Pegasys + Ribavirin: 24 vs 48 weeks; 800 vs 1000/1200 ribavirin
Reported by Jules Levin
(full slide show of data link at the end of this article)
In the opening oral session at EASL Professor Stephanos Hadziyannis (Dept. of Medicine, Henry Dunant Hospital, Athens, Greece) reported new information and data from a large study of Pegasys in combination with ribavirin in HCV monoinfected patients who never before received interferon or ribavirin.. This study has 4 arms and compares two dosing schemes of ribavirin (800 mg or 1000/1200 mg daily based on weight (1000 if <75 kg, 1200 if >75 kg) and two treatment dose periods (24 vs 48 weeks). The study uses the standard dose of Pegasys (180 ug once per week by subcutaneous injection). Ribavirin is capsules and is dosed either 800 or 1000/1200 mg per day and is dosed twice per day. The study was conducted in 21 countries and at 99 sites. Roche said this is a modified ITT analysis; patients who received one dose of study drug were included in the analysis.
A total of 1284 patients were randomized and treated:
Arm A: Pegasys 180 ug once per week + ribavirin 800 mg for 24 weeks
Arm B: Pegasys 180 ug once weekly + ribavirin 1000/1200 mg for 24 weeks
Arm C: Pegasys 180 ug once weekly + ribavirin 800 mg for 48 weeks
Arm D: Pegasys 180 ug once weekly + ribavirin 1000/1200 mg for 48 weeks
There was a 24 week treatment free follow-up period for all patients after either 24 or weeks study treatment.
Patients were stratified by either genotype 1 or non-genotype 1 and by viral load. Low viral load was <2 million copies/ml vs high viral load of >2 million copies/ml. Patients were also stratified by geographic region but the author did not present these results. Patients with wither genotype 1 or non-1 with low viral load were equally distributed among the 4 treatment arms. Patients with genotype 1 and high viral load were distributed 1:1:4:4 to the 4 arms. So patients with genotype 1 and high viral load were mostly placed in the 48 week treatment arms because these patients are the hardest to treat. Treatment duration was blinded until week 24 and ribavirin dose was blinded throughout the study.
The primary study goal was to see how many patients achieved undetectable viral load following either 24 or 48 weeks treatment and after a 24 week treatment free period (COBAS Amplicor HCV test v2.0, sensitivity 50 IU/ml). Secondary endpoints are ALT responses, end of treatment responses, histologic responses.
The patient characteristics were comparable in all 4 study arms: 66% men, 43 years/age, 77 kg. But the patients in the 48 week treatment arms understandably had higher viral loads (7.2 million in the 800 mg RBV and 6.1 million in the 1000/1200 mg RBV) compared to the 24 week groups (5 million in the 800 mg and 5.5 million in the 1000/1200 RBV group). About 25% had cirrhosis or transition to cirrhosis although it was 21% in the 24 week 800 mg arm. 25% is a bit high. 62%-69% had genotype 1 in the 48 week groups vs 42-49% in the 24 week groups.
Sustained Virologic response in Genotype 1
Pegasys + 800 RBV 24 wks (n=101) 29%
Pegasys + 1000/1200 RBV 24 wks (n=118) 41%
Pegasys + 800 RBV 48 weeks (n=250) 40%
Pegasys + RBV 1000/1200 48 wks (n=271) 51%
Genotype 1 and Low Viral Load (20% of patient population)
Pegasys + 800 RBV 24 weeks (n=51) 41%
Pegasys + 1000/1200 RBV 24 weeks (n=71) 51%
Pegasys + 800 RBV 48 weeks (n=60) 53%
Pegasys + 1000/1200 RBV 48 weeks (n=85) 61%
These results find 48 weeks treatment is preferable for genotype 1 and low viral load. The genotype 1/low viral load patients who received 1000/1200 mg had better results than patients who received 800 mg.
Genotype 1 and High Viral Load (the most prevalent & hardest group to treat)
Pegasys + 800 RBV 24 weeks (n=50)- 16%
Pegasys + 1000/1200 RBV 24 weeks (n=47)- 26%
Pegasys + 800 RBV 48 weeks (n=190)- 35%
Pegasys + 1000/1200 RBV 48 weeks (n=186)- 46%
These data find that genotype 1 and high viral load patients should be treated for 48 weeks. Patients receiving 1000/1200 RBV did better than those with 800 mg. This study found that all patients with genotype 1 whether they had low or high viral load did better with 48 weeks treatment rather than 24 weeks.
Pegasys + 800 RBV 24 weeks (n=106) - 78%
Pegasys + 1000/1200 RBV 24 weeks (n=162)- 78%
Pegasys + 800 RBV 48 weeks (n=111) - 73%
Pegasys + 1000/1200 RBV 48 weeks (n=165) - 77%
The study authors said these results in non-1 genotypes are independent of viral load and cirrhosis.
Patients without cirrhosis had a 65% SVR (n=321) and patients with cirrhosis had a 50% SVR (treatment was Pegasys + RBV 1000/1200 for 48 weeks).
Rate of Withdrawal From Treatment
3.7% in Pegasys + RBV 800 24 wks
3.5% in Pegasys + RBV 1000/1200 24 weeks
14.2% in the Pegasys + 800 RBV 48 weeks
12.4% in the Pegasys + 1000/1200 RBV 48 weeks
Withdrawal Due To Lab Abnormality
0.9% in Arm A
1.0% in Arm B
1.9% in Arm C
2.7% in Arm D
Ribavirin Discontinuations for Adverse Events/Lab Abnormalities
7% - Pegasys + 800 RBV 24 weeks
6% - Pegasys + 1000/1200 RBV 24 weeks
18% - Pegasys + 800 RBV 48 weeks
19% - Pegasys + 1000/1200 RBV 48 weeks
Serious Adverse Events
3% (1% treatment-related) in Arm A
7% (3% treatment-related) in Arm B
9% (4% treatment-related) in Arm C
10% (3% treatment-related in arm D
Study authors reported the patient's genotype was the main predictive factor for outcome, and adherence was important. Patients with greater than 80% adherence had much better responses.
Pegasys + Ribavirin slides from presentation of this study...
FDA Peg-Intron Hearing
December 12, Bethesda, MD.