Unity-1: Daclatasvir/asunaprevir/beclabuvir for HCV genotype 1 without cirrhosis

Background: The all-oral combination of daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and beclabuvir (BCV; non-nucleoside NS5B inhibitor) achieved high rates of SVR12 in a phase 2 clinical trial. This regimen, in a twice-daily fixed-dose combination tablet-DCV-TRIO regimen-was evaluated without ribavirin in HCV genotype (GT) 1-infected treatment-naive and -experienced patients without cirrhosis in a phase 3, open-label, international clinical trial. Methods: All patients received 12 weeks of treatment with the fixed-dose combination of DCV 30 mg, ASV 200 mg, and BCV 75 mg twice daily. Key efficacy outcomes were SVR12 rates in the treatment-naive and -experienced cohorts, assessed separately. Results: Baseline characteristics in the treatment-naive (N=312) and treatment-experienced (N=103) cohorts were comparable. Overall, patients were 58% male and 26% IL28B (rs1297860) CC genotype; 73% were infected with GT 1a and 27% with GT 1b. SVR12 was achieved by 92% and 89% of treatment-naive and -experienced patients, respectively. 17 patients with GT1b infection had NS5A resistance-associated variants (RAVs) at baseline; all 17 achieved SVR12. 25 of the 34 GT1a-infected patients with baseline NS5A RAVs achieved SVR12. Overall, 34 (8%) patients experienced virologic failure, including 21 with posttreatment relapse and 13 with on-treatment virologic failure. Among patients with GT1a infection who experienced failure, RAVs at positions NS5A-Q30, NS3-R155 and/or NS5B-P495 were the most frequently observed variants. One death occurred posttreatment and was considered not related to study treatment. There were 7 serious adverse events, all unrelated, and 3 (<1%) adverse events leading to treatment discontinuation. Adverse events (any grade) that were observed in >10% of patients included headache, fatigue, diarrhea, and nausea. Conclusions: Twelve weeks of all-oral treatment with the fixed-dose combination of DCV, ASV, and BCV achieved high SVR12 rates in 415 patients with chronic HCV GT 1 infection without cirrhosis, confirming the potent antiviral activity of the DCV-TRIO regimen. DCV-TRIO demonstrated a favorable safety and tolerability profile in both treatment-naive and treatment experienced patients.