Elsevier

Advanced Drug Delivery Reviews

Volume 59, Issue 12, 10 October 2007, Pages 1222-1241
Advanced Drug Delivery Reviews

Interferon-based therapy of hepatitis C

https://doi.org/10.1016/j.addr.2007.07.002Get rights and content

Abstract

In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN). The first clinical trial of recombinant IFN–α in patients with chronic hepatitis C was published in 1986. This article reviews the classification of IFNs, IFN production during viral infections, IFN signaling pathways and the mechanisms of their antiviral and immunomodulatory properties. Hepatitis C virus infection treatment is currently based on the combination of pegylated IFN–α and ribavirin. The pegylated IFN–α molecules are described, as well as the putative mechanisms of action of ribavirin. Current treatment guidelines are discussed and new results suggesting that the treatment schedule should be tailored to the early virological response during therapy are presented. Finally, insights into new hepatitis C drug developments are given.

Section snippets

Interferons

IFNs are natural glycoproteins produced by the cells of most vertebrates in response to challenge by foreign agents, such as infectious organisms (viruses, bacteria, fungi and parasites), and by tumor cells. IFNs can be produced by cells of the innate and adaptive immune systems and by non-immune cells such as fibroblasts and epithelial cells.

Antiviral properties of type I IFNS in models of HCV infection

Type I IFNs, and especially IFN–α, have been shown to inhibit HCV replication in various productive and nonproductive cellular and animal models. The effects of IFNs on anti-HCV immune responses have not been elucidated in these models.

Treatment of chronic HCV infection with IFN–α

Chronic HCV infection is curable, and cure is the goal of antiviral therapy. Successful treatment is characterized by a “sustained virological response” (SVR), defined by undetectable HCV RNA in a sensitive assay (detection limit ≤ 50 international units (IU)/ml) 6 months after the end of therapy. Recent large-scale follow-up studies have shown no relapse or recurrence after 4 to 6 years in more than 99% of patients who have an SVR [83], [84].

The choice of IFN–α as a potential treatment for

Treatment of acute HCV infection with IFN–α

HCV infection is rarely diagnosed in the acute phase, as most acutely infected individuals are asymptomatic. Between 50% and 90% of patients develop chronic infection, however, and this warrants early therapy. After occupational exposure with a known date, treatment should not be started before the acute episode characterized by alanine aminotransferase elevation, but it should always be started within 24 weeks after symptom onset. The optimal treatment schedule for acute hepatitis C is

IFN–β

Several studies have tested IFN–β for chronic hepatitis C, achieving response rates similar to those obtained with IFN–α and with similar or fewer adverse effects [172], [173], [174], [175], [176]. Recent reports from Japan suggest that daily IFN–β administration is highly effective in patients with low or moderate HCV RNA levels [177], [178]. Twice-daily administration of IFN–β as induction therapy has also been reported to be effective [179], [180]. It is unlikely, however, that IFN–β will be

Conclusion

Treatment of chronic HCV infection is currently based on IFN–α, by virtue of its potent antiviral and immunomodulatory properties. The pegylated IFN–α–ribavirin combination eradicates the infection in approximately half the patients who receive it, and IFN–α is likely to remain the cornerstone of HCV therapy for many years to come. There is still room for improvement in IFN–α-based therapy, by using higher drug dosages, by tailoring administration to the virological response during treatment,

Landmark papers

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

J.H. Hoofnagle, K.D. Mullen, D.B. Jones, V. Rustgi, A. Di Bisceglie, M. Peters, J.G. Waggoner, Y. Park, E.A. Jones, Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report, N. Engl. J. Med. 315 (1986) 1575–1578.

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

T.

Challenges to be met

  • 1.

    Determine whether IFN–α acts essentially through its antiviral properties or if its immunomodulatory properties are important to achieve an HCV clearance.

  • 2.

    Understand the mechanisms by which ribavirin prevents breakthroughs and relapses in patients who respond to IFN–α antiviral action.

  • 3.

    Better tailor IFN–α-based therapy to the early virological response (at week 2 or week 4).

  • 4.

    Optimize the results of IFN–α-based therapy.

  • 5.

    Ultimately replace IFN–α-based therapies by well-tolerated combinations of oral

References (211)

  • E.M. Creagh et al.

    TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity

    Trends Immunol.

    (2006)
  • L. Dumoutier et al.

    Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling

    J. Biol. Chem.

    (2004)
  • D.J. Gough et al.

    A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes

    J. Biol. Chem.

    (2007)
  • A.G. Hovanessian et al.

    The human 2′–5′oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2′–5′ instead of 3′–5′ phosphodiester bond formation

    Biochimie

    (2007)
  • A.G. Hovanessian et al.

    Anticellular and antiviral effects of pppA(2′p5′A)n

    Virology

    (1980)
  • A. Zhou et al.

    Expression cloning of 2–5A-dependent RNAase: a uniquely regulated mediator of interferon action

    Cell

    (1993)
  • B.L. Bass

    RNA editing and hypermutation by adenosine deamination

    Trends Biochem. Sci.

    (1997)
  • T. Horio et al.

    Crystal structure of human ISG20, an interferon-induced antiviral ribonuclease

    FEBS Lett.

    (2004)
  • L. Espert et al.

    ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses

    J. Biol. Chem.

    (2003)
  • G. Degols et al.

    ISG20, an actor of the innate immune response

    Biochimie

    (2007)
  • F. Terenzi et al.

    Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56

    J. Biol. Chem.

    (2006)
  • M. Solis et al.

    Distinct functions of IRF-3 and IRF-7 in IFN–alpha gene regulation and control of anti-tumor activity in primary macrophages

    Biochem. Pharmacol.

    (2006)
  • T. Marcello et al.

    Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics

    Gastroenterology

    (2006)
  • N. Sakamoto et al.

    Bone morphogenetic protein-7 and interferon-alpha synergistically suppress hepatitis C virus replicon

    Biochem. Biophys. Res. Commun.

    (2007)
  • G.W. Demers et al.

    Interferon-alpha2b secretion by adenovirus-mediated gene delivery in rat, rabbit, and chimpanzee results in similar pharmacokinetic profiles

    Toxicol. Appl. Pharmacol.

    (2002)
  • N. Hiraga et al.

    Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon

    FEBS Lett.

    (2007)
  • J.G. McHutchison et al.

    Sustained virologic response (SVR) to interferon-alpha-2b ± ribavirin therapy at 6 months reliably predicts long-term clearance of HCV at 5-year follow-up

    J. Hepatol.

    (2006)
  • M.G. Swain et al.

    Durable sustained virological response after treatment with peginterferon alfa-2a (Pegasys) alone or in combination with ribavirin (Copegus): 5-year follow-up and the criteria for a cure

    J. Hepatol.

    (2007)
  • K.L. Lindsay 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)
  • J.M. Pawlotsky et al.

    Antiviral action of ribavirin in chronic hepatitis C

    Gastroenterology

    (2004)
  • S. Foser et al.

    Isolation, structural characterization, and antiviral activity of positional isomers of monopegylated interferon alpha-2a (Pegasys)

    Protein Expr. Purif.

    (2003)
  • M. Silva et al.

    A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE)

    J. Hepatol.

    (2006)
  • A. Isaacs et al.

    Virus interference. I. The interferon

    Proc. R. Soc. Lond., B. Biol. Sci.

    (1957)
  • S. Nagata et al.

    Synthesis in E. coli of a polypeptide with human leukocyte interferon activity

    Nature

    (1980)
  • J.H. Hoofnagle et al.

    Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report

    N. Engl. J. Med.

    (1986)
  • K.E. Mogensen et al.

    The type I interferon receptor: structure, function, and evolution of a family business

    J. Interferon Cytokine Res.

    (1999)
  • E.A. Bach et al.

    The IFN gamma receptor: a paradigm for cytokine receptor signaling

    Annu. Rev. Immunol.

    (1997)
  • S.V. Kotenko et al.

    IFN–lambdas mediate antiviral protection through a distinct class II cytokine receptor complex

    Nat. Immunol.

    (2003)
  • P. Sheppard et al.

    IL-28, IL-29 and their class II cytokine receptor IL-28R

    Nat. Immunol.

    (2003)
  • L. Dumoutier et al.

    Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3

    Biochem. J.

    (2003)
  • S. Pestka et al.

    Interferons, interferon-like cytokines, and their receptors

    Immunol. Rev.

    (2004)
  • J. Chen et al.

    Diversity and relatedness among the type I interferons

    J. Interferon Cytokine Res.

    (2004)
  • E.F. Wheelock et al.

    Circulating virus, interferon and antibody after vaccination with the 17-D strain of yellow-fever virus

    N. Engl. J. Med.

    (1965)
  • U. Boehm et al.

    Cellular responses to interferon-gamma

    Annu. Rev. Immunol.

    (1997)
  • S.E. Ealick et al.

    Three-dimensional structure of recombinant human interferon-gamma

    Science

    (1991)
  • N. Ank et al.

    IFN–lambda: novel antiviral cytokines

    J. Interferon Cytokine Res.

    (2006)
  • M. Gale et al.

    Evasion of intracellular host defence by hepatitis C virus

    Nature

    (2005)
  • M.J. Clemens

    Interferons and apoptosis

    J. Interferon Cytokine Res.

    (2003)
  • M. Yoneyama et al.

    The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

    Nat. Immunol.

    (2004)
  • N. Ank et al.

    Lambda interferon (IFN–lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo

    J. Virol.

    (2006)
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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Toward Evidence Based Control of Hepatitis C Virus Infection”.

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