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Double-Dose Peginterferon Alfa-2b with weight-Based Ribavirin Improves Response for Interferon/Ribavirin Non-Responders with Hepatitis C: Final Results of RENEW Study
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Reported by Jules Levin
SVR rates were 12% for patients receiving standard dose Pegintron 1.5 ug/kg (+RBV) vs 17% for patients receiving 3.0 mcg/kg double dose. But of particular note SVR rates were improved when hard-to-treat patients (African-Americans [16% vs 4%] & stage 3-4) received double dose. The improved results were more prominent for African-Americans but there appeared to also be improvement for patients with advanced stage disease. Patients with stage 3-4 had 12% SVR with double dose compared to 8% for patients who received standard dose of 1.5 mcg/kg.
At AASLD Nov 2005 interim 12 week REPEAT Study results were reported. The REPEAT Study provides retreatment with Pegasys/RBV for patients who did not respond previously to peginterferon alfa-2b (Pegintron) plus ribavirin therapy. Rates of early response at 12 weeks in REPEAT (>2 log drop) were: 45% with standard Pegasys+RBV, and 62% with induction dosing of double dose Pegasys for 12 weeks plus ribavirin. You can see the full report on the NATAP website in the AASLD reports section. So, bear in mind the RENEW & REPEAT Studies are different: REPEAT treats Pegintron nonresponders with an induction high dose of Pegasys & RENEW treats standard interferon nonresponders with high-dose Pegintron.
REPEAT Study reports:
http://www.natap.org/2005/AASLD/aasld_36.htm
http://www.natap.org/2005/AASLD/aasld_56.htm
The RENEW Study final results were reported by John Gross (Mayo Clinic, Rochester, MN), but this study looked at nonresponders to standard interferon plus ribavirin, not nonresponders to peginterferon plus ribavirin (RBV).
Gross provided this background. Three large trials showed viral response (SVR) rates of 10-12% when retreating with peginterferon plus RBV for interferon/RBV nonresponders.. In one study the SVR rate among African-American nonresponders was less than 6%. In the RENEW Study Gross reports African-Americans achieved a 16% SVR rate using double-dose Pegintron plus ribavirin. The RENEW Study also reports the safety and tolerability of the double-dose Pegintron.RENEW was conducted at 100 academic and community centers in the USA was investigator initiatied. The study included only IFN/RBV nonresponders & they were retreated with Pegintron + RBV. Nonresponders study patients were randomized to Pegintron 3.0 ug/kg plus RBV 800-1400 mg/day or one of two lower Pegintron doses (0.5 ug/kg or 1.5 ug/kg, but the 0.5 group was discontinued). After 24 weeks treatment was continued if HCV RNA was negative.
Patients had compensated liver disease. Doses were reduced 33% in RENEW for toxicity. Growth factors were not used. Sample size: detect 12% vs 19% with 80% power. Intent-To-Treat analysis, assuming missing data as non-response.
963 patients were enrolled. 137 patients to 0.5 ug/kg, enrollment was stopped for this dose group. 411 patients enrolled in 1.5 ug/kg group & 352 started study. 415 patients enrolled in 3.0 ug/kg group & 352 started therapy.
Average age was 48 yrs in both groups (1.5 & 3.0 ug/kg). weight was 87 kg in 1.5 group & 89 kg in 3.0 group (ns). 29-30% in both groups were female. 39% in 1.5 group & 41% in 3.0 group had stage 3-4 fibrosis (ns), quite a high rate of advanced disease. 91-92% of patients had genotype 1. 16% in both dose groups were African-American.
RESULTS
Viral Response Rates
End Of Treatment: 24% of patients were HCV negative in both dose groups at the end of treatment.
SVR: 17% in the 3.0 dose group achieved SVR vs 12% in the 1.5 dose group (p=0.03).
Of note, responses were stratified by baseline disease stage and body weight, and of course for African-Americans. Patients with early disease (stage 0-2) achieved 17% SVR compared to 10% SVR for patients with advanced HCV disease (stage 3-4). Patients with body weight <85 kg achieved a 12% SVR compared to patients with body weight >85 kg who achieved 17% SVR, go figure. Caucasians had a 15% SVR rate compared to 10% for African-Americans.
Results among Patients With Inherently Low Response Rates
Of particular note was the improved response rates for these traditionally hard to treat patient groups when using the 3.0 double-dose compared to 1.5 lower dose. African-Americans achieved 16% SVR rate when using 3.0 double dose compared to only 4% when using the 1.5 dose. Patients with advanced disease (stage 3-4) also improved response rates when using 3.0 double dose: 12% SVR rate vs 8% for patients who received the 1.5 lower dose.
Results According to Body Weight
>65 kg: 13% SVR
65-85 kg: 15% SVR
85-105 kg: 16% SVR
>105 kg: 20% SVR
In a graph of the White Cell Counts, the two doses did not appear to show much difference, both groups appeared to show comparable reductions in WBC while on therapy, and a return to normal after stopping therapy.
Dose Reduction
First 12 weeks: 25% dose reduced on 1.5 dose compared to 33% taking 3.0 dose
Overall: 37% dose reduced on 1.5 dose compared to 45% on 3.0 dose.
Discontinuation
Discontinuation due to adverse event was 11% in 1.5 dose group & 13% in 3.0 dose group. Overall discontinuation rates were 35% in 1.5 group & 36% in 3.0 group.
Conclusions by Authors
Among non-responders to interferon/ribavirin, peginterferon alfa-2b 3.0 mcg/kg weekly is more effective than 1.5 mcg/kg weekly combined with 800-1200 mg/day. The safety and tolerability of peginterferon alfa-2b 3.0 mcg/kg weekly and 1.5 mcg/kg weekly are similar.
Comment by Gross
High-dose peginterferon/ribavirin treatment deserves further study as initial therapy for patients with inherently low response rates.
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