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DDW 2013: Advanced Fibrosis Does Not Affect Response to Faldaprevir All-oral Regimen

An interferon-free combination of faldaprevir, BI 207127, and ribavirin produced high and similar sustained response rates for treatment-naive genotype 1b hepatitis C patients with either absent-to-moderate liver fibrosis or advanced fibrosis/cirrhosis, according to a presentation at the Digestive Disease Week conference (DDW 2013) this week in Orlando.

The introduction of direct-acting antiviral agents (DAAs) has changed the treatment paradigm for chronic hepatitis C, but even with second-generation drugs, treatment can be challenging for difficult-to-treat patients including people with advanced fibrosis or cirrhosis.

The SOUND-C2 study was an open-label Phase 2b trial that evaluated all-oral regimens containing the HCV protease inhibitor faldaprevir (formerly BI 201335) dosed at 120 mg once-daily, plus the polymerase inhibitor BI 207127 at 600 mg twice-daily (BID) or 3-times-daily (TID), with or without ribavirin, taken for 16, 28, or 40 weeks.

As reported at the AASLD Liver Meeting last November, rates of sustained virological response at 12 weeks post-treatment (SVR12) were unimpressive overall compared with some other interferon-free regimens -- 52% to 69% in the ribavirin-containing arms -- but reached 85% for patients with easier-to-treat HCV subtype 1b (the ribavirin-free arm was halted early due to lower efficacy). Patients with cirrhosis generally did well, but represented only about 9% of the study population.

The present analysis by Tarik Asselah from Hôpital Beaujon in Paris and colleagues categorized SOUND-C2 participants differently to more closely balance the numbers, comparing patients with absent-to-moderate fibrosis (Metavir stages F0-F2 or FibroScan score < 9.5 kiloPascals [kPa]) versus those with advanced fibrosis or cirrhosis (stage F3-F4 or FibroScan score > 9.5 kPa).

The analysis included 362 participants, most of whom had baseline liver stiffness or FibroScan data and APRI scores to estimate extent of fibrosis. A majority were men, almost all were white, and the mean age was about 50 years. Most had elevated alanine aminotransferase (ALT) at baseline, being higher among people with stage F3-F4. Roughly one-third had HCV genotype 1a, but this ranged widely across the treatment arms, from 18% to 47%.

Results

• There were no statistically significance differences in SVR12 rates between participants with stage F0-F2 and those with F3-F4 for any treatment regimen:

o   BI 207127 TID 16 weeks: 63% vs 47%, respectively;

o   BI 207127 TID 28 weeks: 53% vs 76%, respectively;

o   BI 207127 TID 40 weeks: 48% vs 60%, respectively;

o   BI 207127 BID 28 weeks: 70% vs 67%, respectively;

o   BI 207127 TID 28 weeks, no ribavirin: 40% vs 36%, respectively.

• Response rates were lower and more variable for HCV subtype 1a, ranging from 40% to 44% for people with F0-F2 taking triple regimens, and from 14% to 67% for people with F3-F4.
• Looking at subtype 1b, corresponding SVR12 rates ranged from 52% to 91% for people with F0-F2 (highest with the BID triple regimen), and from 70% to 80% for people with F3-F4.
• Conversely, no significant differences were observed in the degree of baseline fibrosis in patients who achieved SVR12 and those who did not, regardless of fibrosis estimation method used
• Overall, people with F0-F2 fibrosis were less likely to stop treatment early due to adverse events (though this was not the case in every regimen arm).
• Severe adverse events and serious laboratory abnormalities were rare in both the F0-F2 and F3-F4 groups.

"The observation that the degree of fibrosis had no or a minimal effect on the probability of SVR12 in patients infected with HCV genotype 1b may reflect the potency of faldaprevir, BI 207127, and ribavirin in this patient population," the researchers concluded.

5/22/13

Reference

T Asselah, S Zeuzem, V Soriano, et al. An Analysis of Response Rates by Fibrosis Stage in Patients Treated With Faldaprevir, BI 207127 and Ribavirin in the Sound-C2 Study. Digestive Disease Week. Orlando, May 18-21, 2013. Abstract Sa1029.