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Table of Contents
Vol. 45, No. 1, 2002
Issue release date: January–February 2002
Intervirology 2002;45:11–19
(DOI:10.1159/000050082)

Analysis of Background Factors Influencing Long-Term Prognosis of Patients with Chronic Hepatitis C Treated with Interferon

Yoneyama K.a · Yamaguchi M.b · Kiuchi Y.b · Morizane T.c · Shibata M.d · Mitamura K.d
aShowa University Health Service Center, bDepartment of Pathophysiology, Showa University School of Pharmaceutical Sciences, Tokyo, cDepartment of Medicine, Kanagawa Dental College, Kanagawa, dSecond Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan
email Corresponding Author

Abstract

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.


 goto top of outline Key Words

  • Chronic hepatitis C
  • Interferon therapy
  • Background factors
  • Cirrhosis and hepatocellular carcinoma
  • Platelet count

 goto top of outline Abstract

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.

Copyright © 2002 S. Karger AG, Basel


 goto top of outline References
  1. Yokosuka O, Kojima H, Imazeki F, Tagawa M, Saisho H, Tamatsukuri S, Omata M: Spontaneous negativation of serum hepatitis C virus RNA is a rare event in type C chronic liver diseases: Analysis of HCV RNA in 320 patients who were followed for more than 3 years. J Hepatol 1999;31:394–399.
  2. Takano S, Omata M, Ohto M, Satomura Y: Prospective assessment of donor blood screening for antibody to hepatitis C virus and high-titer antibody to HBcAg as a means of preventing posttransfusion hepatitis. Hepatology 1993;18:235–239.
  3. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ: Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology 1991;14:969–974.
  4. Caporaso N, Romano M, Marmo R, de Sio I, Morisco F, Minerva A, Coltorti M: Hepatitis C virus infection is an additive risk factor for development of hepatocellular carcinoma in patients with cirrhosis. J Hepatol 1991;12:367–371.
  5. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M: A multivariate analysis of risk factors for hepatocellular carcinogenesis: A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.
  6. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G: Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: A multicenter Italian study. Hepatology 1994;20:1225–1230.
  7. Seeff LB: Natural history of hepatitis C. Am J Med 1999;107:10S–15S.

    External Resources

  8. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.
  9. Shev S, Dhillon AP, Lindh M, Serleus Z, Wejstal R, Widell A, Norkrans G: The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C. Liver 1997;17:215–223.
  10. Verbaan H, Widell A, Bondeson L, Andersson K, Eriksson S: Factors associated with cirrhosis development in chronic hepatitis C patients from an area of low prevalence. J Viral Hepat 1998;5:43–51.

    External Resources

  11. Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, Hashimoto E, Lefkowitch JH, Ludwig J, Okuda K: The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334–1340.
  12. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H: Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: A prospective observation of 2215 patients. J Hepatol 1998;28:930–938.
  13. 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. Osaka Liver Disease Study Group. Hepatology 1998;27:1394–1402.
  14. Miyajima I, Sata M, Kumashiro R, Uchimura Y, Ide T, Suzuki H, Tanikawa K: The incidence of hepatocellular carcinoma in patients with chronic hepatitis C after interferon treatment. Oncol Rep 1998;5:201–204.
  15. Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Tsubota A, Nakamura I, Murashima N, Kumada H, Kawanishi M: Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999;29:1124–1130.
  16. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M: Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:174–181.
  17. Bellobuono A, Mondazzi L, Tempini S, Silini E, Ideo G: Prospective comparison of four lymphoblastoid interferon alpha schedules for chronic hepatitis C. A multivariate analysis of factors predictive of sustained response to treatment. Eur J Gastroenterol Hepatol 1997;9:1169–1177.
  18. Schlaak JF, Trippler M, Ernst I, Meyer zum Buschenfelde KH, Gerken G: Chronic hepatitis C: The viral load per liver cell before treatment as a new marker to predict long-term response to IFN-alpha therapy. J Hepatol 1997;27:917–921.
  19. Tassopoulos NC, Karvountzis G, Touloumi G, Delladetsima JK, Papatheodoridis GV, Katsoulidou A, Retalis G, Hatzakis A: Comparative efficacy of a high or low dose of interferon alpha 2b in chronic hepatitis C: A randomized controlled trial. Am J Gastroenterol 1996;91:1734–1738.

    External Resources

  20. Kurosaki M, Enomoto N, Murakami T, Sakuma I, Asahina Y, Yamamoto C, Ikeda T, Tozuka S, Izumi N, Marumo F, Sato C: Analysis of genotypes and amino acid residues 2,209 to 2,248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy. Hepatology 1997;25:750–753.
  21. Kagawa T, Hosoi K, Takashimizu S, Kawazoe K, Mochizuki K, Wasada M, Nagata N, Uchiyama J, Nakano A, Nishizaki Y, Watanabe N, Matsuzaki S: Comparison of two interferon-alpha treatment regimens characterized by an early virological response in patients with chronic hepatitis C. Am J Gastroenterol 1998;93:192–196.
  22. Wada M, Kang KB, Nishigami T, Shimoyama T: Importance of pretreatment viral load and monitoring of serum hepatitis C virus RNA in predicting responses to interferon-alpha2a treatment of chronic hepatitis C. Hanshin Chronic Hepatitis C Study Group. J Interferon Cytokine Res 1997;17:707–712.

    External Resources

  23. Tong MJ, Blatt LM, McHutchison JG, Co RL, Conrad A: Prediction of response during interferon-alpha 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: A comparison. Hepatology 1997;26:1640–1645.
  24. Kaserer K, Fiedler R, Steindl P, Muller CH, Wrba F, Ferenci P: Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C. Histopathology 1998;32:454–461.
  25. Kasahara A, Hayashi N, Hiramatsu N, Oshita M, Hagiwara H, Katayama K, Kato M, Masuzawa M, Yoshihara H, Kishida Y, et al: Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: A multicenter randomized controlled trial. Hepatology 1995;21:291–297.
  26. Moreno MG, Muriel P: Remission of liver fibrosis by interferon-alpha 2b. Biochem Pharmacol 1995;50:515–520.
  27. Inoue A, Tsukuma H, Oshima A, Yabuuchi T, Nakao M, Matsunaga T, Kojima J, Tanaka S: Effectiveness of interferon therapy for reducing the incidence of hepatocellular carcinoma among patients with type C chronic hepatitis. J Epidemiol 2000;10:234–240.
  28. Horiike N, Fujisawa T, Michitaka K, Tada K, Masumoto T, Iuchi H, Kojima N, Onji M: The effectiveness of interferon therapy on occurrence of hepatocellular carcinoma in chronic hepatitis C. Oncol Rep 1998;5:1171–1174.
  29. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: A retrospective cohort study. International Interferon-alpha Hepatocellular Carcinoma Study Group. Lancet 1998;351:1535–1539.

 goto top of outline Author Contacts

Keiichiro Yoneyama
Showa University Health Service Center
1-4-5 Hatanodai, Shinagawa-ku, Tokyo 142-8666 (Japan)
Tel. +81 3 3784 8071, Fax +81 3 3784 8248
E-Mail yoneyama@med.showa-u.ac.jp


 goto top of outline Article Information

Received: Received: August 30, 2001
Accepted after revision: October 15, 2001
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 5, Number of References : 29


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)
Founded 1973 by J.L. Melnick; continued by F. Rapp (1986–1990); M.J. Buchmeier and C.R. Howard (1991–1993)

Vol. 45, No. 1, Year 2002 (Cover Date: January-February 2002)

Journal Editor: Rüdiger W. Braun, Stuttgart
ISSN: 0300–5526 (print), 1423–0100 (Online)

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

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.



 goto top of outline Author Contacts

Keiichiro Yoneyama
Showa University Health Service Center
1-4-5 Hatanodai, Shinagawa-ku, Tokyo 142-8666 (Japan)
Tel. +81 3 3784 8071, Fax +81 3 3784 8248
E-Mail yoneyama@med.showa-u.ac.jp


 goto top of outline Article Information

Received: Received: August 30, 2001
Accepted after revision: October 15, 2001
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 5, Number of References : 29


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)
Founded 1973 by J.L. Melnick; continued by F. Rapp (1986–1990); M.J. Buchmeier and C.R. Howard (1991–1993)

Vol. 45, No. 1, Year 2002 (Cover Date: January-February 2002)

Journal Editor: Rüdiger W. Braun, Stuttgart
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/journals/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. Yokosuka O, Kojima H, Imazeki F, Tagawa M, Saisho H, Tamatsukuri S, Omata M: Spontaneous negativation of serum hepatitis C virus RNA is a rare event in type C chronic liver diseases: Analysis of HCV RNA in 320 patients who were followed for more than 3 years. J Hepatol 1999;31:394–399.
  2. Takano S, Omata M, Ohto M, Satomura Y: Prospective assessment of donor blood screening for antibody to hepatitis C virus and high-titer antibody to HBcAg as a means of preventing posttransfusion hepatitis. Hepatology 1993;18:235–239.
  3. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ: Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology 1991;14:969–974.
  4. Caporaso N, Romano M, Marmo R, de Sio I, Morisco F, Minerva A, Coltorti M: Hepatitis C virus infection is an additive risk factor for development of hepatocellular carcinoma in patients with cirrhosis. J Hepatol 1991;12:367–371.
  5. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M: A multivariate analysis of risk factors for hepatocellular carcinogenesis: A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.
  6. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G: Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: A multicenter Italian study. Hepatology 1994;20:1225–1230.
  7. Seeff LB: Natural history of hepatitis C. Am J Med 1999;107:10S–15S.

    External Resources

  8. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.
  9. Shev S, Dhillon AP, Lindh M, Serleus Z, Wejstal R, Widell A, Norkrans G: The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C. Liver 1997;17:215–223.
  10. Verbaan H, Widell A, Bondeson L, Andersson K, Eriksson S: Factors associated with cirrhosis development in chronic hepatitis C patients from an area of low prevalence. J Viral Hepat 1998;5:43–51.

    External Resources

  11. Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, Hashimoto E, Lefkowitch JH, Ludwig J, Okuda K: The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334–1340.
  12. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H: Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: A prospective observation of 2215 patients. J Hepatol 1998;28:930–938.
  13. 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. Osaka Liver Disease Study Group. Hepatology 1998;27:1394–1402.
  14. Miyajima I, Sata M, Kumashiro R, Uchimura Y, Ide T, Suzuki H, Tanikawa K: The incidence of hepatocellular carcinoma in patients with chronic hepatitis C after interferon treatment. Oncol Rep 1998;5:201–204.
  15. Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Tsubota A, Nakamura I, Murashima N, Kumada H, Kawanishi M: Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999;29:1124–1130.
  16. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M: Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131:174–181.
  17. Bellobuono A, Mondazzi L, Tempini S, Silini E, Ideo G: Prospective comparison of four lymphoblastoid interferon alpha schedules for chronic hepatitis C. A multivariate analysis of factors predictive of sustained response to treatment. Eur J Gastroenterol Hepatol 1997;9:1169–1177.
  18. Schlaak JF, Trippler M, Ernst I, Meyer zum Buschenfelde KH, Gerken G: Chronic hepatitis C: The viral load per liver cell before treatment as a new marker to predict long-term response to IFN-alpha therapy. J Hepatol 1997;27:917–921.
  19. Tassopoulos NC, Karvountzis G, Touloumi G, Delladetsima JK, Papatheodoridis GV, Katsoulidou A, Retalis G, Hatzakis A: Comparative efficacy of a high or low dose of interferon alpha 2b in chronic hepatitis C: A randomized controlled trial. Am J Gastroenterol 1996;91:1734–1738.

    External Resources

  20. Kurosaki M, Enomoto N, Murakami T, Sakuma I, Asahina Y, Yamamoto C, Ikeda T, Tozuka S, Izumi N, Marumo F, Sato C: Analysis of genotypes and amino acid residues 2,209 to 2,248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy. Hepatology 1997;25:750–753.
  21. Kagawa T, Hosoi K, Takashimizu S, Kawazoe K, Mochizuki K, Wasada M, Nagata N, Uchiyama J, Nakano A, Nishizaki Y, Watanabe N, Matsuzaki S: Comparison of two interferon-alpha treatment regimens characterized by an early virological response in patients with chronic hepatitis C. Am J Gastroenterol 1998;93:192–196.
  22. Wada M, Kang KB, Nishigami T, Shimoyama T: Importance of pretreatment viral load and monitoring of serum hepatitis C virus RNA in predicting responses to interferon-alpha2a treatment of chronic hepatitis C. Hanshin Chronic Hepatitis C Study Group. J Interferon Cytokine Res 1997;17:707–712.

    External Resources

  23. Tong MJ, Blatt LM, McHutchison JG, Co RL, Conrad A: Prediction of response during interferon-alpha 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: A comparison. Hepatology 1997;26:1640–1645.
  24. Kaserer K, Fiedler R, Steindl P, Muller CH, Wrba F, Ferenci P: Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C. Histopathology 1998;32:454–461.
  25. Kasahara A, Hayashi N, Hiramatsu N, Oshita M, Hagiwara H, Katayama K, Kato M, Masuzawa M, Yoshihara H, Kishida Y, et al: Ability of prolonged interferon treatment to suppress relapse after cessation of therapy in patients with chronic hepatitis C: A multicenter randomized controlled trial. Hepatology 1995;21:291–297.
  26. Moreno MG, Muriel P: Remission of liver fibrosis by interferon-alpha 2b. Biochem Pharmacol 1995;50:515–520.
  27. Inoue A, Tsukuma H, Oshima A, Yabuuchi T, Nakao M, Matsunaga T, Kojima J, Tanaka S: Effectiveness of interferon therapy for reducing the incidence of hepatocellular carcinoma among patients with type C chronic hepatitis. J Epidemiol 2000;10:234–240.
  28. Horiike N, Fujisawa T, Michitaka K, Tada K, Masumoto T, Iuchi H, Kojima N, Onji M: The effectiveness of interferon therapy on occurrence of hepatocellular carcinoma in chronic hepatitis C. Oncol Rep 1998;5:1171–1174.
  29. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: A retrospective cohort study. International Interferon-alpha Hepatocellular Carcinoma Study Group. Lancet 1998;351:1535–1539.