Pegylated interferons in the treatment of patients with Hepatitis C

Over the past few years, hepatitis C has emerged as a disease of immense global significance and public health implications. In the United States, it is estimated that 2.7 million people are infected with the hepatitis C virus and have HCV RNA measurable in their serum.1 It is also estimated that approximately 30% of the HIV patients are coinfected with hepatitis C‹this translates to approximately 240,000 patients!2

Until two years ago, interferon alpha monotherapy was the mainstay for treating patients with chronic hepatitis C. However, only 15% to 20% of patients achieved a sustained reduction in HCV RNA (to an undetectable level) following 48 weeks of therapy.3­6 The introduction of combination therapy (interferon alpha 2b plus ribavirin) has improved the clinical outcome of patients; about 38% now achieve a sustained virologic response.7,8 The tolerability of the combination regimen, however, has been of some concern: substantially more patients treated with interferon alpha 2b plus ribavirin discontinue therapy because of side effects compared to patients treated with interferon alone.8

Given the limitations of the currently approved therapies for treating hepatitis C, clinicians and researchers have been keenly interested in developing and evaluating more "patient-friendly" treatments. Pegylated interferons hold that promise.

Pegylation involves the attachment of a polyethylene glycol (PEG) moiety to an interferon molecule. Polyethylene glycols are amphiphilic polymers of ethylene glycol that can be attached to proteins via covalent bonds. The resulting modified proteins have prolonged half-lives and reduced immunogenicity.9 The properties of pegylated proteins vary with the molecular weight of PEG, the number of PEG molecules attached per protein, and the structure (e.g., linear or branched) of PEG.9

Peginterferon alpha 2a (Pegasys) is a 60 kilodalton pegylated interferon developed via covalent attachment of a branched methoxy polyethylene glycol moiety to an interferon alpha 2a molecule. Early studies in healthy volunteers have show that Pegasys decreased the rate of drug clearance, producing an approximately 10-fold increase in serum half-life compared with unmodified interferon alpha-2a; thus Pegasys circulates in the blood much longer than the parent compound does.10 Clinical trials of Pegasys in treatment-naïve patients with chronic hepatitis C have shown this drug to be efficacious and safe; it provides a new alternative for patients.

In an earlier Phase II dose-finding study, Pegasys 180 µg was administered as a once-weekly subcutaneous injection for 48 weeks to interferon- or ribavirin-naïve patients with chronic hepatitis C; 36% of patients had undetectable HCV RNA 6 months after completion of treatment.11 Among patients with cirrhosis or transition to cirrhosis, Pegasys administration 180 µg weekly for 48 weeks resulted in a sustained virologic response of 30% 24 weeks after treatment completion; the response was 6% in the interferon-treated group.12 Of note, over 50% of patients in this trial were infected with hepatitis C virus genotype 1, which has traditionally responded very poorly to interferon therapy.

More recent larger Phase III clinical studies have confirmed earlier efficacy results obtained with Pegasys in treatment-naïve patients.13 In a clinical study involving 531 patients with chronic hepatitis C, 39% of those randomized to Pegasys 180 µg treatment achieved a sustained virologic response as compared to 19% of those who received interferon alpha-2a induction therapy (i.e., 6 million units subcutaneously three times weekly for 12 weeks followed by 3 MU SC three times weekly for 36 weeks).13

A number of other ongoing trials with Pegasys are examining the role of this therapy in combination with ribavirin and other agents among patients with chronic hepatitis C who have not responded to interferon or who relapsed following treatment with interferon. The results of these studies are currently being analyzed.

As the life expectancy of patients with HIV infection has significantly improved, hepatitis C has emerged as a significant opportunistic disease requiring immediate evaluation.2,14 Preliminary studies with a small number of patients have reported encouraging clinical efficacy results for combination interferon alpha plus ribavirin treatment in HIV patients with chronic hepatitis C.15­17 But the tolerability of this combination has been limited, especially with the degree of anemia observed.17 There are currently a number of clinical studies evaluating the use of Pegasys in patients with chronic hepatitis C who are HIV-positive. It is expected that preliminary results from these studies will become available within the next 4 to 6 months.

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10. Peginterferon alpha 2-a. Investigator Drug Brochure, April 2000.

11. Shiffman M, et al. Presented at Digestive Disease Week, 1999.

12. Heathcote J, et al. American Association for the Study of Liver Diseases, 1999.

13. Zeuzem S, Feinman S, Rasenack J, et al. Evaluation of the safety and efficacy of once-weekly PEG/interferon alfa-2a (PEGASYS) for chronic hepatitis C: A multinational, randomized study. European Association for the Study of the Liver, Netherlands, 2000.

14. Soriano V, Rodriguez­Rosado R, Garcia­Samaniego J. Management of chronic hepatitis C in HIV-infected patients. AIDS. 1999;13:539­546.

15. Landau A, Batisse D, Van Huyen JP, et al. Efficacy and safety of combination therapy with interferon-alpha 2b and ribavirin for chronic hepatitis C in HIV-infected patients. AIDS. 2000;14:839­844.

16. Perez­Olmeda M, Gonzalez J, Garcia­Samaniego J, et al. Interferon plus ribavirin in HIV + patients with chronic hepatitis C. 7th Conference on Retroviruses and Opportunistic Infections, 2000. Abstract 284.

17. Weisz K, Goldman D, Talal A, et al. Interferon (IFN) and ribavirin (RBV) therapy for hepatitis C (HCV) in HIV coinfected patients: 12-month follow-up. 7th Conference on Retroviruses and Opportunistic Infections, 2000. Abstract 283.