Journal of Gastroenterology

, Volume 46, Issue 7, pp 929–937 | Cite as

Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients

  • Itaru Ozeki
  • Jun Akaike
  • Yoshiyasu Karino
  • Tomohiro Arakawa
  • Yasuaki Kuwata
  • Takumi Ohmura
  • Takahiro Sato
  • Naohiro Kamiya
  • Ichimaro Yamada
  • Kazuaki Chayama
  • Hiromitsu Kumada
  • Joji ToyotaEmail author
Original Article—Liver, Pancreas, and Biliary Tract



Anemia is commonly observed as a side effect in a treatment with protease inhibitors combined with peginterferon alpha and ribavirin for hepatitis C virus infection. This study assessed the safety, tolerability, viral kinetics, and selection of variants in telaprevir monotherapy for 24 weeks, and outcomes of the off-study treatment with peginterferon alpha-2b and ribavirin among Japanese female patients at a median age of 54 years who were difficult to treat with the standard therapy (peginterferon alpha-2b and ribavirin) alone in Japan.


Four treatment-naïve patients with chronic hepatitis C virus subtype 1b infection received telaprevir (750 mg every 8 h) alone for 24 weeks. All patients then started the off-study treatment with peginterferon alpha-2b and ribavirin. Safety, tolerability, hepatitis C virus RNA levels, and emergence of telaprevir-resistant variants were monitored.


During the 24 weeks of telaprevir monotherapy, there was no discontinuation due to adverse events, but 2 patients stopped the intake at weeks 6 and 15 because of viral breakthrough. Emergence of telaprevir-resistant variants was observed in 3 patients who showed viral breakthrough. These variants were eliminated by the off-study treatment, and sustained virological response was achieved in all patients.


Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin.


Hepatitis C therapy Telaprevir Ribavirin Anemia 


  1. 1.
    Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20:1–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med. 2000;132:296–305.PubMedGoogle Scholar
  4. 4.
    Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362:2095–100.PubMedCrossRefGoogle Scholar
  5. 5.
    Fried MW, Shiffman M, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010;138:447–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50:899–909.PubMedCrossRefGoogle Scholar
  9. 9.
    Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839–50.PubMedCrossRefGoogle Scholar
  10. 10.
    McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, 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.
    McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292–303.PubMedCrossRefGoogle Scholar
  12. 12.
    Okamoto H, Mishiro S. Genetic heterogeneity of hepatitis C virus. Intervirology. 1994;37:68–76.PubMedGoogle Scholar
  13. 13.
    Yoshizawa H, Tanaka J, Miyakawa Y. National prevention of hepatocellular carcinoma in Japan based on epidemiology of hepatitis C virus infection in the general population. Intervirology. 2006;49:7–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Chung H, Ueda T, Kudo M. Changing trends in hepatitis C infection over the past 50 years in Japan. Intervirology. 2010;53:39–43.PubMedCrossRefGoogle Scholar
  15. 15.
    Honda T, Katano Y, Urano F, Murayama M, Hayashi K, Ishigami M, et al. Efficacy of ribavirin plus interferon-α in patients aged 60 years with chronic hepatitis C. J Gastroenterol Hepatol. 2007;22:989–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, et al. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral load. Dig Dis Sci. 2009;54:1317–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Laperche S, Lunel F, Izopet J, Alain S, Dény P, Duverlie G, et al. Comparison of hepatitis C virus NS5b and 5′ noncoding gene sequencing methods in a multicenter study. J Clin Microbiol. 2005;43:733–9.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki 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
  20. 20.
    Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Müh U, Welker M, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767–77.PubMedCrossRefGoogle Scholar
  21. 21.
    Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology. 2007;46:631–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology. 2009;50:1709–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Qiu P, Sanfiorenzo V, Curry S, Guo Z, Liu S, Skelton A, et al. Identification of HCV protease inhibitor resistance mutations by selection pressure-based method. Nucleic Acids Res. 2009;37:e74.PubMedCrossRefGoogle Scholar
  24. 24.
    Perelson AS, Ribeiro RM. Estimating drug efficacy and viral dynamic parameters: HIV and HCV. Stat Med. 2008;27:4647–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, 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
  27. 27.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, 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
  28. 28.
    Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, et al. Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study. J Gastroenterol. 2009;44:952–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Suzuki F, Suzuki Y, Akuta N, Sezaki H, Yatsuji H, Arase Y, et al. Sustained virological response in a patient with chronic hepatitis C treated by monotherapy with the NS3-4A protease inhibitor telaprevir. J Clin Virol. 2010;47:76–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Suzuki F, Akuta N, Suzuki Y, Sezaki H, Yatsuji H, Kawamura Y, et al. Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks. Hepatol Res. 2009;39:1056–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Hiramatsu N, Oze T, Yakushijin T, Inoue Y, Igura T, Mochizuki K, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586–94.PubMedCrossRefGoogle Scholar
  32. 32.
    Conjeevaram HS, Fried MW, Jeffers LJ, Terrault NA, Wiley-Lucas TE, Afdhal N, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology. 2005;42:962–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Itaru Ozeki
    • 1
  • Jun Akaike
    • 1
  • Yoshiyasu Karino
    • 1
  • Tomohiro Arakawa
    • 1
  • Yasuaki Kuwata
    • 1
  • Takumi Ohmura
    • 1
  • Takahiro Sato
    • 1
  • Naohiro Kamiya
    • 2
  • Ichimaro Yamada
    • 2
  • Kazuaki Chayama
    • 3
  • Hiromitsu Kumada
    • 4
  • Joji Toyota
    • 1
    Email author
  1. 1.Department of GastroenterologySapporo Kosei General HospitalSapporoJapan
  2. 2.Research and Development DivisionMitsubishi Tanabe Pharma CorporationTokyoJapan
  3. 3.Programs for Biomedical Research, Division of Frontier Medical Science, Department of Medical and Molecular Science, Graduate School of Biomedical ScienceHiroshima UniversityHiroshimaJapan
  4. 4.Department of HepatologyToranomon HospitalKawasakiJapan

Personalised recommendations