Interferon alfa2a and its Limitations as a Therapeutic Agent

A cornerstone of the treatment regimen for chronic hepatitis C infection is an alpha interferon (IFN). IFNs are endogenous glycoproteins produced by a variety of cells, usually in response to a viral infection. The mechanism by which IFN acts against the hepatitis C virus is not completely understood. Possible actions include a direct antiviral effect and to a lesser extent, immune system modulation6'7. Immune system modulation by IFN may be important in that decreases in liver inflammation and fibrosis are considered to be long-term goals in the disease's management.

Clearly, an immediate goal in the treatment of chronic hepatitis C infection is the eradication of the virus from the serum. A sustained virological response is defined as the inability to detect hepatitis C virus in the serum 6 months after treatment has been completed. The antiviral effect of IFN in patients with chronic hepatitis C infection is well established8. The standard therapeutic schedule of IFN consists of 3 MIU administered subcutaneously three times a week for up to 48 weeks. IFN therapy alone produces a sustained virological response in less than 20% of patients9.

IFN's pharmacokinetic characteristics limit its therapeutic efficacy. IFN is rapidly absorbed from the subcutaneous injection site, and peak serum concentrations occur 3 to 8 hours after dosing. IFN is rapidly cleared by renal filtration, reabsorption and catabolism in the kidney10' 11. The rapid absorption and avid renal clearance of IFN produce the large fluctuations in IFN serum concentrations that are seen after each dose (Figure 1). IFN's therapeutic efficacy is limited by its relatively brief residence time in a patient's circulation. Indeed, the amount of IFN left in the body after 24 hours is so insignificant that the three times weekly regimen is unlikely to maintain serum levels that are required for adequate antiviral or immunomodulatory activity.

A rapid and dose-dependent decline in serum HCV RNA titre is seen within the first 24 hours of subcutaneous administration of the first IFN dose12, 13. Viral titres continue to decline 36 to 48 hours after the first IFN dose, but at a more variable and slower rate. At 48 hours after the first IFN dose, the HCV RNA viral titre is elevated again. The viral titre appears to rebound during periods of time when IFN serum concentrations are declining13. The rates of both the first and second phase of viral decline are much faster in patients infected with hepatitis C virus genotype 2, and may explain why a greater proportion of patients with genotype non-1 hepatitis C viral infection experience a sustained virological response compared to those infected with genotype 1 virus12. Patients with the genotype 1 virus are considered harder-to-treat.

Interferon 3 Mill given three times a week (Mon-Wed-Fri) First week of Dosing

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