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Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of simeprevir and peginterferon-α-2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection.

Methods

In CONCERTO-2, prior non-responders to IFN-based therapy (N = 106) received simeprevir (TMC435) 100 mg QD with PR for 12 (SMV12, n = 53) or 24 weeks (SMV24, n = 53) followed by response-guided therapy (RGT) with PR for 12/36 (SMV12) or 0/24 (SMV24) weeks. In CONCERTO-3, relapsers after IFN-based therapy (N = 49) received simeprevir 100 mg QD with PR for 12 weeks followed by RGT with PR for 12/36 weeks. Primary endpoints were the rates of sustained virologic response 12 weeks after treatment end (SVR12).

Results

SVR12 rates were 52.8 % (SMV12) and 35.8 % (SMV24) for prior non-responders, and 95.9 % for prior relapsers (SMV12; p ≤ 0.0001 vs null hypothesis, respectively). Most prior non-responders (SMV12: 81.1 %; SMV24: 73.6 %) and prior relapsers (95.9 %) met RGT criteria and completed PR to Week 24. Of these, 60.5 %, 48.7 %, and 95.7 %, respectively, achieved SVR12. Viral breakthrough occurred in 13.2 % (SMV12) and 11.3 % (SMV24) of prior non-responders; no viral breakthrough occurred in prior relapsers. Viral relapse occurred in 38.6 % (SMV12) and 51.1 % (SMV24) of prior non-responders and 8.2 % of prior relapsers. Simeprevir with PR was generally well tolerated in both studies.

Conclusion

Re-treatment with 12 weeks of simeprevir QD with PR provided high SVR in treatment-experienced patients with chronic HCV genotype 1 infection, and allowed most patients to complete treatment in 24 weeks.

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References

  1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17:107–15.

    Article  CAS  PubMed  Google Scholar 

  2. Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. Intervirology. 2010;53:39–43.

    Article  PubMed  Google Scholar 

  3. Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K. Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol. 2009;44(Suppl 19):102–7.

    Article  PubMed  Google Scholar 

  4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55:245–64.

    Article  Google Scholar 

  5. Izumi N. Diagnostic and treatment algorithm of the Japanese society of hepatology: a consensus-based practice guideline. Oncology. 2010;78(Suppl 1):78–86.

    Article  PubMed  Google Scholar 

  6. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.

    Article  CAS  PubMed  Google Scholar 

  7. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–65.

    Article  CAS  PubMed  Google Scholar 

  8. Iino S, Okita K, Omata M, Kumada H, Hayashi N, Tanigawa H. Clinical efficacy of PEG-interferon alpha-2b and ribavirin combination therapy for 48 weeks in chronic hepatitis C patients with genotype 1 and high viral load: retrospective comparison with interferon alpha-2b and ribavirin combination therapy for 24 weeks. Kantansui. 2004;49:1099–121.

    Google Scholar 

  9. Kuboki M, Iino S, Okuno T, Omata M, Kiyosawa K, Kumada H, et al. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. J Gastroenterol Hepatol. 2007;22:645–52.

    CAS  PubMed  Google Scholar 

  10. Jacobson IM, Gonzalez SA, Ahmed F, Lebovics E, Min AD, Bodenheimer HC Jr, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol. 2005;100:2453–62.

    Article  CAS  PubMed  Google Scholar 

  11. Welsch C, Jesudian A, Zeuzem S, Jacobson I. New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. Gut. 2012;61(Suppl 1):i36–46.

    Article  CAS  PubMed  Google Scholar 

  12. Chayama K, Hayes CN, Ohishi W, Kawakami Y. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48:1–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hayashi N, Okanoue T, Tsubouchi H, Toyota J, Chayama K, Kumada H. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.

    Article  CAS  PubMed  Google Scholar 

  15. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014–24.

    Article  CAS  PubMed  Google Scholar 

  16. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.

    Article  CAS  PubMed  Google Scholar 

  17. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int. 2012;32(Suppl 1):32–8.

    Article  CAS  PubMed  Google Scholar 

  19. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2014;49:138–47.

    Google Scholar 

  21. Kaiser S, Lutze B, Hass HG, Werner CR. High sustained virologic response rates in HCV genotype 1 relapser patients retreated with peginterferon alfa-2a (40KD) plus ribavirin for 72 weeks. Hepatology. 2008;48:1140A (abstract).

    Google Scholar 

  22. Jensen DM, Marcellin P, Freilich B, Andreone P, Di BA, Brandao-Mello CE, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med. 2009;150:528–40.

    Article  PubMed  Google Scholar 

  23. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146:430–41.e6.

    Google Scholar 

  24. Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, et al. Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther. 2011;16:1021–33.

    Article  CAS  PubMed  Google Scholar 

  25. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–28.

    Article  CAS  PubMed  Google Scholar 

  26. Martinot-Peignoux M, Stern C, Maylin S, Ripault MP, Boyer N, Leclere L, et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology. 2010;51:1122–6.

    Article  CAS  PubMed  Google Scholar 

  27. Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobsen I, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58:1918–29.

    Article  CAS  PubMed  Google Scholar 

  28. Reddy KR, Lin F, Zoulim F. Response-guided and -unguided treatment of chronic hepatitis C. Liver Int. 2012;32(Suppl 1):64–73.

    Article  CAS  PubMed  Google Scholar 

  29. Pol S, Aerssens J, Zeuzem S, et al. Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure. J Hepatol. 2013;58:883–9.

    Article  CAS  PubMed  Google Scholar 

  30. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54:1878–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol. 2011;55:192–206.

    Article  CAS  PubMed  Google Scholar 

  32. Huisman MT, Snoeys J, Monbaliu J, Martens M, Sekar V, Raoof A. In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters. Poster 278 presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, USA, 29 Oct-2 Nov, 2010.

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Acknowledgments

The authors would like to thank all patients, their families, principal investigators, and their staff at the following 28 study sites (in alphabetical order): Akio Ido (Kagoshima University Medical and Dental Hospital); Akito Sakai (Kanazawa University Hospital); Eiji Mita (National Hospital Organization Osaka National Hospital); Harumasa Yoshihara (Osaka Rosai Hospital); Hideki Hagiwara (Kansai Rosai Hospital); Hideyuki Nomura (Shin-Kokura Hospital); Hiromitsu Kumada (Toranomon Hospital); Hiroshi Yatsuhashi (National Hospital Organization Nagasaki Medical Center); Katsuaki Tanaka (Yokohama City University Medical Center); Kawakami Yoshiiku (Hiroshima University Hospital); Kiyomi Yasuda (Kiyokawa Hospital); Masashi Mizokami (Kohnodai Hospital, National Center for Global Health and Medicine); Masatoshi Kudo (Kinki University Hospital); Mina Nakagawa (Tokyo Medical And Dental University Hospital Faculty of Medicine); Kiyohide Kioka (Osaka City General Hospital); Namiki Izumi (Musashino Red Cross Hospital); Syuhei Nishiguchi (The Hospital of Hyogo College of Medicine); Takayoshi Ito (Showa University Hospital); Takeji Umemura (Shinshu University Hospital); Tatsuya Ide (Kurume University Hospital); Tetsuo Takehara (Osaka University Hospital); Toshifumi Ito (Osaka Koseinenkin Hospital); Toshihide Shima (Saiseikai Suita Hospital); Yoichi Hiasa (Ehime University Hospital); Yoshito Ito (University Hospital, Kyoto Prefectural University of Medicine); Yutaka Sasaki (Kumamoto University Hospital); Yoshiyasu Karino (Sapporo Kosei General Hospital). These studies were funded by Janssen Pharmaceutical K.K. Medical writing support was provided by Julie Adkins on behalf of Complete Medical Communications and was funded by Janssen Research & Development.

Conflict of interest

Namiki Izumi received honoraria for lectures from MSD Co., Chugai Co., Daiichi-Sankyo Co., and Bayer Co.. Norio Hayashi, Hiromitsu Kumada, Takeshi Okanoue, and Hiroshi Yatsuhashi have no conflict of interest. Hirohito Tsubouchi has an advisory relationship with Janssen Paharmacutical K.K. Mai Kato, Ki Ritou, Yuji Komada, Chiharu Seto, and Shoichiro Goto are employees of Janssen Pharmaceutical K.K.

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Authors and Affiliations

  1. Musashino Red-Cross Hospital, Tokyo, Japan

    Namiki Izumi

  2. Kansai Rosai Hospital, Hyogo, Japan

    Norio Hayashi

  3. Toranomon Hospital, Tokyo, Japan

    Hiromitsu Kumada

  4. Saiseikai Suita Hospital, Osaka, Japan

    Takeshi Okanoue

  5. Kagoshima University Medical and Dental Hospital, Kagoshima, Japan

    Hirohito Tsubouchi

  6. National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan

    Hiroshi Yatsuhashi

  7. Research and Development, Janssen Pharmaceutical K.K, Tokyo, Japan

    Mai Kato, Rito Ki, Yuji Komada, Chiharu Seto & Shoichiro Goto

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  1. Namiki Izumi
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Correspondence to Namiki Izumi.

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Izumi, N., Hayashi, N., Kumada, H. et al. Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies. J Gastroenterol 49, 941–953 (2014). https://doi.org/10.1007/s00535-014-0949-8

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  • DOI: https://doi.org/10.1007/s00535-014-0949-8

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