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.
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Shepard, C. W., Finelli, L. & Alter, M. J. Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis. 5, 558–567 (2005).
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).
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).
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).
Lauer, G. M. & Walker, B. D. Hepatitis C virus infection. N. Engl. J. Med. 345, 41–52 (2001).
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).
Moradpour, D., Penin, F. & Rice, C. M. Replication of hepatitis C virus. Nature Rev. Microbiol. 5, 453–463 (2007).
Neumann, A. U. et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 282, 103–107 (1998).
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).
Kuiken, C. & Simmonds, P. Nomenclature and numbering of the hepatitis C virus. Methods Mol. Biol. 510, 33–53 (2009).
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).
Heim, M. H. Innate immunity and HCV. J. Hepatol. 58, 564–574 (2013).
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).
Fried, M. W. et al. Peginterferon-α2a plus ribavirin for chronic hepatitis C virus infection. New Engl. J. Med. 347, 975–982 (2002).
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).
Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).
Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nature Genet. 41, 1100–1104 (2009).
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).
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).
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).
Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. Proc. R. Soc. Lond. B Biol. Sci. 147, 258–267 (1957).
Pestka, S. The interferons: 50 years after their discovery, there is much more to learn. J. Biol. Chem. 282, 20047–20051 (2007).
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).
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).
Stetson, D. B. & Medzhitov, R. Type I interferons in host defense. Immunity 25, 373–381 (2006).
Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nature Rev. Immunol. 8, 559–568 (2008).
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).
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).
Metz, P. et al. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. Hepatology 56, 2082–2093 (2012).
Wilkins, C. et al. IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57, 461–469 (2013).
Everitt, A. R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–523 (2012).
Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034–7039 (2008).
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).
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).
Lee, C. K. et al. Distinct requirements for IFNs and STAT1 in NK cell function. J. Immunol. 165, 3571–3577 (2000).
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).
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).
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).
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).
Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).
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).
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).
Barnes, E. et al. The dynamics of T-lymphocyte responses during combination therapy for chronic hepatitis C virus infection. Hepatology 36, 743–754 (2002).
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).
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).
Goeddel, D. V. et al. Human leukocyte interferon produced by E. coli is biologically active. Nature 287, 411–416 (1980).
Nagata, S. et al. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature 284, 316–320 (1980).
Weimar, W. et al. Double-blind study of leucocyte interferon administration in chronic HBsAg-positive hepatitis. Lancet 1, 336–338 (1980).
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).
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).
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).
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).
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).
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).
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).
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).
Reichard, O., Andersson, J., Schvarcz, R. & Weiland, O. Ribavirin treatment for chronic hepatitis C. Lancet 337, 1058–1061 (1991).
Di Bisceglie, A. M. et al. A pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 16, 649–654 (1992).
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).
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).
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).
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).
Feld, J. J. & Hoofnagle, J. H. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436, 967–972 (2005).
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).
Zeuzem, S. et al. Peginterferon-α2a in patients with chronic hepatitis C. N. Engl. J. Med. 343, 1666–1672 (2000).
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).
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).
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).
Poordad, F. et al. Boceprevir for untreated chronic HCV genotype 1 infection. New Engl. J. Med. 364, 1195–1206 (2011).
Jacobson, I. M. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. New Engl. J. Med. 364, 2405–2416 (2011).
Poordad, F. & Dieterich, D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J. Viral Hepat. 19, 449–464 (2012).
Sarrazin, C., Hezode, C., Zeuzem, S. & Pawlotsky, J. M. Antiviral strategies in hepatitis C virus infection. J. Hepatol. 56, S88–S100 (2012).
Lok, A. S. et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. New Engl. J. Med. 366, 216–224 (2012).
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).
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).
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).
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).
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).
Cox, A. L. et al. Cellular immune selection with hepatitis C virus persistence in humans. J. Exp. Med. 201, 1741–1752 (2005).
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).
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).
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).
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).
Chen, L. et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128, 1437–1444 (2005).
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).
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).
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).
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).
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).
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).
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).
Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).
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).
Zeuzem, S. et al. Telaprevir for retreatment of HCV infection. New Engl. J. Med. 364, 2417–2428 (2011).
Bacon, B. R. et al. Boceprevir for previously treated chronic HCV genotype 1 infection. New Engl. J. Med. 364, 1207–1217 (2011).
Gale, M. Jr & Foy, E. M. Evasion of intracellular host defence by hepatitis C virus. Nature 436, 939–945 (2005).
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).
Kotenko, S. V. et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4, 69–77 (2003).
Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immunol. 4, 63–68 (2003).
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).
Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189 (2003).
Alter, H. J. et al. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 2, 838–841 (1975).
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).
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).
Ago, H. et al. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7, 1417–1426 (1999).
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).
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).
Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005).
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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
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