Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection

Nature volume 432, pages 922–924 (2004)Cite this article

Abstract

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV)1. Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated2,3,4. No effective alternative treatments exist for non-responders5. Consequently, significant efforts are continuing to maximize response to combination therapy6,7. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV8. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load9,10,11,12, but in combination with interferon it significantly improves long-term response rates2,3,4,13,14,15. Here we present a model of HCV dynamics in which, on the basis of growing evidence16,17,18,19,20,21, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Theoretical viral load decay profiles.
Figure 2: Comparison of theoretical viral load decay profiles with patient data.
Figure 3: Model predictions of ETR and SVR.

Similar content being viewed by others

References

  1. World Health Organization, Hepatitis C—global prevalence (update). World Health Org. Weekly Epidemiol. Rec. 75, 18–19 (2000)

    Google Scholar 

  2. National Institutes of Health. Consensus Statement on Management of Hepatitis C. NIH Consens. State Sci. Statements 19, 1–46 (2002)

    Google Scholar 

  3. Manns, M. P. et al. Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965 (2001)

    Article  CAS  Google Scholar 

  4. Fried, M. W. et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347, 975–982 (2002)

    Article  CAS  Google Scholar 

  5. Tan, S.-L., Pause, A., Shi, Y. & Sonenberg, N. Hepatitis C therapeutics: Current status and emerging strategies. Nature Rev. Drug Discov. 1, 867–881 (2002)

    Article  CAS  Google Scholar 

  6. Shiffman, M. L. et al. A randomized, controlled trial to determine whether continued ribavirin monotherapy in hepatitis C virus-infected patients who responded to interferon–ribavirin combination therapy will enhance sustained virologic response. J. Infect. Dis. 184, 405–409 (2001)

    Article  CAS  Google Scholar 

  7. Hoofnagle, J. H. et al. Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alpha and ribavirin. Hepatology 38, 66–74 (2003)

    Article  CAS  Google Scholar 

  8. Lau, J. Y. N., Tam, R. C., Liang, T. J. & Hong, Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 35, 1002–1009 (2002)

    Article  CAS  Google Scholar 

  9. Dusheiko, G. et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J. Hepatol. 25, 591–598 (1996)

    Article  CAS  Google Scholar 

  10. Bodenheimer, H. C. et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: A multicenter trial. Hepatology 26, 473–477 (1997)

    Article  CAS  Google Scholar 

  11. Zoulim, F. et al. Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients. J. Viral Hepat. 5, 193–198 (1998)

    Article  CAS  Google Scholar 

  12. Pawlotsky, J.-M. et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 126, 703–714 (2004)

    Article  CAS  Google Scholar 

  13. McHutchison, J. G. et al. Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Engl. J. Med. 339, 1485–1492 (1998)

    Article  CAS  Google Scholar 

  14. Reichard, O. et al. Randomized, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C. Lancet 351, 83–87 (1998)

    Article  CAS  Google Scholar 

  15. Poynard, T. et al. Randomized 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. Lancet 352, 1426–1432 (1998)

    Article  CAS  Google Scholar 

  16. Lanford, R. E. et al. Antiviral effect and virus-host interactions in response to alpha interferon, gamma interferon, poly(I)-poly(C), tumor necrosis factor alpha, and ribavirin in hepatitis C virus subgenomic replicons. J. Virol. 77, 1092–1104 (2003)

    Article  CAS  Google Scholar 

  17. Contreras, A. M., Viral, R. N. A. et al. mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system. J. Virol. 76, 8505–8517 (2002)

    Article  CAS  Google Scholar 

  18. Young, K.-C. et al. Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology 38, 869–878 (2003)

    Article  CAS  Google Scholar 

  19. Lanford, R. E. et al. Ribavirin induces error-prone replication of GB virus B in primary tamarin hepatocytes. J. Virol. 75, 8074–8081 (2001)

    Article  CAS  Google Scholar 

  20. Hong, Z. The role of ribavirin-induced mutagenesis in HCV therapy: A concept or a fact? Hepatology 38, 807–810 (2003)

    Article  CAS  Google Scholar 

  21. Crotty, S., Cameron, C. E. & Andino, R. RNA virus error catastrophe: Direct molecular test by using ribavirin. Proc. Natl Acad. Sci. USA 98, 6895–6900 (2001)

    Article  ADS  CAS  Google Scholar 

  22. Neumann, A. U. et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 282, 103–107 (1998)

    Article  ADS  CAS  Google Scholar 

  23. Layden-Almer, J. E., Ribeiro, R. M., Wiley, T., Perelson, A. S. & Layden, T. J. Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin. Hepatology 37, 1343–1350 (2003)

    Article  CAS  Google Scholar 

  24. Herrmann, E., Lee, J.-H., Marison, G., Modi, M. & Zeuzem, S. Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 37, 1351–1358 (2003)

    Article  CAS  Google Scholar 

  25. Glue, P. The clinical pharmacology of ribavirin. Semin. Liv. Dis. 19, 17–24 (1999)

    CAS  Google Scholar 

  26. Steindl-Munda, P. et al. in Abstracts 11th Int. Symp. Viral Hepatitis and Liver Dis. 75–76 (2003).

  27. Tsuboto, A. et al. Viral dynamics and pharmacokinetics in combined interferon α-2b and ribavirin therapy for patients infected with hepatitis C virus of genotype 1b and high pretreatment viral load. Intervirology 45, 33–42 (2002)

    Article  Google Scholar 

  28. Neumann, A. U. et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J. Infect. Dis. 182, 28–35 (2000)

    Article  CAS  Google Scholar 

  29. McHutchison, J. G. et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. Gastroenterology 119, 1317–1323 (2000)

    Article  CAS  Google Scholar 

  30. Powers, K. A. et al. Modeling viral and drug kinetics: hepatitis C virus treatment with pegylated interferon α-2b. Semin. Liv. Dis. 23, 13–18 (2003)

    Article  Google Scholar 

Download references

Acknowledgements

We thank R. M. Ribeiro, J.-M. Pawlotsky, S. Zeuzem, X. Tong and B. Malcolm for helpful comments. Portions of this work were performed under the auspices of the US Department of Energy and supported by grants from the NIH, the University of Illinois and the Chicago VA.

Author information

Authors and Affiliations

  1. Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, 87545, USA

    Narendra M. Dixit & Alan S. Perelson

  2. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, USA

    Jennifer E. Layden-Almer & Thomas J. Layden

Authors
  1. Narendra M. Dixit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer E. Layden-Almer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas J. Layden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alan S. Perelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan S. Perelson.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Notes

Contains Supplementary Notes S1–S5, additional comments on the text. (DOC 25 kb)

Supplementary Tables S1–S3

Supplementary Table 1: Best-fit parameter estimates obtained from comparisons of model predictions with experimental viral load data from 17 patients who were given high dose daily interferon along with 1000 or 1200 mg ribavirin daily for the first 28 days of therapy; Supplementary Table 2: Model calculations of end-of-treatment (ETR) and sustained virological responses (SVR) for different initial viral loads, V0, interferon effectiveness, ε, and durations of treatment (24 or 48 weeks), with and without ribavirin; Supplementary Table 3: Estimates of ETR and SVR values as percentages of patients who completed therapy in various studies. (DOC 154 kb)

Supplementary Figure S1

Contains Supplementary Figure S1 and legends. (DOC 1041 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dixit, N., Layden-Almer, J., Layden, T. et al. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 432, 922–924 (2004). https://doi.org/10.1038/nature03153

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03153

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing