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Vol. 48, No. 1, 2005
Issue release date: 2005
Intervirology 2005;48:59–63
(DOI:10.1159/000082096)

Development of Hepatocellular Carcinoma after Interferon Therapy in Chronic Hepatitis C

Is It Possible to Reduce the Incidence by Ribanirin and IFN Combination Therapy?

Izumi N. · Yasuhiro A. · Kurosaki M. · Onuki Y. · Nishimura Y. · Inoue K. · Ueda K. · Tsuchiya K. · Nakanishi H. · Uchihara M. · Miyake S.
Division of Gastroenterology and Hepatology, Musashino Red-Cross Hospital, Tokyo, Japan
email Corresponding Author

Abstract

Objectives: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. Methods: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. Results: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. Conclusion: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.


 goto top of outline Key Words

  • Chronic hepatitis C
  • Hepatocellular carcinoma
  • Interferon
  • Ribavirin

 goto top of outline Abstract

Objectives: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. Methods: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. Results: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. Conclusion: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26:34–38S.
  2. Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Puecell RH: Interrelationship of blood transfusion, non-A non-B hepatitis and hepatocellular carcinoma analysis of detection of antibody to hepatitis C virus. Hepatology 1990;12:671–675.
  3. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, Shibata M, Morishima T: Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: Relationship to genotypes of hepatitis C virus. Hepatology 1992;16:293–299.
  4. 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 infection. N Engl J Med 1996;334:77–81.
  5. Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, Iijima A, Urushihara A, Kiyosawa K, Okuda M, Hino K, Okita K: Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Hepatology 1998;27:1394–1402.
  6. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group. N Engl J Med 1998;19:1485–1492.
  7. Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y, Tanaka T, Sato K, Tsuda F, Miyakawa Y, Mayumi M: Typing hepatitis C virus by polymerase chain reaction with type specific primers: Application to clinical surveys and tracing infectious sources. J Gen Virol 1992;73:673–679.
  8. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classifications of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  9. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750.
  10. Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M: Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;ii:1006–1008.
  11. Imai Y, Kawata S, Tamura S, Yubuuchi I, Noda S, Inada M, Maeda Y, Shirai Y, Fukizaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y: Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med 1998;129:94–99.
  12. Yoshida H, Tateishi R, Arakawa Y, Sata M, Fujiyama S, Nishiguchi S, Ishibashi H, Yamada G, Yokosuka O, Shiratori Y, Omata M: Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C. Gut 2004;53:425–430.
  13. Kasahara A, Tanaka H, Okanoue T, Imai Y, Tsubouchi H, Yoshioka K, Kawata S, Tanaka E, Hino K, Hayashi K, Tamura S, Itoh Y, Kiyosawa K, Kakumu S, Okita K, Hayashi N: Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death. J Viral Hepat 2004;11:148–156.
  14. Manns MP, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomized trial. Lancet 2001;358:958–965.
  15. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H, Omata M: Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;18:299–306.

    External Resources

  16. Ikeda K, Kobayashi M, Saitoh S, Someya T, Hosoda T, Akuta N, Suzuki F, Tsubota A, Suzaki Y, Arase Y, Kumada H: Recurrence rate and prognosis with hepatocellular carcinoma that developed after elimination of hepatitis C virus RNA by interferon therapy: A closed cohort study including matched control patients. Oncology 2003;65:204–210.
  17. Komorizono Y, Sako K, Yamasaki N, Hiwaki T, Sakurai K, Shibatou T, Maeda M, Kohara K. Shigenobu S, Hasegawa S, Arima T, Oketani M, Ishibashi K, Arima T: Outcome of patients with hepatitis C virus-related hepatocellular carcinoma occurring after interferon therapy. Anticancer Res 2002;22:3573–3578.

 goto top of outline Author Contacts

Namiki Izumi, MD
Chief, Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital
1-26-1 Kyonancho, Musashinoshi
Tokyo 180-8610 (Japan)
Tel. +81 422 32 3111, Fax +81 422 32 9551, E-Mail nizumi@musashino.jrc.or.jp


 goto top of outline Article Information

Number of Print Pages : 5
Number of Figures : 3, Number of Tables : 4, Number of References : 17


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 1, Year 2005 (Cover Date: 2005)

Journal Editor: U.G. Liebert, Leipzig
ISSN: 0300–5526 (print), 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: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. Methods: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. Results: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. Conclusion: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.



 goto top of outline Author Contacts

Namiki Izumi, MD
Chief, Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital
1-26-1 Kyonancho, Musashinoshi
Tokyo 180-8610 (Japan)
Tel. +81 422 32 3111, Fax +81 422 32 9551, E-Mail nizumi@musashino.jrc.or.jp


 goto top of outline Article Information

Number of Print Pages : 5
Number of Figures : 3, Number of Tables : 4, Number of References : 17


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 1, Year 2005 (Cover Date: 2005)

Journal Editor: U.G. Liebert, Leipzig
ISSN: 0300–5526 (print), 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. Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26:34–38S.
  2. Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Puecell RH: Interrelationship of blood transfusion, non-A non-B hepatitis and hepatocellular carcinoma analysis of detection of antibody to hepatitis C virus. Hepatology 1990;12:671–675.
  3. Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, Shibata M, Morishima T: Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: Relationship to genotypes of hepatitis C virus. Hepatology 1992;16:293–299.
  4. 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 infection. N Engl J Med 1996;334:77–81.
  5. Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, Iijima A, Urushihara A, Kiyosawa K, Okuda M, Hino K, Okita K: Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Hepatology 1998;27:1394–1402.
  6. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis interventional therapy group. N Engl J Med 1998;19:1485–1492.
  7. Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y, Tanaka T, Sato K, Tsuda F, Miyakawa Y, Mayumi M: Typing hepatitis C virus by polymerase chain reaction with type specific primers: Application to clinical surveys and tracing infectious sources. J Gen Virol 1992;73:673–679.
  8. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classifications of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  9. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750.
  10. Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M: Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;ii:1006–1008.
  11. Imai Y, Kawata S, Tamura S, Yubuuchi I, Noda S, Inada M, Maeda Y, Shirai Y, Fukizaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y: Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med 1998;129:94–99.
  12. Yoshida H, Tateishi R, Arakawa Y, Sata M, Fujiyama S, Nishiguchi S, Ishibashi H, Yamada G, Yokosuka O, Shiratori Y, Omata M: Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C. Gut 2004;53:425–430.
  13. Kasahara A, Tanaka H, Okanoue T, Imai Y, Tsubouchi H, Yoshioka K, Kawata S, Tanaka E, Hino K, Hayashi K, Tamura S, Itoh Y, Kiyosawa K, Kakumu S, Okita K, Hayashi N: Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death. J Viral Hepat 2004;11:148–156.
  14. Manns MP, et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomized trial. Lancet 2001;358:958–965.
  15. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H, Omata M: Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;18:299–306.

    External Resources

  16. Ikeda K, Kobayashi M, Saitoh S, Someya T, Hosoda T, Akuta N, Suzuki F, Tsubota A, Suzaki Y, Arase Y, Kumada H: Recurrence rate and prognosis with hepatocellular carcinoma that developed after elimination of hepatitis C virus RNA by interferon therapy: A closed cohort study including matched control patients. Oncology 2003;65:204–210.
  17. Komorizono Y, Sako K, Yamasaki N, Hiwaki T, Sakurai K, Shibatou T, Maeda M, Kohara K. Shigenobu S, Hasegawa S, Arima T, Oketani M, Ishibashi K, Arima T: Outcome of patients with hepatitis C virus-related hepatocellular carcinoma occurring after interferon therapy. Anticancer Res 2002;22:3573–3578.