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-timesdaily (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.)

Effect of Steady‐State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open‐Label, Fixed‐Sequence Crossover Study

“…2 In addition, it was also shown in phase 2 trials that faldaprevir could be used in interferon-free regimens in which faldaprevir was combined with the NS5B polymerase inhibitor deleobuvir. [3][4][5][6] An interferon-free regimen for faldaprevir is currently being developed for the treatment of HCV infection. 7,8 In vivo data suggest that with a twice-daily dose of 240 mg in healthy volunteers, faldaprevir is a weak inhibitor of CYP2C9 and a moderate inhibitor of CYP3A, whereas a dose of 120 mg faldaprevir once daily in HCV patients results in weak in-hibition of CYP3A.…”

“…Results from the phase 3 trial, STARTVerso1, in treatment‐naive patients with HCV GT‐1 infection demonstrated a sustained virologic response 12 weeks after completion of treatment in 80% of patients who received 240 mg faldaprevir once daily combined with PegIFN and RBV . In addition, it was also shown in phase 2 trials that faldaprevir could be used in interferon‐free regimens in which faldaprevir was combined with the NS5B polymerase inhibitor deleobuvir . An interferon‐free regimen for faldaprevir is currently being developed for the treatment of HCV infection…”

Faldaprevir for the Treatment of Hepatitis C

“…The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection, although further improvements will still be needed [ 38 ]. Interferon-free regimens will be useful for these patients as well as for those patients intolerant to interferon [ 37 , 39 , 40 ]. During the preparation of this manuscript, Boehringer Ingelheim has decided not to move forward in the therapeutic area of HCV.…”

Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis

“…Patients achieved SVR12 of 91.8% and 95.9% in the 12-wk and 24-wk treatment arm, respectively. In addition, differences in rates of SVR12 between patients with mild to moderate fibrosis (F0 to F2) vs F3 to F4 were not statistically significant [27] . These outstanding SVR rates accompanied by a high safety and tolerability profile in cirrhotics allow IFN-free DAA regimens to be much more available to even decompensated cirrhosis patients.…”