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Vol. 48, No. 4, 2005
Issue release date: July–August 2005
Section title: Original Paper
Intervirology 2005;48:230–238
(DOI:10.1159/000084600)

Prediction of Treatment Outcome in Chronic Hepatitis C Patients Based on Early Viral Dynamics during High-Dose Induction Interferon and Ribavirin Therapy

Kim T.H.a · Kim K.A.a · Lim Y.S.a · Gwak G.a · Yoon J.-H.a · Kang G.H.b · Lee H.-S.a
aDepartment of Internal Medicine and Liver Research Institute, and bDepartment of Pathology, Seoul National University College of Medicine, Seoul, Korea
email Corresponding Author

Abstract

Objective:In chronic hepatitis C, early viral load decline after interferon administration is dose dependent and reflects the intrinsic viral susceptibility to the antiviral action of interferon. We examined whether the augmented suppression of susceptible viral loads by high-dose induction interferon could possibly discriminate responsive patients from non-responsive patients at an early stage of treatment. Methods: Fifty-nine chronic hepatitis C patients were randomly allocated to receive one of two treatment regimens; 3 MU interferon three times weekly plus ribavirin 1,000 mg/day for 24 weeks in the CR group (n = 30), and the same regimen as in the CR group except 10 MU interferon daily for the first week in the HR group (n = 29). Changes in viral loads during the first week of treatment were analyzed in terms of sustained virological response (SVR). Results: The positive predictive values of undetectable (<100 IU/ml) or low serum HCV RNA (<2,000 IU/ml) after 1 week of treatment for SVR were 100% in both treatment groups, whereas the negative predictive values of the low viral titer were 91% in the HR group and 70% in the CR group. Conclusion: One-week virological response to high-dose induction interferon/ribavirin combination therapy is more predictive of SVR than conventional combination therapy in chronic hepatitis C.

© 2005 S. Karger AG, Basel


  

Key Words

  • High-dose induction interferon
  • Response prediction
  • Early viral dynamics

References

  1. Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825–832.
  2. National Institutes of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology 1997;26(suppl 1):2S–10S.
  3. Pagliaro L, Craxi A, Cammaa C, Tine F, Di Marco V, Lo Iacono O, Almasio P: Interferon-α for chronic hepatitis C: An analysis of pretreatment clinical predictors of response. Hepatology 1994;19:820–828.
  4. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, et al: Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989;321:1501–1506.
  5. Gaeta GB, Precone DF, Felaco FM, Bruno R, Spadaro A, Stornaiuolo G, Stanzione M, Ascione T, De Sena R, Campanone A, Filice G, Piccinino F: Premature discontinuation of interferon plus ribavirin for adverse effects: A multicenter survey in ‘real world’ patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1633–1639.
  6. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS: Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 1998;282:103–107.
  7. Ferenci P, Brunner H, Nachbaur K, Datz C, Gschwantler M, Hofer H, Stauber R, Hackl F, Jessner W, Rosenbeiger M, Munda-Steindl P, Hegenbarth K, Gangl A, Vogel W: Australian Hepatitis Study Group. Combination of interferon induction therapy and ribavirin in chronic hepatitis C. Hepatology 2001;34:1006–1011.
  8. De Ledinghen V, Trimoulet P, Winnock M, Foucher J, Bourliere M, Desmorat H, Canva V, Capron D, Levy S, Mion F, Mannant PR, Chene G, Fleury H, Couzigou P, Bernard PH; French Multicenter Study Group: Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C. J Hepatol 2002;36:672–680.
  9. Karino Y, Toyota J, Sugawara M, Higashino K, Sato T, Ohmura T, Suga T, Okuuchi Y, Matsushima T: Early loss of serum hepatitis C virus RNA can predict a sustained response to interferon therapy in patients with chronic hepatitis C. Am J Gastroenterol 1997;92:61–65.
  10. Yamaji K, Hayashi J, Kawakami Y, Furusyo N, Sawayama Y, Kishihara Y, Etoh Y, Kashiwagi S: Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response. J Clin Gastroenterol 1998;26:193–199.
  11. Kato N, Yokosuka O, Omata M, Hosoda K, Ohto M: Detection of hepatitis C virus ribonucleic acid in the serum by amplification with polymerase chain reaction. J Clin Invest 1990;86:1764–1767.
  12. 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.
  13. Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K, Matsumoto T, Kobayashi M, Iwasaki S, Koyama S, et al: Genotypic subtyping of hepatitis C virus. J Gastroenterol Hepatol 1993;8:150–156.
  14. Bjoro K, Bell H, Hellum KB, Skaug K, Raknerud N, Sandvei P, Doskeland B, Maeland A, Lund-Tonnesen S, Myrvang B: Effect of combined interferon-α induction therapy and ribavirin on chronic hepatitis C virus infection: A randomized multicenter study. Scand J Gastroenterol 2002;37:226–232.
  15. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden TJ: Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997;26:226–231.
  16. Bekkering FC, Brouwer JT, Schalm SW, Elewaut A: Hepatitis C: Viral kinetics. Hepatology 1997;26:1691–1693.
  17. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK: 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;339:1485–1492.
  18. Iino S, Hino K, Yasuda K: Current state of interferon therapy for chronic hepatitis C. Intervirology 1994;37:87–100.
  19. Hu KQ, Vierling JM, Redeker AG: Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection. J Viral Hepat 2001;8:1–18.
  20. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2a plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 2001;358:958–965.
  21. 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.
  22. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, Joh T: Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology 1999;30:787–793.
  23. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, Morgan T, Yao R, Albrecht J: The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology. 2000;119:1317–1323.
  24. Han CJ, Lee HS, Kim HS, Choe JH, Kim CY: Hepatitis C virus genotypes in Korea and their relationship to clinical outcome in type C chronic liver diseases. Korean J Intern Med 1997;12:21–27.
  25. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J: Randomised trial of interferon-α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon-α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet 1998;352:1426–1432.
  26. Martinot-Peignoux M, Boyer N, Pouteau M, Castelnau C, Giuily N, Duchatelle V, Auperin A, Degott C, Benhamou JP, Erlinger S, Marcellin P: Predictors of sustained response to interferon-α therapy in chronic hepatitis C. J Hepatol 1998;29:214–223.
  27. Lee SS: Indicators and predictors of response to anti-viral therapy in chronic hepatitis C. Aliment Pharmacol Ther 2003;17:611–621.
  28. European Association for the Study of the Liver: Consensus Statement. EASL International Consensus Conference on Hepatitis C, Paris, Feb 26–28, 1999. J Hepatol 1999;30:956–961.
  29. McHutchison JG, Shad JA, Gordon SC, Morgan TR, Ling MH, Garaud JJ, Albrecht JK, Dienstag JL: Predicting response to initial therapy with interferon plus ribavirin in chronic hepatitis C using serum HCV RNA results during therapy. J Viral Hepat 2001;8:414–420.
  30. Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Hepatology 2000;31:211–218.
  31. 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.
  32. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK; International Hepatitis Interventional Therapy Group: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.

  

Author Contacts

Hyo-Suk Lee, MD
Department of Internal Medicine
Seoul National University Hospital
28 Yungun-dong Chongno-gu, Seoul 110-744 (Korea)
Tel. +82 2 7602240, Fax +82 2 7436701, E-Mail hsleemd@snu.ac.kr

  

Article Information

Received: July 12, 2004
Accepted after revision: September 6, 2004
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 5, Number of References : 32

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 4, Year 2005 (Cover Date: July-August 2005)

Journal Editor: Liebert, U.G. (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

Objective:In chronic hepatitis C, early viral load decline after interferon administration is dose dependent and reflects the intrinsic viral susceptibility to the antiviral action of interferon. We examined whether the augmented suppression of susceptible viral loads by high-dose induction interferon could possibly discriminate responsive patients from non-responsive patients at an early stage of treatment. Methods: Fifty-nine chronic hepatitis C patients were randomly allocated to receive one of two treatment regimens; 3 MU interferon three times weekly plus ribavirin 1,000 mg/day for 24 weeks in the CR group (n = 30), and the same regimen as in the CR group except 10 MU interferon daily for the first week in the HR group (n = 29). Changes in viral loads during the first week of treatment were analyzed in terms of sustained virological response (SVR). Results: The positive predictive values of undetectable (<100 IU/ml) or low serum HCV RNA (<2,000 IU/ml) after 1 week of treatment for SVR were 100% in both treatment groups, whereas the negative predictive values of the low viral titer were 91% in the HR group and 70% in the CR group. Conclusion: One-week virological response to high-dose induction interferon/ribavirin combination therapy is more predictive of SVR than conventional combination therapy in chronic hepatitis C.

© 2005 S. Karger AG, Basel


  

Author Contacts

Hyo-Suk Lee, MD
Department of Internal Medicine
Seoul National University Hospital
28 Yungun-dong Chongno-gu, Seoul 110-744 (Korea)
Tel. +82 2 7602240, Fax +82 2 7436701, E-Mail hsleemd@snu.ac.kr

  

Article Information

Received: July 12, 2004
Accepted after revision: September 6, 2004
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 5, Number of References : 32

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 4, Year 2005 (Cover Date: July-August 2005)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 1423–0100 (Online)

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


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 7/12/2004
Accepted: 9/6/2004
Published online: 5/24/2005
Issue release date: July–August 2005

Number of Print Pages: 9
Number of Figures: 2
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. Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825–832.
  2. National Institutes of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology 1997;26(suppl 1):2S–10S.
  3. Pagliaro L, Craxi A, Cammaa C, Tine F, Di Marco V, Lo Iacono O, Almasio P: Interferon-α for chronic hepatitis C: An analysis of pretreatment clinical predictors of response. Hepatology 1994;19:820–828.
  4. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, et al: Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989;321:1501–1506.
  5. Gaeta GB, Precone DF, Felaco FM, Bruno R, Spadaro A, Stornaiuolo G, Stanzione M, Ascione T, De Sena R, Campanone A, Filice G, Piccinino F: Premature discontinuation of interferon plus ribavirin for adverse effects: A multicenter survey in ‘real world’ patients with chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1633–1639.
  6. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS: Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 1998;282:103–107.
  7. Ferenci P, Brunner H, Nachbaur K, Datz C, Gschwantler M, Hofer H, Stauber R, Hackl F, Jessner W, Rosenbeiger M, Munda-Steindl P, Hegenbarth K, Gangl A, Vogel W: Australian Hepatitis Study Group. Combination of interferon induction therapy and ribavirin in chronic hepatitis C. Hepatology 2001;34:1006–1011.
  8. De Ledinghen V, Trimoulet P, Winnock M, Foucher J, Bourliere M, Desmorat H, Canva V, Capron D, Levy S, Mion F, Mannant PR, Chene G, Fleury H, Couzigou P, Bernard PH; French Multicenter Study Group: Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C. J Hepatol 2002;36:672–680.
  9. Karino Y, Toyota J, Sugawara M, Higashino K, Sato T, Ohmura T, Suga T, Okuuchi Y, Matsushima T: Early loss of serum hepatitis C virus RNA can predict a sustained response to interferon therapy in patients with chronic hepatitis C. Am J Gastroenterol 1997;92:61–65.
  10. Yamaji K, Hayashi J, Kawakami Y, Furusyo N, Sawayama Y, Kishihara Y, Etoh Y, Kashiwagi S: Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response. J Clin Gastroenterol 1998;26:193–199.
  11. Kato N, Yokosuka O, Omata M, Hosoda K, Ohto M: Detection of hepatitis C virus ribonucleic acid in the serum by amplification with polymerase chain reaction. J Clin Invest 1990;86:1764–1767.
  12. 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.
  13. Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K, Matsumoto T, Kobayashi M, Iwasaki S, Koyama S, et al: Genotypic subtyping of hepatitis C virus. J Gastroenterol Hepatol 1993;8:150–156.
  14. Bjoro K, Bell H, Hellum KB, Skaug K, Raknerud N, Sandvei P, Doskeland B, Maeland A, Lund-Tonnesen S, Myrvang B: Effect of combined interferon-α induction therapy and ribavirin on chronic hepatitis C virus infection: A randomized multicenter study. Scand J Gastroenterol 2002;37:226–232.
  15. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden TJ: Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997;26:226–231.
  16. Bekkering FC, Brouwer JT, Schalm SW, Elewaut A: Hepatitis C: Viral kinetics. Hepatology 1997;26:1691–1693.
  17. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK: 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;339:1485–1492.
  18. Iino S, Hino K, Yasuda K: Current state of interferon therapy for chronic hepatitis C. Intervirology 1994;37:87–100.
  19. Hu KQ, Vierling JM, Redeker AG: Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection. J Viral Hepat 2001;8:1–18.
  20. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2a plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 2001;358:958–965.
  21. 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.
  22. Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, Albert D, Joh T: Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology 1999;30:787–793.
  23. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, Morgan T, Yao R, Albrecht J: The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology. 2000;119:1317–1323.
  24. Han CJ, Lee HS, Kim HS, Choe JH, Kim CY: Hepatitis C virus genotypes in Korea and their relationship to clinical outcome in type C chronic liver diseases. Korean J Intern Med 1997;12:21–27.
  25. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J: Randomised trial of interferon-α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon-α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet 1998;352:1426–1432.
  26. Martinot-Peignoux M, Boyer N, Pouteau M, Castelnau C, Giuily N, Duchatelle V, Auperin A, Degott C, Benhamou JP, Erlinger S, Marcellin P: Predictors of sustained response to interferon-α therapy in chronic hepatitis C. J Hepatol 1998;29:214–223.
  27. Lee SS: Indicators and predictors of response to anti-viral therapy in chronic hepatitis C. Aliment Pharmacol Ther 2003;17:611–621.
  28. European Association for the Study of the Liver: Consensus Statement. EASL International Consensus Conference on Hepatitis C, Paris, Feb 26–28, 1999. J Hepatol 1999;30:956–961.
  29. McHutchison JG, Shad JA, Gordon SC, Morgan TR, Ling MH, Garaud JJ, Albrecht JK, Dienstag JL: Predicting response to initial therapy with interferon plus ribavirin in chronic hepatitis C using serum HCV RNA results during therapy. J Viral Hepat 2001;8:414–420.
  30. Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Hepatology 2000;31:211–218.
  31. 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.
  32. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK; International Hepatitis Interventional Therapy Group: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069.