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Journal of Gastroenterology

, Volume 44, Issue 9, pp 952–963 | Cite as

Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study

  • Takeshi OkanoueEmail author
  • Yoshito Itoh
  • Hiroaki Hashimoto
  • Kohichiroh Yasui
  • Masahito Minami
  • Tetsuo Takehara
  • Eiji Tanaka
  • Morikazu Onji
  • Joji Toyota
  • Kazuaki Chayama
  • Kentaro Yoshioka
  • Namiki Izumi
  • Norio Akuta
  • Hiromitsu Kumada
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Chronic hepatitis C (CHC) genotype 1b patients with high viral load are resistant to peginterferon (PEG-IFN) and ribavirin (RBV) combination therapy, especially older and female patients.

Methods

To elucidate the factors affecting early and sustained viral responses (EVR and SVR), 409 genotype 1b patients CHC with high viral loads who had received 48 weeks of PEG-IFN/RBV therapy were enrolled. The amino acid (aa) sequences of the HCV core at positions 70 and 91 and of the interferon sensitivity determining region (ISDR) were analyzed. Host factors, viral factors, and treatment-related factors were subjected to multivariate analysis.

Results

Male gender, low HCV RNA load, high platelet count, two or more aa mutations of ISDR, and wild type of core aa 70 were independent predictive factors for SVR. In patients with over 80% adherences to both PEG-IFN and RBV, male gender, mild fibrosis stage, and wild type of core aa 70 were independent predictors for SVR.

Conclusions

Independent predictive factors for SVR were: no aa substitution at core aa 70, two or more aa mutations in the ISDR, low viral load, high values of platelet count, mild liver fibrosis and male gender.

Keywords

Chronic hepatitis C Peginterferon and ribavirin Core amino acid Interferon sensitivity determining region 

Abbreviations

CHC

Chronic hepatitis C

PEG-IFN

Peginterferon

RBV

Ribavirin

RVR

Rapid viral response

cEVR

Complete early viral response

LVR

Late viral response

ETR

End of treatment response

NR

Non response

SVR

Sustained viral response

ISDR

Interferon sensitivity determining region

Aa

Amino acid

ALT

Alanine aminotransferase

PLT

Platelet

HCC

Hepatocellular carcinoma

Notes

Acknowledgments

We express our thanks to other members of the Study Group of Optimal Treatment of Viral Hepatitis; Hideyuki Nomura, Shin-Kokura Hospital; Yoshiyuki Ueno, University of Tohoku; Hisataka Moriwaki, Gifu University; Makoto Oketani, Kagoshima University Graduate School of Medical and Dental Sciences; Masataka Seike, Oita University; Hiroshi Yotsuyanagi, The University of Tokyo. This study was supported in part by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan.

References

  1. 1.
    Manns MP, McHutchinson JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  2. 2.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonzales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Hadziyannis S, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alfa-2a plus ribavirin combination therapy in chronic hepatitis C. a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;40:346–55.Google Scholar
  4. 4.
    Hiramatsu N, Kurashige N, Oze T, Takehara T, Tamura S, Kasahara A, et al. Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C. Hepatol Res. 2008;38:52–9.PubMedCrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    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;54:1317–24Google Scholar
  7. 7.
    Puoti C, Castellacci R, Montagness F, Zaltron S, Stornaiuolo G, Bergami N, et al. Histological and virological features and follow-up of HCV carriers with normal aminotransferase levels: the Italian Study of the Asymptomatic C Carriers (ISACC). J Hepatol. 2002;37:117–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Hui CK, Belaye T, Montegrande K, Wright TL. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase. J Hepatol. 2003;38:511–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Okanoue T, Makiyama A, Nakayama M, Sumida Y, Mitsuyoshi H, Nakajima T, et al. A follow-up study to determine the value of liver biopsy and need for antiviral therapy for hepatitis C virus carriers with persistently normal serum aminotransferase. J Hepatol. 2005;43:599–605.PubMedCrossRefGoogle Scholar
  10. 10.
    Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index in an independent risk factor for non response to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38:639–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Walsh MJ, Jonsson JR, Richardson MM, Lipka GM, Purdi DM, Clouston AD, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55:604–9.CrossRefGoogle Scholar
  12. 12.
    Patton HM, Patel K, Behling C, Bylund C, Blatt LM, Vallee M, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004;40:484–90.PubMedCrossRefGoogle Scholar
  13. 13.
    Asselah T, Rubbia-Brandt L, Marcellin M, Negro F. Steatosis in chronic hepatitis C: why does it really matter? Gut. 2006;55:123–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, Cammozzi M, et al. Peginterferon alfa-2b plus ribavirin for native patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol. 2004;41:474–81.PubMedCrossRefGoogle Scholar
  16. 16.
    Everson GT, Hoefs JC, Seeff LB, Bonkovsky HL, Naishadham D, Shiffman ML, et al. Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial. Hepatology. 2006;44:1675–84.PubMedCrossRefGoogle Scholar
  17. 17.
    McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy R. Peginterferon alfa-2a (40kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004;39:1702–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Muir AJ, Bornstein JD, Killenberg PG, Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa 2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomized trial of interferon alpha 2b plus ribavirin for 48 weeks or 24 weeks versus interferon alpha 2b plus placebo for 48 weeks for treatment for chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, et al. Mutations in the nonstructural protein 5 A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med. 1996;334:77–81.PubMedCrossRefGoogle Scholar
  22. 22.
    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 in interferon-ribavirin combination therapy. Intervirology. 2005;48:372–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, et al. Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J Virol. 2007;81:8211–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Goncales FL, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a ribavirin. J Hepatol. 2005;43:425–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Moucari R, Ripault M-P, Oules V, Martinot-Peignoux M, Asselah T, Boyer N, et al. High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy. J Hepatol. 2007;46:596–604.PubMedCrossRefGoogle Scholar
  27. 27.
    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 1a: amino acid substitutions in the core region and low-density lipoprotein cholesterol level. J Hepatol. 2007;46:403–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Desmet VJ, Gerber M, Hoofnagle JH, Manna M, Scheuer PJ. Classification of chronic hepatitis: grading and staging. Hepatology. 1994;19:1513–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, et al. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA. 1990;87:9524–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Okanoue T, Itoh Y, Minami M, Sakamoto S, Yasui K, Sakamoto M, et al. Interferon therapy lowers the rate of progression to hepatocellualr carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients. J Hepatol. 1999;30:653–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Okanoue T, Itoh Y, Minami M, Hashimoto H, Yasui K, Yotsuyanagi H, et al. Guidelines for the antiviral therapy of hepatitis C virus carriers with normal serum aminotransferase based on platelet count. Hepatol Res. 2008;38:27–36.PubMedCrossRefGoogle Scholar
  32. 32.
    Iwasaki Y, Ikeda H, Araki Y, Osawa T, Kita K, Ando M, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis. Hepatology. 2006;43:54–63.PubMedCrossRefGoogle Scholar
  33. 33.
    El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H. Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology. 2008;48:38–47.PubMedCrossRefGoogle Scholar
  34. 34.
    Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Vallee M, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004;40:484–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Lagging M, Romero A, Westin J, Norkrans G, Dhillon AP, Palwlosky JM, et al. IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology. 2006;44:1617–25.PubMedCrossRefGoogle Scholar
  36. 36.
    Pilli M, Zerbini A, Penna A, Orlandini A, Lukasiewicz E, Pawlotsky JM, et al. HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV Project). Gastroenterology. 2007;133:1132–43.PubMedCrossRefGoogle Scholar
  37. 37.
    Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, et al. Pretreatment prediction of virological response to peginterferon plus ribabirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology. 2008;48:1753–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Takeshi Okanoue
    • 1
    • 2
    Email author
  • Yoshito Itoh
    • 2
  • Hiroaki Hashimoto
    • 2
  • Kohichiroh Yasui
    • 2
  • Masahito Minami
    • 2
  • Tetsuo Takehara
    • 3
  • Eiji Tanaka
    • 4
  • Morikazu Onji
    • 5
  • Joji Toyota
    • 6
  • Kazuaki Chayama
    • 7
  • Kentaro Yoshioka
    • 8
  • Namiki Izumi
    • 9
  • Norio Akuta
    • 10
  • Hiromitsu Kumada
    • 10
  1. 1.Hepatology CenterSaiseikai Suita HospitalSuitaJapan
  2. 2.Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Department of Gastroenterology and HepatologyOsaka University Graduate School of MedicineSuitaJapan
  4. 4.Department of MedicineShinshu University School of MedicineMatsumotoJapan
  5. 5.Department of GastroenterologyEhime UniversityEhimeJapan
  6. 6.Departmet of GastroenterologySapporo-Kosei General HospitalSapporoJapan
  7. 7.Department of Medicine and Molecular Science, Graduate School of ScienceHiroshima UniversityHiroshimaJapan
  8. 8.Department of Hepato-Biliary-PancreasFujita Health ScienceToyoakeJapan
  9. 9.Department of Gastroenterology and HepatologyMusashino Red Cross HospitalMusashinoJapan
  10. 10.Department of Hepatology, Toranomon HospitalKawasakiJapan

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