May 20-23, 2001
Pegasys + Ribavirin
Pegylated (40kDa) Interferon Alfa-2a (Pegasys) in Combination With Ribavirin: efficacy and Safety Results From a Phase III Randomized, Actively Controlled Multicenter Study
Presented by Michael Fried, MD, Associate Professor of Medicine, Dir. Of Clinical Hepatology, University of North Carolina at Chapel Hill
This study compared, in previously untreated patients with chronic hepatitis C, the efficacy and safety of these three study regimens
Biopsy was performed at baseline for further analysis and treatment was for 48 weeks with a 24-week follow-up.
The primary outcome of the study is undetectable serum HCV RNA (amplicor HCV v 2.0, sensitivity <50 IU/mL) at end of 24 week treatment free follow-up. Secondary endpoints of the study are end-of-treatment and biochemical response (ALT), sustained biochemical response end-of-follow-up histologic response, and quality of life measures.
Inclusion criteria: elevated ALT, quanitifiable HCV RNA, hitologic changes on liver biopsy consistent with chronic HCV.
Exclusion criteria: decompensated cirrhosis, coinfection with HIV or HBV, anemia or inability to tolerate anemia, significant comorbid medical condition.
Patient characteristics at baseline: age about 42 in all 3 arms; male 68% in Pegasys monotherapy, 73% in standard IFN/RBV, and 71% in Pegasys/RBV; weight-about 78 kg in all 3 arms; 64-66% genotype 1 across 3 arms; genotype 2/3-31-33% in all 3 arms; HCV viral load about 6 million in all 3 arms; cirrhosis-15% in Peg monotherapy and 12% in each of other 2 arms.
In response to questions from the audience Fried said SVR for patients in study with cirrhosis was 43% vs 33% (Pegasys/RBV vs Standard IFN/RBV, for patients without cirrhosis SVR was 58% vs 47%, and SVR was 53% vs 43% comparing Caucasians vs non-Hispanic Caucasians which includes Asians and Blacks. Response by African-Americans is being analyzed.
END-Of-Treatment Virologic Responses
Pegasys monotherapy (n=224):
Standard IFN+RBV (n=444): 52%
Pegasys+RBV (n=453): 69%
Differences between Peg+RBV and other 2 groups are statistically significant.
END Of Follow-up Virologic Response (SVR)
Pegasys monotherapy (n=224):
Standard IFN/RBV (n=444): 45%
Fried said that any patient that received at least one dose of study drug was included in the analysis (Intent-To-Treat analysis).
SVR by Genotype
Pegasys+RBV: 46% (n=298)
Standard IFN/RBV: 37% (n=285)
Pegasys monotherapy: 21% (n=145)
Pegasys+RBV (n=140): 76%
Standard IFN/RBV (n=145): 61%
Pegasys monotherapy (n=59): 45%
Data reported for PegIntron+RBV, the other pegylated interferon, was 54%
Several studies, including this one, of Pegasys monotherapy have reported SVRs of 30-39%. So, previous Pegasys monotherapy monotherapy studies have yielded a better SVR. There has been one PegIntron monotherapy study and it reported 23% SVR.
Sustained virologic responses reported for PegIntron+800 mg RBV was 54% (42% for genotype 1), and 47% (33% for genotype 1) for standard IFN 3 MIU 3x/wk+RBV.
To read the PegIntron data
reported at EASL, April 2001, see
"Peginterferon Alfa-2b (Pegintron) Plus Ribivarin Update (Section A)"
(see parts 4 & 5)
Predictability / Compliance Analysis
Initial viral load response and patient adherence appear to be key factors in achieving sustained virologic response.
Two-thirds of patients with 2 log drop or undetectable PCR at week 12 went on to sustained virologic response 24 weeks after stopping 48 weeks of therapy.
At week 12 (n=453), 86% (n=390) had a 2 log drop in HCV-RNA and 14% did not (n=63). Of these 14% only 2 (3%) went on to have a SVR 24 weeks after stopping treatment. Thus Fried concluded that there is a 97% predictive value that if a patient does not have 2 log drop or negative PCR by week 12 they will not reach SVR. Of the 86% with the viral response, 65% (n=253) went on to SVR and 35% (n=137) did not.
based on patient diaries, pill counts and pharmacy records.
Of the 86% responders at week 12, 75% (n=184) achieved SVR when adherence was >80%. While only 48% (n=69) with <80% adherence achieved a SVR.
Rate of Withdrawal From Treatment
Due To Adverse Event:
Pegasys monotherapy: 5.7%
Standard IFN/RBV: 9.4%
Due to lab abnormality:
Pegasys monotherapy: 0.9%
Standard IFN/RBV: 0.9%
Pegasys/RBV: 2.6% (The most common lab abnormality leading to withdrawal was neutropenia which occurred in 3 patients).
When looking at adverse events there was less incidence in the Pegasys/RBV arm than in the standard IFN/RBV arm in certain categories: myalgia 42% vs 50%, rigors 24% vs 35%, pyrexia 43% vs 56%, depression 21% vs 30%. For other adverse events the incidence reported was about the same. However, anecdotal reports I have heard are that the severity of the adverse events may be less with Pegasys/RBV compared to standard IFN/RBV for some individuals.