Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis

Abstract

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.).

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

SVR12 in patients according to fibrosis stage. SVR12 was defined as undetectable HCV RNA 12 weeks after completion of treatment. P values were determined using the chi-squared test. BID, twice daily; HCV, hepatitis C virus; NR, no ribavirin; SVR12, sustained virologic response 12 weeks after completion of treatment; TID, three times daily. Numbers at the bottom of bars are number of patients with SVR12/total number of patients. Numbers above the bars are percentages.

FIG 2

Probability of SVR12, with 95% confidence limits, in patients with HCV GT-1a (solid lines) or GT-1b (dashed lines) infection according to liver elasticity. For the pooled analysis, the plot is based on a multiple logistic regression model of SVR12 versus log10(Fibroscan) and genotype, with data restricted to ribavirin-containing groups. Odds ratios (ORs), 95% confidence intervals (CIs), and P values are outlined below. BID, twice daily; GT, genotype; NR, no ribavirin; SVR12, sustained virologic response 12 weeks after completion of treatment; TID, three times daily. For the multiple regression model detailed in panels A to E, OR (95% CI) and P value for increasing Fibroscan by 1 log were 0.33 (0.06, 1.80) and 0.2008, respectively. The ORs (95% CIs) and P values for GT-1a versus GT-1b were 0.10 (0.05, 0.20) and <0.0001 and for treatment TID16W versus TID28W were 0.91 (0.36, 2.31) and 0.8489, respectively; those for TID40W versus TID28W were 1.37 (0.48, 3.89) and 0.5550, respectively; those for BID28W versus TID28W were 1.31 (0.50, 3.44) and 0.5782, respectively; those for TID28W-NR versus TID28W were 0.25 (0.08, 0.78) and 0.0173, respectively. For the multiple regression model detailed in panel F, pooled data (excluding the no-RBV arm) are used. OR (95% CI) and P value for increasing Fibroscan by 1 log were 0.47 (0.08, 2.74) and 0.3986, respectively. The OR (95% CI) and P value for GT-1a versus GT-1b in this model were 0.11 (0.05, 0.22) and <0.0001, respectively.

FIG 3

Probability of SVR12, with 95% confidence limits, in patients with HCV GT-1a (solid lines) or GT-1b (dashed lines) infection according to APRI score. For the pooled analysis, the plot is based on a multiple logistic regression model of SVR12 versus log10(APRI) and genotype, with data restricted to ribavirin-containing groups. Odds ratios (ORs), 95% confidence intervals (CIs), and P values are outlined below. APRI, aspartate aminotransferase/platelet ratio index; BID, twice daily; GT, genotype; NR, no ribavirin; SVR12, sustained virologic response 12 weeks after completion of treatment; TID, three times daily. For the multiple regression model detailed in panels A to E, OR (95% CI) and P value for increasing APRI by 1 log were 0.77 (0.31, 1.95) and 0.5852, respectively. The ORs (95% CIs) and P value for GT-1a versus GT-1b in this model were 0.15 (0.09, 0.26) and < 0.0001 and for treatment TID16W versus TID28W were 0.85 (0.39, 1.86) and 0.6916, respectively; those for TID40W versus TID28W were 0.97 (0.42, 2.23) and 0.9469, respectively; those for BID28W versus TID28W were 1.07 (0.48, 2.35) and 0.8750, respectively; those for TID28W-NR versus TID28W were 0.28 (0.11, 0.71) and 0.0071, respectively. For the multiple regression models detailed in panel F, pooled data (excluding the no-RBV arm) are used. OR (95% CI) and P value for increasing APRI by 1 log were 0.81 (0.30, 2.20) and 0.6805, respectively. The OR (95% CI) and P value for GT-1a versus GT-1b in this model were 0.16 (0.09, 0.29) and <0.0001, respectively.

FIG 4

Probability of SVR12, with 95% confidence limits, in patients with HCV GT-1a (solid lines) or GT-1b (dashed lines) infection according to APRI score (top) or liver elasticity (bottom). The plots are based on a multiple logistic regression model of interaction of SVR12 versus log10(APRI score or Fibroscan), genotype, and genotype by log10(APRI score or Fibroscan) and are limited to ribavirin-containing groups. Genotype by log10(APRI), P = 0.3867; genotype by log10(Fibroscan), P = 0.5041. APRI, aspartate aminotransferase/platelet ratio index; GT, genotype; SVR12, sustained virologic response 12 weeks after completion of treatment.