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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

  • Original Article—Liver, Pancreas, and Biliary Tract
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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.

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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

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Acknowledgments

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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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Mina Nakagawa, Naoya Sakamoto, Mayumi Ueyama, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma & Mamoru Watanabe

  2. Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan

    Mina Nakagawa, Naoya Sakamoto & Sei Kakinuma

  3. Information Center for Medical Science, Tokyo Medical and Dental University, Tokyo, Japan

    Kaoru Mogushi, Satoshi Nagaie & Hiroshi Tanaka

  4. Department of Internal Medicine, Soka Municipal Hospital, Saitama, Japan

    Yasuhiro Itsui

  5. First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan

    Nobuyuki Enomoto

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  1. Mina Nakagawa
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  2. Naoya Sakamoto
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  3. Mayumi Ueyama
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  4. Kaoru Mogushi
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  5. Satoshi Nagaie
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  6. Yasuhiro Itsui
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  7. Seishin Azuma
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  8. Sei Kakinuma
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  9. Hiroshi Tanaka
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  10. Nobuyuki Enomoto
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  11. Mamoru Watanabe
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Corresponding author

Correspondence to Naoya Sakamoto.

Additional information

M. Nakagawa and N. Sakamoto contributed equally to this work.

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Nakagawa, M., Sakamoto, N., Ueyama, M. et al. 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. J Gastroenterol 45, 656–665 (2010). https://doi.org/10.1007/s00535-009-0195-7

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  • DOI: https://doi.org/10.1007/s00535-009-0195-7

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