Direct-acting antiviral agents have brought about a revolution in treatment, especially with the arrival of all-oral regimens without interferon and its difficult side effects, which can include flu-like symptoms and depression. While the first-generation HCV protease inhibitors (boceprevir [Victrelis] and telaprevir [Incivek]) added their own side effects when used with pegylated interferon and ribavirin, the next generation of hepatitis C drugs have minimal adverse effects.

Ronald Nahass and fellow investigators presented pooled data on adverse events in the pivotal Phase 3 PEARL trials, which evaluated the 3D combination, with or without ribavirin, in people without liver cirrhosis infected with either easier-to-treat HCV genotype 1b or harder-to-treat genotype 1a:

• PEARL-II:(n=186) treatment-experienced genotype 1b -- 3D with or without ribavirin for 12 weeks;
• PEARL-III:(n=419) treatment-naive genotype 1b -- 3D with or without ribavirin for 12 weeks;
• PEARL-IV:(n=305) treatment-naive genotype 1a -- 3D with or without ribavirin for 12 weeks.

As previously reported, the PEARL trials enrolled participants in the U.S., Canada, U.K. Europe, Israel, and Russia. In the combined studies just over half were men, more than 90% were white, and the mean age was approximately 51 years. Looking at predictors of poorer response, about one-third overall had HCV 1a, 78% had an unfavorable IL28B gene pattern, about 18% had a body mass index >30, and 6% had a history of diabetes. Two-thirds had absent-to-mild liver fibrosis (stage F0-F1), 19% had moderate fibrosis (stage F2), and 13% had advanced fibrosis (stage F3); those with cirrhosis (stage F4) were excluded.

The primary endpoint in all the trials was sustained virological response, or continued undetectable HCV RNA viral load, at 12 weeks after completion of treatment (SVR12).

Results

• A pooled efficacy analysis showed that SVR12 rates were 96% for people treated with the 3D regimen alone and 99% for those treated with 3D + ribavirin.
• The 3D regimen was generally safe and well-tolerated.
• 75% of patients receiving 3D alone and 83% receiving 3D + ribavirin experienced any adverse event, most of which were mild to moderate.
• 1.4% of patients receiving 3D alone and 2.2% receiving 3D + ribavirin experienced serious adverse events.
• Overall, 4 people (0.4%) -- 2 taking 3D alone and 2 taking ribavirin -- discontinued treatment due to adverse events.
• The most common side effects were fatigue and headache, occurring with similar frequency in 3D only and 3D + ribavirin recipients.
• Nausea, insomnia, itching, and bilirubin elevations were more common among people taking ribavirin.
• 6% of ribavirin recipients reduced their dose due to anemia, but all went on to achieve SVR12.
• Adverse events were similar across subgroups categorized by sex, race/ethnicity, age, and history of diabetes.

"In a pooled analysis of treatment-naive and treatment-experienced patients with HCV genotype 1 without cirrhosis, high rates of SVR12 were achieved with 3D therapy, with or without ribavirin," the researchers concluded.

"With either treatment regimen, most adverse events were mild," they continued. "Both treatment regimens were well-tolerated, as evidenced by treatment discontinuation rates <0.5% due to adverse events and serious adverse events."

The findings from this analysis are comparable to those of a similar pooled analysis of participants in the Phase 3 SAPPHIRE trials, presented last month at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

The 3D regimen is currently under regulatory review in the U.S. and Europe. The FDA has designated it as a "breakthrough therapy"and is expected to issue an approval decision by the end of the year.

10/15/14

Reference

R Nahass, R Nahass, J Vierling, H Van Vlierberghe, et al. Safety of ABT-450/r/Ombitasvir + Dasabuvir With or Without Ribavirin in HCV Genotype 1-infected Patients, by Baseline Demographics. Abstract 818.