SPECIAL ISSUE: HIGHLIGHTS OF ROCHE SATELLITE SYMPOSIA
OCTOBER 19, 2001 acg ANNUAL MEETING: PROGRESS IN THE MANAGEMENT OF HEPATITIS C

NOVEMBER 12, 2001 AASLD ANNUAL MEETING: PEGYLATED INTERFERONS IN HCV – TREATMENT OUTCOMES

GOALS OF THERAPY IN PATIENTS WITH HEPATITIS C: Dr. Raymond Koff reviewed recent evidence that treatment with interferon (IFN) alfa-2b (5 MU daily x 4 wk and then tiw x 20 wk) resulted in an SVR in 98% (43/44) of patients with acute hepatitis C and thus definitively achieves the goal of decreasing the risk of chronicity following acute infection (Jaeckel et al. N Engl J Med 2001;345:1452). In patients with chronic hepatitis C, eradication of HCV and cessation of disease progression can be achieved overall in approximately 55% of naïve patients treated with peginterferon (PEG IFN) alfa-2a or alfa-2b plus ribavirin. In relapsers to prior antiviral therapy, HCV eradication can be achieved in a smaller percentage of patients. In nonresponders, rates of HCV eradication with retreatment are low and a new strategy under study is HCV suppression with interruption of progression to fibrosis.

PHARMACOLOGY OF PEGYLATION: Dr.Thomas Shaw-Stiffel reviewed pharmacokinetic (PK) profiles associated with the attachment of polyethylene glycol (PEG) to IFN and differences between PEG IFN alfa-2a and PEG IFN alfa-2b. Standard IFN has a very short half-life (6 hr), wide distribution throughout the body, and rapid clearance by the kidneys. PEG IFN alfa-2a results from the strong, covalent attachment of a 40-kDa branched PEG to IFN alfa-2a. At a dosage of 180 mg once weekly (qw), a steady state is reached at 5-8 wk; volume of distribution approaches total blood volume; and clearance is primarily by the liver. PEG INF alfa-2b results from the weak, noncovalent attachment of a 12-kDa linear PEG to IFN alfa-2b, and renal elimination accounts for 30% of the clearance. For PEG IFN alfa-2a, PK properties are unchanged in patients with renal impairment down to a Cr clearance of 20 mL/min, but some dose adjustment is needed with PEG IFN alfa-2b below a Cr clearance of 50 mL/min. There are no differences in the PK properties of PEG IFN alfa-2a and alfa-2b between men and women, and PK profiles are unchanged in the elderly. PEG IFN alfa-2a has been extensively studied in patients with cirrhosis, and the PK and pharmacodynamic (PD) properties are unchanged in Child’s A cirrhosis. The different PK and PD profiles, especially volume of distribution, result in different dosing regimens for the two PEG compounds: PEG IFN alfa-2a is dispensed as a stable solution and can be administered at a uniform dose of 180 mg, while PEG INF alfa-2b is dispensed as a lyophilized powder that needs to be reconstituted before injection and must be dosed by weight.

MONOTHERAPY AND VIRAL KINETICS WITH PEGYLATED INTERFERON: Dr. Mitchell Schiffman reviewed the results of PEG IFN monotherapy in patients with chronic hepatitis C. In a phase III multinational study of 531 treatment-naïve patients with chronic hepatitis C, patients were randomized to IFN alfa-2a 6 MU tiw x 12 wk and then 3 MU x 36 wk vs PEG IFN alfa-2a 180 mg qw for 48 wk (Zeuzem et al. N Engl J Med 2000;343:1666). The SVR was 19% vs 39% for the two treatment arms, respectively. In a similar study of PEG INF alfa-2b, 1219 patients were randomized to 48 wk of IFN alfa-2b 3 MU tiw or PEG IFN alfa-2b qw at doses of 0.5 mg/kg, 1.0 mg/kg qw, or 1.5 mg/kg (Lindsay et al. Hepatology 2001;34:395). The SVR was 12%, 18%, 25%, and 23%, respectively. Thus, although overall response rates varied, both PEG IFN alfa-2a and alfa-2b were approximately twice as effective as respective standard IFN products in inducing an SVR. Dr. Stefan Zeuzem reviewed viral kinetics and treatment outcomes. In an intent-to-treat analysis of 564 patients receiving PEG IFN alfa-2a, patients who did not clear virus or have at least a 2-log10 drop in viral load from baseline at wk 12 of therapy had a 98% chance of nonresponse. The study of combination PEG IFN alfa-2a and ribavirin also showed that the lack of an early response at wk 12 is highly predictive of eventual nonresponse (negative predictive response = 97%) (Fried et al. Gastroenterology 2001;120:A-55). In the Fried trial, the overall SVR was 56%; in those patients with a viral response at wk 12, the SVR was 65%.

COMBINATION THERAPY WITH PEGINTERFERON AND RIBAVIRIN: Drs. Luis Balart and Morris Sherman reviewed the intention-to-treat results of combination therapy with PEG IFN and ribavirin in patients with chronic hepatitis C. Studies using PEG IFN alfa-2a 180 mg plus ribavirin 1000-1200 mg/d (Fried et al. Gastronterology 2001;120:A-55) and PEG IFN alfa-2b with the 1.5 mg/kg dose plus ribavirin 800 mg/d (Manns et al. Lancet 2001;358:958) showed the following SVR, respectively: 56% vs 54% overall; 46% vs 42% in patients with genotype 1; and 75% vs 82% in patients with genotypes 2 and 3. In the PEG IFN alfa-2a pivotal study, several adverse events (including flu-like symptoms and depression) occurred less frequently with PEG IFN alfa-2a in combination with ribavirin compared with standard IFN alfa-2b plus ribavirin. Comparison of safety and tolerability between the two PEG IFN products is difficult, but injection side effects, depression, and flu-like symptoms may be more common with PEG INF alfa-2b. Rates of withdrawal in the two studies were 10.5% for PEG IFN alfa-2a vs 14% for PEG IFN alfa-2b.

HISTOLOGIC OUTCOMES AND SPECIAL POPULATIONS: Dr. Russell Wiesner reviewed published data demonstrating that IFN-based therapies decrease both necroinflammatory and fibrosis scores, particularly in patients with a SVR, and even show reversal of cirrhosis in a relatively large number of successfully treated patients (Poynard et al. Hepatology 2001;34:244A). However, nonresponders also show a decrease in fibrosis formation, raising the potential benefit of long-term IFN therapy – presently being addressed by the Halt-C study sponsored by the National Institutes of Health. African Americans have been shown to be unresponsive to IFN monotherapy, but PEG IFN alfa-2a and alfa-2b achieve a SVR of 15% and 14%. Finally, PEG IFN plus ribavirin may achieve an SVR in up to 36% of patients with recurrent HCV posttransplant (Ferenci et al. Hepatology 2001;34:351A