Interferon-based therapy of hepatitis C☆
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
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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”.