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Table of Contents
Vol. 50, No. 6, 2007
Issue release date: February 2008
Section title: Original Paper
Intervirology 2007;50:439–446
(DOI:10.1159/000114718)

Eicosapentaenoic Acid Could Permit Maintenance of the Original Ribavirin Dose in Chronic Hepatitis C Virus Patients during the First 12 Weeks of Combination Therapy with Pegylated Interferon-α and Ribavirin

A Prospective Randomized Controlled Trial

Takaki S.a · Kawakami Y.a · Imamura M.a · Aikata H.a · Takahashi S.a · Ishihara H.b · Tsuji K.c · Aimitsu S.d · Kawakami H.e · Nakanishi T.f · Kitamoto M.g · Moriya T.h · Satoh K.i · Chayama K.a
aDepartment of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, bDepartment of Internal Medicine, Chuden Hospital, cDepartment of Internal Medicine, Hiroshima City Asa Hospital, dDepartment of Hepatology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, and eKawakami Gastroenterology Clinic, Hiroshima; fDepartment of Gastroenterology, Shobara Red Cross Hospital, Shobara; gDepartment of Gastroenterology, Hiroshima Prefectural Hospital, hDepartment of Gastroenterology, Chugoku Rousai Hospital, and iDepartment of Environmetrics and Biometrics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
email Corresponding Author

Abstract

Objective: To evaluate the efficacy of eicosapentaenoic acid (EPA) against ribavirin (RBV)-associated hemolytic anemia during the first 12 weeks in chronic hepatitis C virus (HCV) combination therapy. Methods: This study was a prospective open-label, randomized controlled trial. 100 HCV patients were randomized to either the EPA group (n = 49) or non-EPA group (n = 51) who received combination therapy with or without EPA. We compared the changes in hemoglobin level and RBV plasma concentrations at week 12 in each group with RBV dose reduction rate and performed multivariate analysis to identify independent variables associated with RBV dose reduction. Results: 8 patients (17%) in the EPA group and 20 patients (29%) in the non-EPA group required RBV dose reduction, respectively. The cumulative RBV reduction rate was significantly lower in the EPA group than in the non-EPA group (p = 0.017), while the decrease of hemoglobin and RBV plasma concentrations from baseline was not significantly different. However, in the multivariate analysis, treatment with EPA showed significant variables for the reduction of RBV dose (odds ratio 3.235, p = 0.023). Conclusion: EPA could prevent the RBV dose reduction during the first 12 weeks in combination therapy, although further large-scale double-blind randomized controlled trials are required.

© 2008 S. Karger AG, Basel


  

Key Words

  • Chronic hepatitis C
  • Ribavirin
  • PEG interferon
  • Combination therapy
  • Anemia
  • Eicosapentaenoic acid

References

  1. Akuta N, Suzuki F, Kawamura Y, et al: Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients in- fected with hepatitis C virus genotype 1b: Amino acid substitutions in the core region and low-density lipoprotein cholesterol. J Hepatol 2007;46:403–410.
  2. Berg T, Sarrazin C, Herrmann E, et al: Prediction of treatment outcome in patients with chronic hepatitis C: Significance of baseline parameters and viral dynamics during therapy. Hepatology 2003;37:600–609.
  3. Gopal K, Johnson TC, Gopal S, et al: Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment. Hepatology 2006;44:335–340.
  4. Nishiguchi S, Ueda T, Itoh T, et al: Method to detect substitutions in the interferon-sensitivity-determining region of hepatitis C virus 1b for prediction of response to interferon therapy. Hepatology 2001;33:241–247.
  5. Arase Y, Ikeda K, Tsubota A, et al: Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C. Intervirology 2005;48:138–144.
  6. Bruchfeld A, Lindahl K, Reichard O, et al: Pegylated interferon and ribavirin treatment for hepatitis C in hemodialysis patients. J Viral Hepat 2006;13:316–321.
  7. Lindahl K, Stahle L, Bruchfeld A, et al: High-dose ribavirin in combination with standard-dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005;41:275–279.
  8. Shiffman ML, Di Bisceglie AM, Lindsay KL, Schvarcz R: Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015–1023.
  9. McHutchison JG, Manns MP, Longo DL: Definition and management of anemia in patients infected with hepatitis C virus. Liver Int 2006;26:389–398.
  10. Hino K, Murakami Y, Nagai A, et al: Alpha-2α-tocopherol and ascorbic acid attenuates the ribavirin-induced decrease of eicosapentaenoic acid in erythrocyte membrane in chronic hepatitis C patients. J Gastroenterol Hepatol 2006;21:1269–1275.
  11. Jen JF, Glue P, Gupta S, Zambas D, Hajian G: Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000;22:555–565.
  12. Khakoo S, Glue P, Grellier L, et al: Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetics and pharmacodynamic interactions. Br J Clin Pharmacol 1998;46:563–570.
  13. Ide T, Okamura T, Kumashiro R, et al: A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C. Int J Mol Med 2003;11:729–732.
  14. Terano T, Hirai A, Hamazaki T, et al: Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis 1983;46:321–331.
  15. Yokoyama M, Origasa H, for the JELIS Investigators Kobe and Toyama, Japan: Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613–620.
  16. Mori TA, Watts GF, Burke V, Hilme E, Puddey IB, Beilin LJ: Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men. Circulation 2000;102:1264–1269.
  17. Franceschi LD, Fattovich G, Turrini F, et al: Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004.
  18. McHutchison JG, Manns M, Patel K, et al: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.
  19. Schalm SW, Weiland O, Hansen BE: Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials. Eurohep Study Group for Viral Hepatitis. Gastroenterology 1999;117:408–413.
  20. 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.
  21. Takaki S, Tsubota A, Hosaka T, et al: Factors contributing to ribavirin dose reduction due to anemia during interferon alfa-2b and ribavirin combination therapy for chronic hepatitis C. J Gastroenterol 2004;39:668–673.
  22. Maddrey WC: Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis 1999;19(suppl 1): 67–75.

    External Resources

  23. Davis GL, Wong JB, McHutchison JG, et al: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–652.
  24. Zeuzem S, Herrmann E, Lee JH, et al: Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology 2001;120:1438–1447.
  25. Enomoto M, Nishiguchi S, Kohmoto M, et al: Effects of ribavirin combined with interferon-alpha 2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads. J Viral Hepat 2004;11:448–454.
  26. Tsubota A, Akuta N, Suzuki F, et al: Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis c virus of genotype 1b and high pretreatment viral load. Intervirology 2002;45:33–42.
  27. Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  28. Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon-2b plus ribavirin compared with interferon-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–965.
  29. Reddy KR, Wright TL, Pockros PJ, et al: Efficacy and safety of pegylated (40-kD) interferon alpha-2a compared with interferon alpha-2a in non-cirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433–438.
  30. Lindsay KL, Trepo C, Heintges T, et al: A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395–403.
  31. Heathcote EJ, Shiffman ML, Cooksley WG, et al: Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–1680.
  32. Zeuzem S, Feinman SV, Rasenack J, et al: Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666–1672.
  33. Poynaud T, Marcellin P, Lee SS, et al: Randomised trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426–1432.
  34. McHutchison JG, Gordon SC, Schiff ER, et al: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–1492.
  35. Lauer GM, Walker BD: Hepatitis C virus infection. N Engl J Med 2001;345:41–52.
  36. Niederau C, Lange S, Heintges T, et al: Prognosis of chronic hepatitis C: Results of a large prospective cohort study. Hepatology 1998;28:1687–1695.
  37. Di Bisceglie AM: Hepatitis C. Lancet 1998;351:351–355.
  38. Alter MJ, Margolis HS, Krawzcynski K, et al: The natural history of community-acquired chronic hepatitis C in the United States. N Engl J Med 1992;327:1899–1905.

  

Author Contacts

Shintaro Takaki, Department of Medicine and Molecular Science
Division of Frontier Medical Science, Programs for Biomedical Research
Graduate School of Biomedical Sciences, Hiroshima University
1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551 (Japan)
Tel. +81 82 257 5192, Fax +81 82 257 5194, E-Mail takakiss@hiroshima-u.ac.jp

  

Article Information

Received: April 17, 2007
Accepted after revision: November 20, 2007
Published online: February 4, 2008
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 5, Number of References : 38

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 50, No. 6, Year 2007 (Cover Date: February 2008)

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

Objective: To evaluate the efficacy of eicosapentaenoic acid (EPA) against ribavirin (RBV)-associated hemolytic anemia during the first 12 weeks in chronic hepatitis C virus (HCV) combination therapy. Methods: This study was a prospective open-label, randomized controlled trial. 100 HCV patients were randomized to either the EPA group (n = 49) or non-EPA group (n = 51) who received combination therapy with or without EPA. We compared the changes in hemoglobin level and RBV plasma concentrations at week 12 in each group with RBV dose reduction rate and performed multivariate analysis to identify independent variables associated with RBV dose reduction. Results: 8 patients (17%) in the EPA group and 20 patients (29%) in the non-EPA group required RBV dose reduction, respectively. The cumulative RBV reduction rate was significantly lower in the EPA group than in the non-EPA group (p = 0.017), while the decrease of hemoglobin and RBV plasma concentrations from baseline was not significantly different. However, in the multivariate analysis, treatment with EPA showed significant variables for the reduction of RBV dose (odds ratio 3.235, p = 0.023). Conclusion: EPA could prevent the RBV dose reduction during the first 12 weeks in combination therapy, although further large-scale double-blind randomized controlled trials are required.

© 2008 S. Karger AG, Basel


  

Author Contacts

Shintaro Takaki, Department of Medicine and Molecular Science
Division of Frontier Medical Science, Programs for Biomedical Research
Graduate School of Biomedical Sciences, Hiroshima University
1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551 (Japan)
Tel. +81 82 257 5192, Fax +81 82 257 5194, E-Mail takakiss@hiroshima-u.ac.jp

  

Article Information

Received: April 17, 2007
Accepted after revision: November 20, 2007
Published online: February 4, 2008
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 5, Number of References : 38

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 50, No. 6, Year 2007 (Cover Date: February 2008)

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 Paper

Received: 4/17/2007
Accepted: 11/20/2007
Published online: 2/4/2008
Issue release date: February 2008

Number of Print Pages: 8
Number of Figures: 4
Number of Tables: 5

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. Akuta N, Suzuki F, Kawamura Y, et al: Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients in- fected with hepatitis C virus genotype 1b: Amino acid substitutions in the core region and low-density lipoprotein cholesterol. J Hepatol 2007;46:403–410.
  2. Berg T, Sarrazin C, Herrmann E, et al: Prediction of treatment outcome in patients with chronic hepatitis C: Significance of baseline parameters and viral dynamics during therapy. Hepatology 2003;37:600–609.
  3. Gopal K, Johnson TC, Gopal S, et al: Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment. Hepatology 2006;44:335–340.
  4. Nishiguchi S, Ueda T, Itoh T, et al: Method to detect substitutions in the interferon-sensitivity-determining region of hepatitis C virus 1b for prediction of response to interferon therapy. Hepatology 2001;33:241–247.
  5. Arase Y, Ikeda K, Tsubota A, et al: Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C. Intervirology 2005;48:138–144.
  6. Bruchfeld A, Lindahl K, Reichard O, et al: Pegylated interferon and ribavirin treatment for hepatitis C in hemodialysis patients. J Viral Hepat 2006;13:316–321.
  7. Lindahl K, Stahle L, Bruchfeld A, et al: High-dose ribavirin in combination with standard-dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005;41:275–279.
  8. Shiffman ML, Di Bisceglie AM, Lindsay KL, Schvarcz R: Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015–1023.
  9. McHutchison JG, Manns MP, Longo DL: Definition and management of anemia in patients infected with hepatitis C virus. Liver Int 2006;26:389–398.
  10. Hino K, Murakami Y, Nagai A, et al: Alpha-2α-tocopherol and ascorbic acid attenuates the ribavirin-induced decrease of eicosapentaenoic acid in erythrocyte membrane in chronic hepatitis C patients. J Gastroenterol Hepatol 2006;21:1269–1275.
  11. Jen JF, Glue P, Gupta S, Zambas D, Hajian G: Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000;22:555–565.
  12. Khakoo S, Glue P, Grellier L, et al: Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetics and pharmacodynamic interactions. Br J Clin Pharmacol 1998;46:563–570.
  13. Ide T, Okamura T, Kumashiro R, et al: A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C. Int J Mol Med 2003;11:729–732.
  14. Terano T, Hirai A, Hamazaki T, et al: Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis 1983;46:321–331.
  15. Yokoyama M, Origasa H, for the JELIS Investigators Kobe and Toyama, Japan: Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613–620.
  16. Mori TA, Watts GF, Burke V, Hilme E, Puddey IB, Beilin LJ: Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men. Circulation 2000;102:1264–1269.
  17. Franceschi LD, Fattovich G, Turrini F, et al: Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000;31:997–1004.
  18. McHutchison JG, Manns M, Patel K, et al: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.
  19. Schalm SW, Weiland O, Hansen BE: Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials. Eurohep Study Group for Viral Hepatitis. Gastroenterology 1999;117:408–413.
  20. 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.
  21. Takaki S, Tsubota A, Hosaka T, et al: Factors contributing to ribavirin dose reduction due to anemia during interferon alfa-2b and ribavirin combination therapy for chronic hepatitis C. J Gastroenterol 2004;39:668–673.
  22. Maddrey WC: Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis 1999;19(suppl 1): 67–75.

    External Resources

  23. Davis GL, Wong JB, McHutchison JG, et al: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–652.
  24. Zeuzem S, Herrmann E, Lee JH, et al: Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology 2001;120:1438–1447.
  25. Enomoto M, Nishiguchi S, Kohmoto M, et al: Effects of ribavirin combined with interferon-alpha 2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads. J Viral Hepat 2004;11:448–454.
  26. Tsubota A, Akuta N, Suzuki F, et al: Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis c virus of genotype 1b and high pretreatment viral load. Intervirology 2002;45:33–42.
  27. Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  28. Manns MP, McHutchison JG, Gordon SC, et al: Peginterferon-2b plus ribavirin compared with interferon-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–965.
  29. Reddy KR, Wright TL, Pockros PJ, et al: Efficacy and safety of pegylated (40-kD) interferon alpha-2a compared with interferon alpha-2a in non-cirrhotic patients with chronic hepatitis C. Hepatology 2001;33:433–438.
  30. Lindsay KL, Trepo C, Heintges T, et al: A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395–403.
  31. Heathcote EJ, Shiffman ML, Cooksley WG, et al: Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–1680.
  32. Zeuzem S, Feinman SV, Rasenack J, et al: Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666–1672.
  33. Poynaud T, Marcellin P, Lee SS, et al: Randomised trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426–1432.
  34. McHutchison JG, Gordon SC, Schiff ER, et al: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485–1492.
  35. Lauer GM, Walker BD: Hepatitis C virus infection. N Engl J Med 2001;345:41–52.
  36. Niederau C, Lange S, Heintges T, et al: Prognosis of chronic hepatitis C: Results of a large prospective cohort study. Hepatology 1998;28:1687–1695.
  37. Di Bisceglie AM: Hepatitis C. Lancet 1998;351:351–355.
  38. Alter MJ, Margolis HS, Krawzcynski K, et al: The natural history of community-acquired chronic hepatitis C in the United States. N Engl J Med 1992;327:1899–1905.