Eugene S. Swenson

Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence

Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post‐liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open‐label ALLY‐1 study assessed the safety and efficacy of a 60‐mg once‐daily dosage of daclatasvir (pan‐genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24‐week follow‐up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on‐treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child‐Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%‐92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child‐Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%‐99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment‐related serious adverse events. Conclusion: The pan‐genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post‐liver transplantation recurrence or advanced cirrhosis. (Hepatology 2016;63:1493‐1505)

Daclatasvir With Sofosbuvir and Ribavirin for HCV Infection With Advanced Cirrhosis or Post‐Liver Transplant Recurrence

Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post‐liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open‐label ALLY‐1 study assessed the safety and efficacy of a 60‐mg once‐daily dosage of daclatasvir (pan‐genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24‐week follow‐up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on‐treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child‐Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%‐92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child‐Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%‐99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment‐related serious adverse events. Conclusion: The pan‐genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post‐liver transplantation recurrence or advanced cirrhosis. (Hepatology 2016;63:1493‐1505)

LO8 : Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: Phase 3 ALLY-1 study

LO8 DACLATASVIR, SOFOSBUVIR, AND RIBAVIRIN COMBINATION FOR HCV PATIENTS WITH ADVANCED CIRRHOSIS OR POSTTRANSPLANT RECURRENCE: PHASE 3 ALLY-1 STUDY F. Poordad, E.R. Schiff, J.M. Vierling, C. Landis, R.J. Fontana, R. Yang, F. McPhee, E. Hughes, S. Noviello, E.S. Swenson ALLY-1: Study Design Multicenter, Open-Label Phase 3 Study Primary endpoint: SVR12 in GT1 in each cohort 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV • RBV initially 600 mg/day, adjusted to 1000 mg/day based on Hgb levels and CrCl Advanced cirrhosis patients with treatment interrupted by liver transplantation could receive an additional 12 weeks of treatment immediately post-transplant Follow-up DCV 60 mg QD + SOF 400 mg QD + RBV Week 0 Week 24 SVR12a Week 36 DCV 60 mg QD + SOF 400 mg QD + RBV Week 12 Advanced cirrhosis N = 60 Post-liver transplant N = 53 Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO8. ALLY-1: SVR12 Results (by Cohort) In a regression analysis, no difference by gender, age, IL28B, or HCV RNA in the advanced cirrhosis cohort with GT 1 82 95 0 20 40 60 80 100 SV R 12 , % Post-transplant Advanced Cirrhosis 83 94

Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study)

The phase 2, FOURward study (NCT02175966) investigated short‐duration therapy (4/6 weeks) with four direct‐acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype‐1.

Daclatasvir/asunaprevir/beclabuvir, all-oral, fixed-dose combination for patients with chronic hepatitis C virus genotype 1

This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all‐oral, ribavirin‐free, fixed‐dose combination (DCV‐TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype‐1 infection, with or without compensated cirrhosis.

An HCV-positive recipient of an HCV-positive donor liver successfully treated before and immediately after liver transplant with daclatasvir, sofosbuvir, and ribavirin

This case suggests that initiation of HCV therapy immediately after liver transplantation with well‐tolerated, all‐oral regimens may achieve a virologic cure in HCV‐positive recipients, thus preventing post‐transplant HCV recurrence and associated disease progression. This strategy may broaden utilization of HCV‐positive donor livers, potentially including HCV‐negative transplant recipients.