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Peginterferon Alpha-2a: Improved Therapy for Chronic Hepatitis C, Including Cirrhosis
Chronic hepatitis C virus (HCV) infection affects nearly 3 million Americans, most of whom are unaware they are infected. Although only a small percentage develop cirrhosis, they represent the largest category of liver-transplant recipients. Interferon alpha-2a (IF) therapy is only mildly effective in controlling or eliminating viremia, improving liver function, and retarding cirrhosis; its efficacy is approximately doubled with co-administered ribavirin, but even then, about 60 percent of patients remain viremic when therapy ceases. Peginterferon alpha-2a (PIF), IF with a polyethylene glycol molecule added, was developed to maintain blood levels (and thus antiviral efficacy) longer than IF, avoiding viral rebound between dosing and permitting once-weekly use. In these 2 manufacturer-supported, multinational clinical trials conducted between late 1997 and late 1999, PIF was compared with IF in patients who had chronic HCV infection, with and without cirrhosis.
Zeuzem and colleagues randomized 531 HCV-infected patients to receive subcutaneously either PIF (180 microg once weekly for 48 weeks) or IF (6 million units thrice weekly for 12 weeks, then 3 million units thrice weekly for 36 weeks). "Responses" and "sustained responses" were assessed at completion of therapy and 24 weeks later, respectively. Of 267 PIF patients, 223 finished treatment and 206 completed follow-up. Of 264 IF patients, 161 finished treatment and 154 completed follow-up. Virologic responses (HCV RNA < 100 copies/mL) developed more frequently in PIF than in IF patients (69 percent vs. 28 percent, P=0.001); so did sustained virologic responses (39 percent vs. 19 percent, P=0.001). Sustained serum alanine aminotransferase (ALT) responses (normalized values) were more frequent in PIF than IF patients (45 percent vs. 25 percent, P=0.001). More patients experienced both sustained virologic and serum ALT responses in the PIF than the IF treated group (38 percent vs. 17 percent, P=0.001). Paired pre- and post-treatment liver biopsies showed similar histologic improvements in the 2 groups; adverse events, mostly those typical with interferons, were also similar.
Heathcote and colleagues enrolled 271 patients with HCV-related cirrhosis or bridging fibrosis, randomized to receive subcutaneously for 48 weeks either 180 microg or 90 microg of PIF once weekly (87 patients and 96 patients, respectively), or 3 million units of IF thrice weekly (88 patients). Sustained virologic responses at 72 weeks (24 weeks post-treatment) developed in 30 percent, 15 percent, and 8 percent of the 180-microg PIF, 90-microg PIF, and IF groups, respectively (P=0.001 for 180-microg PIF vs. IF comparison). Sustained serum ALT responses developed in 34 percent, 20 percent, and 15 percent of the 180-microg PIF, 90-microg PIF, and IF groups, respectively (P=0.004 for 180-microg PIF vs. IF comparison). Among 184 patients with paired pre- and post-treatment liver biopsies available at 72 weeks, histologic improvements had developed in 54 percent, 44 percent, and 31 percent of the 180-microg PIF, 90-microg PIF, and IF groups, respectively (P=0.02 for 180-microg PIF vs. IF comparison). Adverse events were similar in all groups, with about 10 percent of patients requiring cessation of therapy.
Comment: PIF offers incremental improvement over IF therapy for chronic HCV infection, with or without cirrhosis, and will likely replace IF in HCV therapeutics. Future studies with PIF will surely evaluate its efficacy when combined with other antivirals such as ribavirin, because its efficacy when used alone, while encouraging, remains modest.
— N Blacklow
Published in Journal Watch Infectious Diseases December 21, 2000
Citation(s):
Zeuzem S et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000 Dec 7 343 1666-1672.
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Heathcote EJ et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000 Dec 7 343 1673-1680.
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Schafer DF and Sorrell MF. Conquering hepatitis C, step by step. N Engl J Med 2000 Dec 7 343 1723-1724.
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