The most effective therapy to date in the treatment of chronic hepatitis C virus (HCV) infection in patients with cirrhosis has been injectable interferon, usually in combination with oral ribavirin. Unfortunately, interferon has significant side effects, and the currently approved formulation must be administered at least three times weekly. A new formulation of the drug, known as peginterferon, has been developed by attaching a branched-chain polyethylene glycol moiety to interferon alfa-2a. Some preliminary studies have shown that peginterferon has a sustained virologic response when administered just once weekly. Tolerability appears to be no worse than that of standard-dose interferon. Heathcote and colleagues recently reported the results of a multi-center trial that compared peginterferon alfa-2a with unmodified interferon alfa-2a in patients with HCV and cirrhosis or bridging fibrosis.
Participants enrolled in the trial had serologic evidence of HCV infection, an elevated level of alanine aminotransferase (ALT) on two occasions and evidence of cirrhosis or bridging fibrosis on liver biopsy. Patients with decompensated cirrhosis, human immunodeficiency virus infection, psychiatric conditions or a platelet count less than 75,000 per mm3 (75,000 per L) were excluded from the trial. Eligible participants were randomized to receive interferon alfa-2a at a dosage of 3 million U subcutaneously three times weekly, or peginterferon alfa-2a at a dosage of 90 μg or 180 μg subcutaneously once weekly. The primary end points were sustained virologic (HCV-RNA level less than 100 copies per mL) and biochemical responses (normal ALT) at the end of treatment (week 48) and through week 72. Repeat liver biopsy specimens were also evaluated and scored on a 22-point histologic activity index.
Almost equal numbers of the 271 patients enrolled in the study were randomized to one of the three treatment groups. About two thirds of the subjects were men, and their mean age was 47 years. At 48 weeks, sustained virologic response was noted in 14 percent of patients in the standard-interferon group, in 42 percent of patients in the 90 μg-peginterferon group and in 44 percent of patients in the 180-μg group. At 72 weeks, the virologic response rates were 8, 15 and 30 percent, respectively. At week 72, biochemical responses in the three groups were 15, 20 and 34 percent, respectively. Two thirds of all participants underwent a repeat liver biopsy; histologic scores improved in 31 percent of patients in the standard interferon group, 44 percent of the 90-μg group and 54 percent of the 180-μg group. There was good correlation between patients with a sustained virologic response and follow-up histology. However, histologic improvement also occurred in about one third of patients from each interferon group who did not have a sustained virologic response to therapy. No major differences in adverse events were noted, including laboratory complications and subjective symptoms such as fatigue, headache, myalgias, rigors and fever. The rate of withdrawal was 8 percent in the standard-therapy group, 7 percent in the 90-μg interferon group and 13 percent in the 180-μg interferon group.
On the basis of these results, the authors conclude that peginterferon alfa-2a administered once weekly produces a higher rate of histologic, virologic and biochemical responses in patients with chronic HCV infection, including those with compensated cirrhosis. Further data from other trials investigating the use of peginterferon with ribavirin is forthcoming.
editor's note: Despite this encouraging data, the overall response rate, even with high-dose peginterferon, was still only about 30 percent. Histologic response, which is actually a more significant clinical outcome, was somewhat greater. Unfortunately, the response rate specific to patients with genotype 1 (the predominant type of HCV in the United States) was only 12 percent with the 180-μg dose. The bottom line is that we still need much more effective and better-tolerated therapies for patients with chronic HCV infection.—j.t.k.