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.

  • Timeline
  • Published:

25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end

Abstract

Chronic hepatitis caused by infection with hepatitis C virus C (HCV) (therefore known as chronic hepatitis C (CHC)) is a leading cause of liver disease worldwide. For the past 25 years, recombinant interferon-α (IFNα) has been the main component of treatments for HCV infection. Treatment efficacy has shown a stepwise improvement following the pegylation of IFNα and its use in combination with other antiviral drugs. However, viral escape mechanisms, refractory IFNα signalling in the liver and substantial drug toxicity still limit the efficacy of this treatment. A new generation of HCV-specific antiviral drugs will probably improve response rates and might replace IFNs in CHC treatment in the next few years. This Timeline article summarizes the history of CHC treatment using recombinant IFNα with an emphasis on the mechanisms of action and the causes of non-response.

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

Access options

Buy this article

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

Figure 1: Natural history of CHC.
Figure 2
Figure 3: Virological responses following CHC treatment with pegIFNα and ribavirin.
Figure 4: The stepwise increase in sustained virological response rates in the past 25 years.
Figure 5: Host and viral factors that regulate endogenous ISG expression in the liver of patients with CHC.

References

  1. Shepard, C. W., Finelli, L. & Alter, M. J. Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis. 5, 558–567 (2005).

    PubMed  Google Scholar 

  2. Bigger, C. B., Brasky, K. M. & Lanford, R. E. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J. Virol. 75, 7059–7066 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Thimme, R. et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc. Natl Acad. Sci. USA 99, 15661–15668 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dill, M. T. et al. Interferon-γ-stimulated genes, but not USP18, are expressed in livers of patients with acute hepatitis C. Gastroenterology 143, 777–786.e1–6 (2012).

    CAS  PubMed  Google Scholar 

  5. Lauer, G. M. & Walker, B. D. Hepatitis C virus infection. N. Engl. J. Med. 345, 41–52 (2001).

    CAS  PubMed  Google Scholar 

  6. Choo, Q. L. et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244, 359–362 (1989).

    CAS  PubMed  Google Scholar 

  7. Moradpour, D., Penin, F. & Rice, C. M. Replication of hepatitis C virus. Nature Rev. Microbiol. 5, 453–463 (2007).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Powdrill, M. H. et al. Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance. Proc. Natl Acad. Sci. USA 108, 20509–20513 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kuiken, C. & Simmonds, P. Nomenclature and numbering of the hepatitis C virus. Methods Mol. Biol. 510, 33–53 (2009).

    CAS  PubMed  Google Scholar 

  11. Hoofnagle, J. H. et al. Treatment of chronic non-A,non-B hepatitis with recombinant human α-interferon. A preliminary report. New Engl. J. Med. 315, 1575–1578 (1986).

    CAS  PubMed  Google Scholar 

  12. Heim, M. H. Innate immunity and HCV. J. Hepatol. 58, 564–574 (2013).

    CAS  PubMed  Google Scholar 

  13. Manns, M. P. et al. Peginterferon-α2b plus ribavirin compared with interferon-α2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958–965 (2001).

    CAS  PubMed  Google Scholar 

  14. Fried, M. W. et al. Peginterferon-α2a plus ribavirin for chronic hepatitis C virus infection. New Engl. J. Med. 347, 975–982 (2002).

    CAS  PubMed  Google Scholar 

  15. Sarasin-Filipowicz, M. et al. α-interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol. Cell. Biol. 29, 4841–4851 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    CAS  PubMed  Google Scholar 

  17. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nature Genet. 41, 1100–1104 (2009).

    CAS  PubMed  Google Scholar 

  18. Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nature Genet. 41, 1105–1109 (2009).

    CAS  PubMed  Google Scholar 

  19. Rauch, A. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138, 1338–1345, 1345.e1–7 (2010).

    CAS  PubMed  Google Scholar 

  20. Prokunina-Olsson, L. et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature Genet. 45, 164–171 (2013).

    CAS  PubMed  Google Scholar 

  21. Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. Proc. R. Soc. Lond. B Biol. Sci. 147, 258–267 (1957).

    CAS  PubMed  Google Scholar 

  22. Pestka, S. The interferons: 50 years after their discovery, there is much more to learn. J. Biol. Chem. 282, 20047–20051 (2007).

    CAS  PubMed  Google Scholar 

  23. Darnell, J. E. Jr., Kerr, I. M. & Stark, G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    CAS  PubMed  Google Scholar 

  24. van Boxel-Dezaire, A. H., Rani, M. R. & Stark, G. R. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25, 361–372 (2006).

    CAS  PubMed  Google Scholar 

  25. Stetson, D. B. & Medzhitov, R. Type I interferons in host defense. Immunity 25, 373–381 (2006).

    CAS  PubMed  Google Scholar 

  26. Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nature Rev. Immunol. 8, 559–568 (2008).

    CAS  Google Scholar 

  27. Terenzi, F., Hui, D. J., Merrick, W. C. & Sen, G. C. Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56. J. Biol. Chem. 281, 34064–34071 (2006).

    CAS  PubMed  Google Scholar 

  28. Schoggins, J. W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Metz, P. et al. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology 56, 2082–2093 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Wilkins, C. et al. IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57, 461–469 (2013).

    CAS  PubMed  Google Scholar 

  31. Everitt, A. R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–523 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034–7039 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dalod, M. et al. Dendritic cell responses to early murine cytomegalovirus infection: subset functional specialization and differential regulation by interferon-α/β. J. Exp. Med. 197, 885–898 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nguyen, K. B. et al. Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection. J. Immunol. 169, 4279–4287 (2002).

    CAS  PubMed  Google Scholar 

  35. Lee, C. K. et al. Distinct requirements for IFNs and STAT1 in NK cell function. J. Immunol. 165, 3571–3577 (2000).

    CAS  PubMed  Google Scholar 

  36. Havenar-Daughton, C., Kolumam, G. A. & Murali-Krishna, K. Cutting Edge: The direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J. Immunol. 176, 3315–3319 (2006).

    CAS  PubMed  Google Scholar 

  37. Kolumam, G. A., Thomas, S., Thompson, L. J., Sprent, J. & Murali-Krishna, K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J. Exp. Med. 202, 637–650 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Aichele, P. et al. CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion. J. Immunol. 176, 4525–4529 (2006).

    CAS  PubMed  Google Scholar 

  39. Shoukry, N. H. et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med. 197, 1645–1655 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).

    CAS  PubMed  Google Scholar 

  41. Kamal, S. M., Fehr, J., Roesler, B., Peters, T. & Rasenack, J. W. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology 123, 1070–1083 (2002).

    CAS  PubMed  Google Scholar 

  42. Cramp, M. E. et al. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology 118, 346–355 (2000).

    CAS  PubMed  Google Scholar 

  43. Barnes, E. et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 36, 743–754 (2002).

    CAS  PubMed  Google Scholar 

  44. Aberle, J. H. et al. CD4+ T cell responses in patients with chronic hepatitis C undergoing peginterferon/ribavirin therapy correlate with faster, but not sustained, viral clearance. J. Infect. Dis. 195, 1315–1319 (2007).

    CAS  PubMed  Google Scholar 

  45. Pilli, M. et al. HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV project). Gastroenterology 133, 1132–1143 (2007).

    CAS  PubMed  Google Scholar 

  46. Goeddel, D. V. et al. Human leukocyte interferon produced by E. coli is biologically active. Nature 287, 411–416 (1980).

    CAS  PubMed  Google Scholar 

  47. Nagata, S. et al. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature 284, 316–320 (1980).

    CAS  PubMed  Google Scholar 

  48. Weimar, W. et al. Double-blind study of leucocyte interferon administration in chronic HBsAg-positive hepatitis. Lancet 1, 336–338 (1980).

    CAS  PubMed  Google Scholar 

  49. Scullard, G. H. et al. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J. Infect. Dis. 143, 772–783 (1981).

    CAS  PubMed  Google Scholar 

  50. Davis, G. L. et al. Treatment of chronic hepatitis C with recombinant interferon-α. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. New Engl. J. Med. 321, 1501–1506 (1989).

    CAS  PubMed  Google Scholar 

  51. Di Bisceglie, A. M. et al. Recombinant interferon-α therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. New Engl. J. Med. 321, 1506–1510 (1989).

    CAS  PubMed  Google Scholar 

  52. Marcellin, P. et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-α therapy. Ann. Internal Med. 127, 875–881 (1997).

    CAS  Google Scholar 

  53. Bedossa, P. & Poynard, T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 24, 289–293 (1996).

    CAS  PubMed  Google Scholar 

  54. D'Ambrosio, R. et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56, 532–543 (2012).

    PubMed  Google Scholar 

  55. Lin, R., Roach, E., Zimmerman, M., Strasser, S. & Farrell, G. C. Interferon-α2b for chronic hepatitis C: effects of dose increment and duration of treatment on response rates. Results of the first multicentre Australian trial. Australia Hepatitis C Study Group. J. Hepatol 23, 487–496 (1995).

    CAS  PubMed  Google Scholar 

  56. Poynard, T. et al. A comparison of three interferon-α2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group. N. Engl. J. Med. 332, 1457–1462 (1995).

    CAS  PubMed  Google Scholar 

  57. Reichard, O., Andersson, J., Schvarcz, R. & Weiland, O. Ribavirin treatment for chronic hepatitis C. Lancet 337, 1058–1061 (1991).

    CAS  PubMed  Google Scholar 

  58. Di Bisceglie, A. M. et al. A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16, 649–654 (1992).

    CAS  PubMed  Google Scholar 

  59. Schalm, S. W. et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers. J. Hepatol. 26, 961–966 (1997).

    CAS  PubMed  Google Scholar 

  60. Schvarcz, R., Yun, Z. B., Sonnerborg, A. & Weiland, O. Combined treatment with interferon-α2b and ribavirin for chronic hepatitis C in patients with a previous non-response or non-sustained response to interferon alone. J. Med. Virol. 46, 43–47 (1995).

    CAS  PubMed  Google Scholar 

  61. Reichard, O. et al. Randomised, double-blind, placebo-controlled trial of interferon-α2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 351, 83–87 (1998).

    CAS  PubMed  Google Scholar 

  62. McHutchison, J. G. et al. Interferon-α2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. New Engl. J. Med. 339, 1485–1492 (1998).

    CAS  PubMed  Google Scholar 

  63. Feld, J. J. & Hoofnagle, J. H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436, 967–972 (2005).

    CAS  PubMed  Google Scholar 

  64. Paeshuyse, J., Dallmeier, K. & Neyts, J. Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr. Opin. Virol. 1, 590–598 (2011).

    CAS  PubMed  Google Scholar 

  65. Zeuzem, S. et al. Peginterferon-α2a in patients with chronic hepatitis C. N. Engl. J. Med. 343, 1666–1672 (2000).

    CAS  PubMed  Google Scholar 

  66. Lindsay, K. L. et al. A randomized, double-blind trial comparing pegylated interferon-α2b to interferon-α2b as initial treatment for chronic hepatitis C. Hepatology 34, 395–403 (2001).

    CAS  PubMed  Google Scholar 

  67. Larner, A. C., Chaudhuri, A. & Darnell, J. E. Jr. Transcriptional induction by interferon. New protein(s) determine the extent and length of the induction. J. Biol. Chem. 261, 453–459 (1986).

    CAS  PubMed  Google Scholar 

  68. Makowska, Z., Duong, F. H., Trincucci, G., Tough, D. F. & Heim, M. H. Interferon-β and interferon-λ signaling is not affected by interferon-induced refractoriness to interferon-α in vivo. Hepatology 53, 1154–1163 (2011).

    CAS  PubMed  Google Scholar 

  69. Poordad, F. et al. Boceprevir for untreated chronic HCV genotype 1 infection. New Engl. J. Med. 364, 1195–1206 (2011).

    CAS  PubMed  Google Scholar 

  70. Jacobson, I. M. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. New Engl. J. Med. 364, 2405–2416 (2011).

    CAS  PubMed  Google Scholar 

  71. Poordad, F. & Dieterich, D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J. Viral Hepat. 19, 449–464 (2012).

    CAS  PubMed  Google Scholar 

  72. Sarrazin, C., Hezode, C., Zeuzem, S. & Pawlotsky, J. M. Antiviral strategies in hepatitis C virus infection. J. Hepatol. 56, S88–S100 (2012).

    CAS  PubMed  Google Scholar 

  73. Lok, A. S. et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. New Engl. J. Med. 366, 216–224 (2012).

    CAS  PubMed  Google Scholar 

  74. Su, A. I. et al. Genomic analysis of the host response to hepatitis C virus infection. Proc. Natl Acad. Sci. USA 99, 15669–15674 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Major, M. E. et al. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees. Hepatology 39, 1709–1720 (2004).

    PubMed  Google Scholar 

  76. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    CAS  PubMed  Google Scholar 

  77. Heim, M. H., Moradpour, D. & Blum, H. E. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J. Virol. 73, 8469–8475 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Garaigorta, U. & Chisari, F. V. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe 6, 513–522 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Cox, A. L. et al. Cellular immune selection with hepatitis C virus persistence in humans. J. Exp. Med. 201, 1741–1752 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Erickson, A. L. et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15, 883–895 (2001).

    CAS  PubMed  Google Scholar 

  81. Tester, I. et al. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J. Exp. Med. 201, 1725–1731 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Urbani, S. et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80, 11398–11403 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Neumann-Haefelin, C. & Thimme, R. Success and failure of virus-specific T cell responses in hepatitis C virus infection. Dig. Dis. 29, 416–422 (2011).

    PubMed  Google Scholar 

  84. Chen, L. et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128, 1437–1444 (2005).

    CAS  PubMed  Google Scholar 

  85. Asselah, T. et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 57, 516–524 (2008).

    CAS  PubMed  Google Scholar 

  86. Feld, J. J. et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 46, 1548–1563 (2007).

    CAS  PubMed  Google Scholar 

  87. Dill, M. T. et al. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology 140, 1021–1031 (2011).

    CAS  PubMed  Google Scholar 

  88. Honda, M. et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139, 499–509 (2010).

    CAS  PubMed  Google Scholar 

  89. Urban, T. J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).

    CAS  PubMed  Google Scholar 

  90. Bellecave, P. et al. Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system. Hepatology 51, 1127–1136 (2010).

    CAS  PubMed  Google Scholar 

  91. Muir, A. J. et al. Phase 1b study of pegylated interferon-λ1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology 52, 822–832 (2010).

    CAS  PubMed  Google Scholar 

  92. Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).

    CAS  PubMed  Google Scholar 

  93. Akuta, N. et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin-28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 52, 421–429 (2010).

    CAS  PubMed  Google Scholar 

  94. Zeuzem, S. et al. Telaprevir for retreatment of HCV infection. New Engl. J. Med. 364, 2417–2428 (2011).

    CAS  PubMed  Google Scholar 

  95. Bacon, B. R. et al. Boceprevir for previously treated chronic HCV genotype 1 infection. New Engl. J. Med. 364, 1207–1217 (2011).

    CAS  PubMed  Google Scholar 

  96. Gale, M. Jr & Foy, E. M. Evasion of intracellular host defence by hepatitis C virus. Nature 436, 939–945 (2005).

    CAS  PubMed  Google Scholar 

  97. Thimme, R., Binder, M. & Bartenschlager, R. Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol. Rev. 36, 663–683 (2012).

    CAS  PubMed  Google Scholar 

  98. Kotenko, S. V. et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4, 69–77 (2003).

    CAS  Google Scholar 

  99. Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immunol. 4, 63–68 (2003).

    CAS  Google Scholar 

  100. Yu, J. W., Wang, G. Q., Sun, L. J., Li, X. G. & Li, S. C. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon-α2a and ribavirin. J. Gastroenterol. Hepatol. 22, 832–836 (2007).

    CAS  PubMed  Google Scholar 

  101. Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189 (2003).

    CAS  PubMed  Google Scholar 

  102. Alter, H. J. et al. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 2, 838–841 (1975).

    CAS  PubMed  Google Scholar 

  103. Feinstone, S. M., Kapikian, A. Z., Purcell, R. H., Alter, H. J. & Holland, P. V. Transfusion-associated hepatitis not due to viral hepatitis type A or B. New Engl. J. Med. 292, 767–770 (1975).

    CAS  PubMed  Google Scholar 

  104. Kim, J. L. et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87, 343–355 (1996).

    CAS  PubMed  Google Scholar 

  105. Ago, H. et al. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7, 1417–1426 (1999).

    CAS  PubMed  Google Scholar 

  106. Lesburg, C. A. et al. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nature Struct. Biol. 6, 937–943 (1999).

    CAS  PubMed  Google Scholar 

  107. Tellinghuisen, T. L., Marcotrigiano, J. & Rice, C. M. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435, 374–379 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Markus H. Heim.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heim, M. 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol 13, 535–542 (2013). https://doi.org/10.1038/nri3463

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3463

This article is cited by

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