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
- 123 Downloads
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.
KeywordsHepatitis C virus (HCV) Chronic hepatitis C PEG-IFN plus RBV therapy Combination therapy Interferon sensitivity determining region (ISDR)
Hepatitis C virus
Interferon sensitivity determining region
Body mass index
- ITT analysis
- PP analysis
Per protocol analysis
Sustained virological response
End of treatment response
Double stranded RNA-dependent protein kinase
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.
- 7.Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426–32.CrossRefPubMedGoogle Scholar
- 11.Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, et al. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest. 1995;96:224–30.CrossRefPubMedGoogle Scholar
- 16.Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, et al. 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. Intervirology. 2005;48:372–80.CrossRefPubMedGoogle Scholar
- 24.Sarrazin C, Berg T, Lee JH, Teuber G, Dietrich CF, Roth WK, et al. Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy. J Hepatol. 1999;30:1004–13.CrossRefPubMedGoogle Scholar
- 26.Hung CH, Chen CH, Lee CM, Wu CM, Hu TH, Wang JH, et al. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J Viral Hepatitis. 2008;15:58–65.Google Scholar
- 28.Mori N, Imamura M, Kawakami Y, Saneto H, Kawaoka T, Takaki S, et al. Randomized trial of high-dose interferon-alpha-2b combined with ribavirin in patients with chronic hepatitis C: correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy. J Med Virol. 2009;81:640–9.CrossRefPubMedGoogle Scholar
- 29.Yen YH, Hun CH, Hu TH, Chen CH, Wu CM, Vvang JH, et al. Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209–2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin. Aliment Pharmacol Ther. 2008;27:72–9.PubMedCrossRefGoogle Scholar
- 31.Murayama M, Katano Y, Nakano I, Ishigami M, Hayashi K, Honda T, et al. A mutation in the interferon sensitivity-determining region is associated with responsiveness to interferon-ribavirin combination therapy in chronic hepatitis patients infected with a Japan-specific subtype of hepatitis C virus genotype 1b. J Med Virol. 2007;79:35–40.CrossRefPubMedGoogle Scholar
- 35.Chayama K, Tsubota A, Kobayashi M, Okamoto K, Hashimoto M, Miyano Y, et al. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology. 1997;25:745–9.CrossRefPubMedGoogle Scholar
- 41.Watanabe H, Enomoto N, Nagayama K, Izumi N, Marumo F, Sato C, et al. Number and position of mutations in the interferon (IFN) sensitivity-determining region of the gene for nonstructural protein 5A correlate with IFN efficacy in hepatitis C virus genotype 1b infection. J Infect Dis. 2001;183:1195–203.CrossRefPubMedGoogle Scholar
- 47.Ferenci P, Laferl H, Scherzer TM, Maieron A, Hofer H, Stauber R, et al. Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C types 1 and 4 patients with slow virologic response. Gastroenterology 2009 [Epub ahead of print].Google Scholar
- 48.Watanabe S, Enomoto N, Koike K, Izumi N, Takikawa H, Hashimoto E, et al. Prolonged treatment with pegylated interferon a 2b plus ribavirin improves sustained virological response in chronic hepatitis C genotype 1 patients with late response in a clinical real-life setting in Japan. Hepatol Res 2009 [Epub ahead of print].Google Scholar