The Role of Pegylated Interferon

Rationale:
Pegylated IFNs are currently under investigation, and at this time are not approved for the treatment of hepatitis C in the United States. The concept behind the pegylation of IFN is to produce a molecule that can maintain longer-lasting therapeutic concentrations by optimizing both the absorption and distribution while decreasing the rate of clearance and reducing proteolysis at the same time. This is accomplished by the addition of a polyethylene glycol molecule (PEG) to standard IFN by means of a covalent bond. This PEG molecule is a nontoxic polymer that is readily excreted in the urine and this moiety may be either linear or branched. Larger PEG molecules lead to a greater reduction in renal clearance and provide greater subcutaneous absorption. Pegylated IFN is metabolized primarily in the liver, and its excretion is not affected by renal abnormalities.

Clinical Trials:

Two pegylated formulations of IFN are currently under investigation in the United States:
A linear 12-kD peginterferon-alfa-2b (Pegintron) and a branched chain 40-kD peginterferon-atfa-2a (Pegasys).

A double-blind, randomized, controlled trial was presented at the 2000 meeting of the European Association for the Study of the Liver that compared 3 regimens of peginterferon-alfa-2b (0.5, 1.0, and 1.5 mcg/kg per week) with standard IFN-alfa-2b 3 MU given 3 times weekly in previously untreated patients with hepatitis C. The sustained response rates for patients who received 0.5, 1.0, and 1.5 mcg/kg of the pegylated IFN were 18%, 25%, and 23%, respectively, compared with a 12% sustained response rate found in patients who received the conventional IFN. The overall genotype 1 response rate was 14% in both the 1.0- and 1.5-mcg/kg groups.

EOT = end-of-treatment response;
SVR = sustained virologic response

Zeuzem and colleagues reported the results of a trial comparing once-weekly peginterferon-alfa-2a at a dose of 180 mcg with standard-dose interferon-alfa-2a 3 times weekly for 48 weeks in previously untreated patients with hepatitis C. All patients were assessed at week 72 for a sustained virologic response. These investigators obtained a sustained response rate of 39% for the pegylated-IFN group compared with a 19% response rate for the standard-IFN group. A sustained response rate of 28% was seen in patients infected with HCV genotype 1 who received peginterferon-alfa-2a. The frequency and severity of adverse events were similar in both treatment groups. Pretreatment factors associated with a sustained response, in order of significance, included genotype other than type 1, alanine aminotransferase quotient> 3, HCV RNA level <2>

EOT = end-of-treatment response; SVR = sustained virologic response

In the largest trial of cirrhotic hepatitis C patients receiving IFN therapy performed to date, Heathcote and colleagues reported on the use of pegylated IFN-alfa-2a in the treatment of patients with bridging fibrosis or cirrhosis. Patients were randomized to receive IFN-alfa-2a 3 MU 3 times per week, 90 mcg of peginterferon-alfa 2a weekly, or 180 mcg of peginterferon-alfa-2a weekly, for a total of 48 weeks, and were followed up for 24 weeks. In an intention-to-treat analysis, a sustained response (response at week 72) was seen in 8%, 15%, and 30% of patients treated with standard IFN-alfa-2a, 90 mcg of peginterferon-alfa-2a, and 180 mcg of peginterferon-alfa-2a, respectively. The difference in rate of response between the standard-IFN and 180-mcg of peginterferon groups was statistically significant. The sustained response of patients infected with genotype 1 and non-1 who were treated with the higher dose of peginterferon was 13% and 51%, respectively.

A previous small dose-finding study by Glue and coworkers showed that peginterferon-alfa-2b and ribavirin were safe when used in combination. The results of a larger trial using combination peginterferon-alfa-2b plus ribavirin in previously untreated patients with hepatitis C were reported in October 2000 at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Dallas, Texas. Results showed that the overall sustained response of patients to peginterferon-alfa-2b given at 1.5 mcg/kg per week, plus ribavirin 1000-1200 mg/day, was 54%. The response rates of patients with genotype 1 and non-1 to this regimen were 42% and 82%, respectively.

The FDA approved pegylated IFN-alfa 2b mono therapy in January 2001. The use of combination pegylated IFN plus ribavirin is still under investigation, with several large trials currently underway to determine the effectiveness of this new regimen.