastroenterology

, Volume 45, Issue 6, pp 656–665 | Cite as

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 SakamotoEmail author
  • 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



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.


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.


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).


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.


Hepatitis C virus (HCV) Chronic hepatitis C PEG-IFN plus RBV therapy Combination therapy Interferon sensitivity determining region (ISDR) 



Hepatitis C virus




Polyethylene glycol


Pegylated-interferon-alpha 2b




Interferon sensitivity determining region


Body mass index


Alanine transaminase


Double mutant

ITT analysis

Intention-to-treat analysis

PP analysis

Per protocol analysis


Sustained virological response


End of treatment response


Double stranded RNA-dependent protein kinase


Toll-like receptor


Myeloid differentiation primary response gene 88



This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology-Japan; the Japan Society for the Promotion of Science; the Ministry of Health, Labour and Welfare-Japan; the Japan Health Sciences Foundation; the Miyakawa Memorial Research Foundation; and the National Institute of Biomedical Innovation. The following hospitals participated in the Ochanomizu-Liver Conference Study Group: Oume City General Hospital, Kashiwa City Hospital, Kudanzaka Hospital, Showa General Hospital, Shuwa General Hospital, Soka Municipal Hospital, Tama-Nambu Chiiki Hospital, Tuchiura Kyodo General Hospital, Tokyo Kyosai Hospital, Tokyo Metropolitan Ohtsuka Hospital, Tokyo Metropolitan Fuchu Hospital, Tokyo Metropolitan Bokutoh Hospital, Toride Kyodo General Hospital, Nakano General Hospital, Hokushin General Hospital, Mishima Social Insurance Hospital, Musashino Red Cross Hospital, Yokosuka Kyosai Hospital, Yokohama City Minato Red Cross Hospital.


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Copyright information

© Springer 2010

Authors and Affiliations

  • Mina Nakagawa
    • 1
    • 2
  • Naoya Sakamoto
    • 1
    • 2
    Email author
  • 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

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