BOSTON — The addition of the protease inhibitor telaprevir to antiviral therapy with pegylated interferon and ribavirin produced sustained virologic response in more than half of hepatitis C patients in a randomized trial who had previously failed the standard interferon/ribavirin protocol, Dr. John G. McHutchison reported at the annual meeting of the American Association for the Study of Liver Diseases.
The 453 patients with hepatitis C virus (HCV) genotype 1 enrolled in the multicenter PROVE3 trial—designed to assess the safety and efficacy of telaprevir plus pegylated interferon with or without ribavirin—were randomized to one of four tegimens.: telaprevir for 12 weeks and pegylated interferonanlus ribavirin for 24 weeks (T12/PR24);, telaprevir for 24 weeks and pegylated interferon plus ribavirin for 48 weeks (T24/PR48);, telaprevir and pegylated interferon only for 24 weeks (T24/P24);, or placebo and pegylated interferonaplus ribavirin for 24 weeks followed by pegylated interferon and ribavirin for 24 weeks (PR48), exid Dr. McHutchison of Duke University Medical Center, Durham, N.C.
The patients received the standard, subcutaneous 180 mcg/week of pegylated interferon, 1,000-1,200 mg of ribavirin according to body weight, and 1,250 mg of telaprevir on day 1 with 750 mg every 8 hours thereafter, he said.
Failure to respond to prior combination pegylated interferon/ribavirin treatment was defined as less than a 2-log decline in the serum HCV RNA level from baseline at 12 weeks;. Virologic breakthroughs, was defined as the development of viremia during treatment of a patient whose HCV RNA had previously become undetectable during ongoing therapy. Relapse, was defined as the reappearance of serum HCV RNA after the discontinuation of antiviral therapy and undetectable HCV RNA at the completion of therapy.
About 92% of the patients included in the intent-to-treat analysis had baseline HCV RNA levels of 800,000 IU/mL or higher, and 43% had cirrhosis or bridging fibrosis, The assigned treatment was completed by 235 of the patients, with discontinuation from protocol-defined stopping rules observed in 15% of the T12/PR 24 group, 23% of the T24/PR48 group, 37% in the T24/P24 group, and 59% in the PR48 group, Dr. McHutchison reported.
At 48 weeks after treatment completion, the sustained virologic response (SVR) rates across all three of the telaprevir-based regimens were significantly higher than in the interferon/ribavirin control arm, In the T12/PR24, the T24/PR48, and the T24/P24 groups, 51%, 53%, and 24% of the patients, respectively, achieved SVR, compared with 14% of the patients in the control group, he said.
Viral breakthrough rates during treatment were highest in the telaprevir/interferon-only group, at 21%, compared with 11%, 10%, and 3% in the T12/PR24, T24/PR48, and PR48 groups. Similarly, Dr. McHutchison noted, relapse rates 24 weeks after treatment were highest in the telaprevir/interferon-only group, at 53%, compared with 28%, 4%, and 52% in the T12/PR24, T24/PR48, and PR48 groups. “No late relapses occurred 48 weeks after treatment in the telaprevir groups,” he said.
The telaprevir-based therapy was most successful in patients who had relapsed after the initial dual combination therapy, In the T12/PR24, T24/PR48, and T24/P24 groups, respectively, SVR was achieved by 69%, 76%, and 42% of patients who had previously relapsed, compared with 39%, 38%, and 11% of patients who had not responded to the initial treatment, Dr. McHutchison said.
“The general safety profile of all of the telaprevir regimens was similar to that seen in treatment-naive patients,” Dr. McHutchison said. Grade 3 rash was observed in 5%, 4%, 3%, and 0% of the T12/PR24, T24/PR48, T24/P24, and PR48 groups, respectively, and grade 3 anemia was observed in 0%, 6%, 1%, and 1% of patients. And while 21 patients in the telaprevir groups discontinued treatment because of rash (18) or anemia (3), he said, “the number of withdrawals is not unusually high and is similar to the rates reported in prior phase II studies.”
The findings of this phase IIb study have important clinical implications, Dr. McHutchison said. “The high rate of cure among previous treatment failures gives hope to a large segment of hepatitis C infected patients who do not respond to the current standard of care,” he said, noting that the results still have to be confirmed in larger phase III clinical trials, that are ongoing.
Disclosures: This study was funded by Vertex Pharmaceuticals and Tibotec, manufacturers of telaprevir. Dr. McHutchison disclosed relationships with multiple pharmaceutical firms, including Vertex.