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Table of Contents
Vol. 53, No. 1, 2010
Issue release date: January 2010
Section title: Original Article
Intervirology 2010;53:60–65
(DOI:10.1159/000252786)

PEG-IFNα/RBV Combination Therapy for Chronic Hepatitis C Patients Increases Serum Ferritin Level while It Improves Sustained Viral Response Rate

Yada N. · Kudo M. · Chung H. · Hayaishi S. · Takita M. · Ueda T. · Tatsumi C. · Hatanaka K. · Kitai S. · Ishikawa E. · Inoue T. · Hagiwara S. · Ueshima K.
Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
email Corresponding Author

Abstract

Objectives: We investigated the significance of serum ferritin levels in pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C (CHC) and examined its correlation with serum alanine aminotransferase (ALT) levels during therapy and response to the therapy. Methods: A total of 175 patients with CHC received the combination therapy. Correlations between serum ferritin levels and serum ALT levels at 12 and 24 weeks of therapy were examined. Differences in serum ferritin levels during therapy between patients with sustained viral response (SVR) and non-SVR were also examined. Results: Only 24 (13.7%) and 20 (11.4%) patients showed elevated serum ALT levels (≧70 IU/l) at 12 and 24 weeks of therapy, respectively. There was no correlation between serum ferritin levels and ALT levels. Ninety-five (54.3%) of 175 patients achieved SVR. Serum ferritin levels increased dramatically in both SVR and non-SVR groups after starting the therapy and were significantly higher in the SVR group throughout the therapy. Conclusions: Serum ferritin level increases during PEG-IFN and RBV combination therapy; however, it did not correlate with either serum ALT level or the total dose of RBV. Higher serum ferritin levels during combination therapy appear to be associated with favorable therapeutic response.

© 2010 S. Karger AG, Basel


  

Key Words

  • Alanine aminotransferase
  • Chronic hepatitis C
  • Combination therapy
  • Hemolytic anemia
  • Hepatic iron overload
  • Pegylated interferon
  • Ribavirin
  • Serum ferritin
  • Sustained viral response

References

  1. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.
  2. Ferrara F, Ventura P, Vegetti A, Guido M, Abbati G, Corradini E, Fattovich G, Ferrari C, Tagliazucchi M, Carbonieri A, Orlandini A, Fagiuoli S, Boninsegna S, Minola E, Rizzo G, Belussi F, Felder M, Massari M, Pozzato G, Bonetto S, Rovere P, Sardini C, Borghi A, Zeneroli ML, Toniutto P, Rossi E, Pietrangelo A: Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009;104:605–616.
  3. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, Rassam S, Fryden A, Reesink H, Bassendine M, Norkrans G, Cuypers T, Lelie N, Telfer P, Watson J, Weegink C, Sillikens P, Weiland O: Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996;25:591–598.
  4. Bodenheimer HC Jr , Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB: Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997;26:473–477.
  5. Abonyi ME, Lakatos PL: Ribavirin in the treatment of hepatitis C. Anticancer Res 2005;25:1315–1320.
  6. Lau JY, Tam RC, Liang TJ, Hong Z: Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002;35:1002–1009.
  7. Nagashima M, Kudo M, Chung H, Ishikawa E, Inoue T, Nakatani T, Dote K: Elevated serum ALT levels during pegylated interferon monotherapy may be caused by hepatic iron overload. Intervirology 2008;51(suppl 1):76–85.
  8. Fujita N, Sugimoto R, Urawa N, Araki J, Mifuji R, Yamamoto M, Horiike S, Tanaka H, Iwasa M, Kobayashi Y, Adachi Y, Kaito M: Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 2007;22:1886–1893.
  9. Arber N, Moshkowitz M, Konikoff F, Halpern Z, Hallak A, Santo M, Tiomny E, Baratz M, Gilat T: Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci 1995;40:2431–2433.
  10. Akiyoshi F, Sata M, Uchimura Y, Suzuki H, Tanikawa K: Hepatic iron stainings in chronic hepatitis C patients with low HCV RNA levels: a predictive marker for IFN therapy. Am J Gastroenterol 1997;92:1463–1466.
  11. Furutani T, Hino K, Okuda M, Gondo T, Nishina S, Kitase A, Korenaga M, Xiao SY, Weinman SA, Lemon SM, Sakaida I, Okita K: Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 2006;130:2087–2098.
  12. Kew MC: Hepatic iron overload and hepatocellular carcinoma. Cancer Lett 2008. DOI: 10.1016/j.canlet.2008.11.001.

    External Resources

  13. Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, Tanaka E, Onji M, Toyota J, Chayama K, Yoshioka K, Izumi N, Akuta N, Kumada H: 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;44:952–963.
  14. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  15. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: 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;96:224–230.
  16. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: 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;48:372–380.
  17. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: 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;46:403–410.
  18. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  19. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.

  

Author Contacts

Masatoshi Kudo, MD, PhD
Department of Gastroenterology and Hepatology
Kinki University School of Medicine
377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan)
Tel. +81 72 366 0221, Fax +81 72 367 2880, E-Mail m-kudo@med.kindai.ac.jp

  

Article Information

Published online: January 5, 2010
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 2, Number of References : 19

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 53, No. 1, Year 2010 (Cover Date: January 2010)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objectives: We investigated the significance of serum ferritin levels in pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C (CHC) and examined its correlation with serum alanine aminotransferase (ALT) levels during therapy and response to the therapy. Methods: A total of 175 patients with CHC received the combination therapy. Correlations between serum ferritin levels and serum ALT levels at 12 and 24 weeks of therapy were examined. Differences in serum ferritin levels during therapy between patients with sustained viral response (SVR) and non-SVR were also examined. Results: Only 24 (13.7%) and 20 (11.4%) patients showed elevated serum ALT levels (≧70 IU/l) at 12 and 24 weeks of therapy, respectively. There was no correlation between serum ferritin levels and ALT levels. Ninety-five (54.3%) of 175 patients achieved SVR. Serum ferritin levels increased dramatically in both SVR and non-SVR groups after starting the therapy and were significantly higher in the SVR group throughout the therapy. Conclusions: Serum ferritin level increases during PEG-IFN and RBV combination therapy; however, it did not correlate with either serum ALT level or the total dose of RBV. Higher serum ferritin levels during combination therapy appear to be associated with favorable therapeutic response.

© 2010 S. Karger AG, Basel


  

Author Contacts

Masatoshi Kudo, MD, PhD
Department of Gastroenterology and Hepatology
Kinki University School of Medicine
377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan)
Tel. +81 72 366 0221, Fax +81 72 367 2880, E-Mail m-kudo@med.kindai.ac.jp

  

Article Information

Published online: January 5, 2010
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 2, Number of References : 19

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 53, No. 1, Year 2010 (Cover Date: January 2010)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Article / Publication Details

First-Page Preview
Abstract of Original Article

Published online: 1/5/2010
Issue release date: January 2010

Number of Print Pages: 6
Number of Figures: 3
Number of Tables: 2

ISSN: 0300-5526 (Print)
eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.
  2. Ferrara F, Ventura P, Vegetti A, Guido M, Abbati G, Corradini E, Fattovich G, Ferrari C, Tagliazucchi M, Carbonieri A, Orlandini A, Fagiuoli S, Boninsegna S, Minola E, Rizzo G, Belussi F, Felder M, Massari M, Pozzato G, Bonetto S, Rovere P, Sardini C, Borghi A, Zeneroli ML, Toniutto P, Rossi E, Pietrangelo A: Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009;104:605–616.
  3. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, Rassam S, Fryden A, Reesink H, Bassendine M, Norkrans G, Cuypers T, Lelie N, Telfer P, Watson J, Weegink C, Sillikens P, Weiland O: Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996;25:591–598.
  4. Bodenheimer HC Jr , Lindsay KL, Davis GL, Lewis JH, Thung SN, Seeff LB: Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997;26:473–477.
  5. Abonyi ME, Lakatos PL: Ribavirin in the treatment of hepatitis C. Anticancer Res 2005;25:1315–1320.
  6. Lau JY, Tam RC, Liang TJ, Hong Z: Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002;35:1002–1009.
  7. Nagashima M, Kudo M, Chung H, Ishikawa E, Inoue T, Nakatani T, Dote K: Elevated serum ALT levels during pegylated interferon monotherapy may be caused by hepatic iron overload. Intervirology 2008;51(suppl 1):76–85.
  8. Fujita N, Sugimoto R, Urawa N, Araki J, Mifuji R, Yamamoto M, Horiike S, Tanaka H, Iwasa M, Kobayashi Y, Adachi Y, Kaito M: Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 2007;22:1886–1893.
  9. Arber N, Moshkowitz M, Konikoff F, Halpern Z, Hallak A, Santo M, Tiomny E, Baratz M, Gilat T: Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci 1995;40:2431–2433.
  10. Akiyoshi F, Sata M, Uchimura Y, Suzuki H, Tanikawa K: Hepatic iron stainings in chronic hepatitis C patients with low HCV RNA levels: a predictive marker for IFN therapy. Am J Gastroenterol 1997;92:1463–1466.
  11. Furutani T, Hino K, Okuda M, Gondo T, Nishina S, Kitase A, Korenaga M, Xiao SY, Weinman SA, Lemon SM, Sakaida I, Okita K: Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 2006;130:2087–2098.
  12. Kew MC: Hepatic iron overload and hepatocellular carcinoma. Cancer Lett 2008. DOI: 10.1016/j.canlet.2008.11.001.

    External Resources

  13. Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, Tanaka E, Onji M, Toyota J, Chayama K, Yoshioka K, Izumi N, Akuta N, Kumada H: 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;44:952–963.
  14. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  15. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: 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;96:224–230.
  16. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: 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;48:372–380.
  17. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: 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;46:403–410.
  18. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  19. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.