Peginterferon-??-2a (40kD)

Abstract

Peginterferon-α-2a (40kD) is a new ‘pegylated’ subcutaneous formulation of interferon-α-2a that has been developed to improve on the pharmacokinetic profile and therapeutic efficacy of interferon-α-2a. Peginterferon-α-2a (40kD) is produced by the covalent attachment of recombinant interferon-α-2a to a branched mobile 40kD polyethylene glycol moiety, which shields the interferon-α-2a molecule from enzymatic degradation, reduces systemic clearance and enables once-weekly administration. Peginterferon-α-2a (40kD) was significantly more effective than interferon-α-2a in interferon-α therapy-naive adults with chronic hepatitis C in three non-blind, randomised, multicentre trials. Virological responses (intention-to-treat results) were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-α-2a (40kD) 180 μg/week; sustained virological responses 24 weeks after the end of treatment occurred in 30 to 39% of patients. Virological responses at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-α-2a. Peginterferon-α-2a (40kD) was significantly more effective than interferon-α in patients with or without cirrhosis infected with HCV genotype 1. Sustained biochemical responses achieved with peginterferon-α-2a (40kD) 180 μg/week ranged from 34 to 45% and were significantly higher than with interferon-α-2a. Recipients of peginterferon-α-2a (40kD) also experienced histological improvements; 24 weeks after discontinuation of treatment with peginterferon-α-2a (40kD) 180 μg/week, 54 to 63% of patients had a ≥2-point improvement in histological activity index score. Peginterferon-α-2a (40kD) produced histological responses in patients (with or without cirrhosis) with or without a sustained virological response. Peginterferon-α-2a (40kD) produced better results than interferon-α-2a alone or interferon-α-2b plus oral ribavirin on various measures of quality of life in patients with chronic hepatitis C. The tolerability profile of peginterferon-α-2a (40kD) is broadly similar to that of interferon-α-2a in patients with chronic hepatitis C with or without cirrhosis. Headache, fatigue and myalgia are among the most common adverse events. Conclusion: Peginterferon-α-2a (40kD) administered once weekly produces significantly higher sustained responses, without compromising tolerability, than interferon-α-2a administered thrice weekly in noncirrhotic or cirrhotic patients with chronic hepatitis C, including those infected with HCV genotype 1 — a group in whom interferon-α treatment has usually been unsuccessful. Peginterferon-α-2a (40kD) is a valuable new treatment option and appears poised to play an important role in the first-line treatment of patients with chronic hepatitis C, including difficult-to-treat patients such as those with compensated cirrhosis and/or those infected with HCV genotype 1. The interferons are naturally occurring proteins with nonspecific regulatory activity. These cytokines are secreted by many mammalian cells and influence cell growth and differentiation, modulate the immune response and inhibit the replication of a number of viruses including hepatitis B and C. The antiviral activity of interferon-α is achieved by its ability to alter interactions between the host and virus in a complex manner. When administered as a drug, interferon-α-2a induces a nonspecific antiviral state in the virus-infected cell which results in the inhibition of HCV replication. The drug also has immunomodulatory effects that intensify specific host immune responses against the virus. These effects include activation of macrophages, natural killer cells and cytotoxic T lymphocytes and stimulation of the production of type 1 T-helper cells. The anti-inflammatory properties of interferon-α-2a are achieved via inhibition of the production of tumour necrosis factor α, interleukin (IL)-1 and IL-8 and stimulation of the production of IL-10. The pharmacological activity of interferon-α-2a is augmented by pegylation. The activity of 2′,5′-oligoadenylate synthetase (OAS), a key effector protein synthesised in response to interferon-α stimulation, increased with dose in volunteers who received single 45, 135 or 270μg subcutaneous doses of peginterferon-α-2a (40kD), or single 3 or 18MU subcutaneous doses of interferon-α-2a. Maximum serum OAS activity occurred approximately 48 hours after administration and remained at about this level for up to 168 hours (1 week) in the peginterferon-α-2a (40kD) [≥135μg] treatment groups. Preliminary results of a small randomised comparative trial indicate that peginterferon-α-2a (40kD) treatment (180 μg/week for 48 weeks; n = 14) produces more robust HCV-specific CD4+ T helper 1 immune responses than interferon-α-2a (6MU three times a week for 12 weeks then 3MU three times a week for 36 weeks) in therapy-naive patients with chronic hepatitis C (with weak or no HCV-specific CD4+ responses before treatment). The rate of viral decline was HCV genotype-dependent in patients treated with peginterferon-α-2a (40kD) or interferon-α-2a. The first and second phases of viral decline were significantly faster in patients infected with HCV non-1 genotypes than in those infected with HCV genotype 1 receiving treatment with peginterferon-α-2a (40kD) 180μg weekly. Peginterferon-α-2a (40kD) is well absorbed after single subcutaneous doses in healthy volunteers or multiple subcutaneous doses in patients with chronic hepatitis C. Three to 8 hours after a single 180μg dose of the drug, ‘substantial’ concentrations (values not reported) of peginterferon-α-2a (40kD) were...