Pegylated Interferons: Clinical Applications in the Management of Hepatitis C Infection

Abstract

Currently, there are two pegylated interferon (PEG-IFN) products available for the treatment of hepatitis C virus (HCV) infection [(pegylated interferon, PEGIFN alpha-2a (PEGASYS ), and pegylated interferon, PEG-IFN alpha-2b (PEGINTRON )]. Pegylation is a process by which the interferon-alpha is bound to a polyethylene glycol moiety (Kozlowski & Harris, 2001). The PEG-IFN-alpha-2a product is bound to a single-branched bis-monomethoxy polyethylene glycol (PEG) chain (40,000 daltons) for a final molecular weight of 60,000 daltons or 60 kDa (kilodaltons). Four major positional isomers exist for this compound (Bailon et al., 2001) In contrast, PEG-IFN-alpha-2b is formed by attaching a single chain of PEG (12 kDa mono-methoxy PEG) to interferon-alpha-2b via an ester linkage. The PEG moiety is conjugated to the His34 amino acid residue, forming 12 positional isomers (Wang et al., 2000). The combined molecular weight of PEG-IFN-alpha-2b is smaller, about 31 kDa. The chemical structure and linkages of PEG-IFNs (alpha-2a and alpha-2b) are shown in Figure 1. Pegylation does change the pharmacokinetic properties of unmodified interferonalpha demonstrably (Luxon et al., 2002; Kozlowski & Harris, 2001). These properties allow for once-weekly dosing, more stable interferon-alpha blood concentrations throughout the dosing interval, and improved efficacy (Luxon et al., 2002; Pockros et al., 2004; Lindsay et al., 2001). Currently, the National Institutes of Health identifies the use of PEG-IFN-alpha plus ribavirin (RBV) as the preferred therapy for the treatment of chronic HCV infection. While an improvement over rates of treatment success with unmodified interferons, the critical endpoint, a sustained virological response (SVR), defined as an undetectable level of HCV RNA 6 months after the completion of therapy, remains low particularly for genotype 1, at 42–52%. Higher rates are observed in patients with genotype 2 or 3, at 76–84% (Fried et al., 2002; Hadziyannis et al., 2004; Manns et al., 2001; National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C, 2002). Efforts to develop more effective dosing regimens, especially for subjects with genotype 1 and patients who do not respond or relapse after completion of therapy, are under study. This chapter will review the pharmacokinetics, efficacy in phase II and III clinical studies,