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Journal of Gastroenterology

, Volume 49, Issue 12, pp 1548–1556 | Cite as

Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C

  • Hatsue Fujino
  • Michio Imamura
  • Yuko Nagaoki
  • Yoshiiku Kawakami
  • Hiromi Abe
  • C. Nelson Hayes
  • Hiromi Kan
  • Takayuki Fukuhara
  • Tomoki Kobayashi
  • Keiichi Masaki
  • Atsushi Ono
  • Takashi Nakahara
  • Youji Honda
  • Noriaki Naeshiro
  • Ayako Urabe
  • Satoe Yokoyama
  • Daisuke Miyaki
  • Eisuke Murakami
  • Tomokazu Kawaoka
  • Nobuhiko Hiraga
  • Masataka Tsuge
  • Akira Hiramatsu
  • Hideyuki Hyogo
  • Hiroshi Aikata
  • Shoichi Takahashi
  • Daiki Miki
  • Hidenori Ochi
  • Waka Ohishi
  • Kazuaki ChayamaEmail author
  • Hiroshima Liver Study Group
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN) treatment compared to younger patients. The efficacy of telaprevir (TVR) and PEG-IFN plus ribavirin combination therapy and the predictive value of recently identified IFN lambda (IFNL) 4 polymorphisms on the outcome of therapy for older patients have not been addressed.

Methods

We assessed predictive factors for sustained virological response (SVR) to triple therapy in 226 younger (≤65 years) and 87 older (>65 years) Japanese patients with chronic genotype 1 hepatitis C. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.

Results

The SVR rate for older patients was slightly lower than for younger patients (69 vs. 82 %, P = 0.043). In the older group, the SVR rate for patients with the IFNL4 TT/TT genotype was significantly higher than patients with TT/ΔG or ΔG/ΔG genotypes (81.8 and 42.9 %, P = 0.003). In multivariate regression analysis, rapid virological response (OR 36.601, P = 0.002) and IFNL4 TT/TT genotype (OR 19.502, P = 0.009) were identified as significant independent predictors for SVR in older patients. Treatment-related decreases in hemoglobin and increases in serum creatinine were higher in older patients than younger patients. Reduction of initial TVR dose to 1,500 mg per day alleviated these adverse events without compromising SVR rate in older patients.

Conclusions

Analysis of IFNL4 polymorphisms is a valuable predictor in older patients receiving TVR triple therapy. 1,500 mg per day is a suitable initial TVR dose for older Japanese patients.

Keywords

Hepatitis C virus Telaprevir Older patients IFNL4 RVR 

Notes

Acknowledgments

This work was supported by Grants-in-Aid for scientific research and development from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology, Government of Japan. The funders had no role in the study's design, data collection and analysis, the decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

The authors thank the other members of the SNP Research Center for assistance with various aspects of this study. Part of this work was carried out at the Analysis Center of Life Science, Hiroshima University. Hiroshima Liver Study Group. Members of the Hiroshima Liver Study Group (listed in alphabetical order) include Shiomi Aimitsu (Hiroshima General Hospital of West Japan Railway Company, Hiroshima, Japan), Yasuyuki Aisaka (Hiroshima Red Cross Hospital, Hiroshima, Japan), Hajime Amano (Onomichi General Hospital, Hiroshima, Japan), Tatsuya Amimoto (Amimoto Clinic, Hiroshima, Japan), Keiko Arataki (Hiroshimakinen Hospital, Hiroshima, Japan), Nobuyuki Asada (Asada Clinic, Hiroshima, Japan), Takahiro Azakami (Miyoshi Cyuo Hospital, Hiroshima, Japan), Kunio Ishida (Hiroshima General Hospital, Hiroshima, Japan), Hiroto Ishihara (Hiroshima-Nishi Medical Center, Hiroshima, Japan), Tomokazu Ishitobi (Hiroshima Chuden Hospital, Hiroshima, Japan), Hiroyuki Ito (Saiseikai Kure Hospital, Hiroshima, Japan), Koji Kamada (Shobara Red Cross Hospital, Hiroshima, Japan), Masaya Kamiyasu (Kamiyasu Clinic, Hiroshima, Japan), Hiroiku Kawakami (Kawakami Clinic, Hiroshima, Japan), Shinsuke Kira (Saiseikai Hiroshima Hospital, Hiroshima, Japan), Mikiya Kitamoto (Hiroshima Prefectural Hospital, Hiroshima, Japan), Hideaki Kodama (Hiroshima Kinen Hospital, Hiroshima, Japan), Hiroshi Kohno (Kure Medical Center, Hiroshima, Japan), Hirotaka Kohno (Kure Medical Center, Hiroshima, Japan), Toshiyuki Masanaga (Masanaga Clinic, Hiroshima, Japan), Toshio Miura (Akitsu Prefectural Hospital, Hiroshima, Japan), Nami Mori (Hiroshima Red Cross Hospital, Hiroshima, Japan), Takashi Moriya (Chugoku Rousai Hospital, Hiroshima, Japan), Yutaka Nabeshima (Chuden Hospital, Hiroshima, Japan), Yuko Nagaoki (Higashihiroshima Medical Center, Hiroshima, Japan), Toshio Nakamura (Nakamura Clinic, Hiroshima, Japan), Toshio Nakanishi (Miyoshi Cyuo Hospital, Hiroshima, Japan), Ryo Nakashio (Nakashio Clinic, Hiroshima, Japan), Michihiro Nonaka (Hiroshima General Hospital, Hiroshima, Japan), Makoto Ohbayashi (Onomichi General Hospital, Hiroshima, Japan), Shintaro Takaki (Hiroshima Red Cross Hospital, Hiroshima, Japan), Eichi Takesaki (Higashihiroshima Medical Center, Hiroshima, Japan), Toru Tamura (Mazda Hospital, Hiroshima, Japan), Keiji Tsuji (Hiroshima City Asa Hospital, Hiroshima, Japan), Koji Waki (Hiroshima City Asa Hospital, Hiroshima, Japan), Masashi Watanabe (Kuchiwa Clinic, Hiroshima, Japan), Syuji Yamaguchi (Kure Kyosai Hospital, Hiroshima, Japan), Keitaro Yamashina (Hiroshima General Hospital of West Japan Railway Company, Hiroshima, Japan).

Conflict of interest

K Chayama received research grants from MSD K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Meiji Seika Pharma Co., Ltd., and received lecture fees from MSD K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd.

References

  1. 1.
    NIH. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C 2002 (June 10–12, 2002). Gastroenterology. 2002;123:2082–99.Google Scholar
  2. 2.
    Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med. 1992;327:1906–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol. 2013;58:495–501.PubMedCrossRefGoogle Scholar
  4. 4.
    Tanaka Y, Hanada K, Mizokami M, et al. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci USA. 2002;99:15584–9.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Lee SS, Heathcote EJ, Reddy KR, et al. Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40 KD). J Hepatol. 2002;37:500–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well. Ann Intern Med. 2004;140:370–81.PubMedGoogle Scholar
  7. 7.
    Kainuma M, Furusyo N, Kajiwara E, et al. Kyushu University Liver Disease Study Group pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol. 2010;16:4400–9.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Iwasaki Y, Ikeda H, Araki Y, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology. 2006;43:54–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Hiramatsu N, Oze T, Tsuda N, et al. Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy. Hepatol Res. 2006;35:185–9.PubMedGoogle Scholar
  10. 10.
    McHutchison JG, Everson GT, Gordon SC, PROVE1 Study Team, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.PubMedCrossRefGoogle Scholar
  11. 11.
    Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Hayashi N, Okanoue T, Tsubouchi H, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19:e134–42.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Chayama K, Hayes CN, Ohishi W, et al. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48:1–12.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Furusyo N, Ogawa E, Nakamuta M, et al. Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C. J Hepatol. 2013;59:205–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRefGoogle Scholar
  17. 17.
    Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Nishiguchi S, et al. Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial. ReGIT-J study. J Gastroenterol. 2013;. doi: 10.1007/s00535-013-0785-2.Google Scholar
  20. 20.
    Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Chayama K, Hayes CN, Abe H, et al. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis. 2011;204:84–93.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Akuta N, Suzuki F, Kawamura Y, et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol. 2007;46:403–10.PubMedCrossRefGoogle Scholar
  24. 24.
    Akuta N, Suzuki F, Sezaki H, et al. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol. 2006;78:83–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Fellay J, Thompson A, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy-a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Suzuki F, Suzuki Y, Akuta N, et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology. 2011;53:415–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Ohnishi Y, Tanaka T, Ozaki K, et al. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.PubMedCrossRefGoogle Scholar
  30. 30.
    Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C. Intervirology. 2007;50:16–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Huang CF, Yang JF, Dai CY, et al. Efficacy and safety of pegylated interferon combination with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis. 2010;201:751–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Honda T, Katano Y, Shimizu J, et al. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int. 2010;30:527–37.PubMedCrossRefGoogle Scholar
  33. 33.
    Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997–1002.PubMedCrossRefGoogle Scholar
  34. 34.
    Suzuki F, Suzuki Y, Sezaki H, et al. Exploratory study on telaprevir given every 8 h at 500 mg or 750 mg with peginterferon-alpha-2b and ribavirin in hepatitis C patients. Hepatol Res. 2013;43:691–701. doi: 10.1111/hepr.12009.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Hatsue Fujino
    • 1
  • Michio Imamura
    • 1
  • Yuko Nagaoki
    • 1
  • Yoshiiku Kawakami
    • 1
  • Hiromi Abe
    • 1
  • C. Nelson Hayes
    • 1
  • Hiromi Kan
    • 1
  • Takayuki Fukuhara
    • 1
  • Tomoki Kobayashi
    • 1
  • Keiichi Masaki
    • 1
  • Atsushi Ono
    • 1
  • Takashi Nakahara
    • 1
  • Youji Honda
    • 1
  • Noriaki Naeshiro
    • 1
  • Ayako Urabe
    • 1
  • Satoe Yokoyama
    • 1
  • Daisuke Miyaki
    • 1
  • Eisuke Murakami
    • 1
  • Tomokazu Kawaoka
    • 1
  • Nobuhiko Hiraga
    • 1
  • Masataka Tsuge
    • 1
  • Akira Hiramatsu
    • 1
  • Hideyuki Hyogo
    • 1
  • Hiroshi Aikata
    • 1
  • Shoichi Takahashi
    • 1
  • Daiki Miki
    • 2
  • Hidenori Ochi
    • 2
  • Waka Ohishi
    • 3
  • Kazuaki Chayama
    • 1
    • 2
    Email author
  • Hiroshima Liver Study Group
  1. 1.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Laboratory for Digestive Diseases, Center for Genomic MedicineThe Institute of Physical and Chemical Research (RIKEN)HiroshimaJapan
  3. 3.Department of Clinical StudiesRadiation Effects Research FoundationHiroshimaJapan

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