الفهرس 
Hepatitis C viral structureOnly 14 pages are availabe for public view
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Abstract
Treatment of Hepatitis C Virus (HCV) infection is rapidly evolving with the introduction of direct acting antiviral agents (DAAs). HCV NS5A replication complex inhibitors represent a new class of DAAs. The exceptional in vitro potency and broad genotype coverage of NS5A inhibitors have translated to robust anti-HCV effects in infected patients making NS5A inhibitors an essential component of effective HCV DAAs combination therapies (Gao, 2013). Daclatasvir (DCV) is the first NS5A inhibitor to enter clinical development. In vitro data show that DCV exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once daily oral administration. DCV, either in combination with PEG-IFN and RBV or in interferon-free regimens with other DAAs, has demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile (Lee, 2013). This study represented the genotype 4 arm of the COMMAND-1 trial that was designed to evaluate the safety and efficacy of DCV administered in combination with PEG-IFN α-2a/RBV to previously untreated patients infected with HCV genotypes 1 or 4. The efficacy and tolerability of two doses of DCV versus placebo in combination with PEG-IFN α-2a/RBV were assessed in 30 treatment naïve patients infected with HCV genotype 4. Patients were randomized 2:2:1 to receive oral DCV 20 or 60 mg or placebo once daily; all patients received PEG-IFN α-2a administered subcutaneously at a dose of 180 μg per week and RBV dosed according to bodyweight (< 75 kg, 1000 mg daily; ≥ 75 kg, 1200 mg daily). Following randomization, 12 patients were assigned to the DCV 20 mg group, 12 patients to the DCV 60 mg group and 6 patients to the placebo group. A protocol defined response (PDR) {HCV RNA < lower limit of quantification [LLQ] target detected [TD] or target not detected [TND] at Week 4 and < LLQ-TND at Week 10} was achieved by 8 patients (67%) receiving DCV 20 mg and all the 12 patients (100%) receiving DCV 60 mg. At Week 12, all DCV patients who achieved a PDR were re-randomized to continue DCV plus PEG-IFN α-2a/RBV at the previously assigned DCV dose for a total duration of 24 weeks or to continue therapy with placebo in combination with PEG-IFN α-2a/RBV for an additional 12 weeks. Patients who did not achieve a PDR and those initially assigned to placebo, received placebo plus PEG-IFN α-2a/RBV until Week 24 followed by an additional 24 weeks of PEG-IFN α-2a/RBV receiving a total of 48 weeks of therapy. For the primary efficacy endpoints of eRVR and SVR24, higher response rates were achieved in those patients who were treated with DCV (both 20 and 60 mg doses) in combination with PEG-IFN α-2a/RBV compared with patients who received placebo plus PEG-IFN α-2a/RBV. A higher proportion of DCV treated patients also achieved the secondary endpoints of RVR, cEVR, end of treatment response and SVR12 when compared with patients who received placebo. SVR24 was reached in 8 (67%) of patients treated with DCV 20 mg and all (100%) patients treated with DCV 60 mg while it was achieved in only 3 (50%) patients who received placebo. Four patients in the DCV 20 mg group experienced treatment failure due to virologic breakthrough (2 patients) or relapse (2 patients). The adverse event profile in patients treated with DCV and PEG-IFN α-2a/RBV was comparable with that observed in patients who received PEG-IFN α-2a/RBV alone with changes in laboratory parameters also consistent across both the DCV and placebo treatment groups. Four patients experienced virologic failures and all were DCV 20 mg recipients. No virological failure occurred in patients given 60 mg DCV suggesting that an appropriate dose of DCV combined with PEG-IFN/RBV is sufficient to suppress the development of HCV drug resistance.