Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus‐infected patients with decompensated liver disease

Abstract

Summary Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1‐ or 4‐infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct‐acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment‐naïve or treatment‐experienced adults with Child‐Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7–9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS‐331007 (sofosbuvir metabolite) was 2.2‐, 1.5‐, 1.2‐ and 1.2‐fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

Safety and efficacy of ledipasvir/sofosbuvir with or without ribavirin in hepatitis C genotype 1 patients including those with decompensated cirrhosis who failed prior treatment with simeprevir/sofosbuvir

“…Based on our findings, a multi‐DAA regimen involving the use of 3 or more DAAs may not be required in the majority of cases of SIM/SOF failure especially in those with decompensated cirrhosis and dual DAA therapy with LDV/SOF could be considered a viable option. Although multi‐DAA regimens utilizing 3 or more DAAs may also be highly effective, limitations to this strategy exist in a real‐world setting related to high cost and decreased access …”

“…Although multi-DAA regimens utilizing 3 or more DAAs may also be highly effective, limitations to this strategy exist in a realworld setting related to high cost and decreased access. 24 MODI ET AL.…”

Resolution of ascites and hepatic encephalopathy and absence of variceal bleeding in decompensated hepatitis C virus cirrhosis patients

“…With the recent advent of direct‐acting antivirals (DAAs), the American Association for the Study of Liver Disease (AASLD), the Infectious Disease Society of America (ISDA), and the European Association for the Study of the Liver (EASL) now have guidelines that recommend the use of all‐oral DAA regimens for decompensated HCV cirrhosis patients . In a recent study conducted by Lawitz et al, 100% of decompensated HCV cirrhosis patients achieved a sustained virological response (SVR). Furthermore, a large‐scale trial conducted by Charlton et al demonstrated decompensated that HCV cirrhosis patients with Child‐Pugh (CP) class B and class C achieved SVR rates greater than 85% with DAA treatment.…”

Specific issues concerning the management of patients on the waiting list and after liver transplantation

“…There is an abundance of data on the clinical improvement of Dec‐HCV patients following HCV eradication. Overall, a sustained virological response (SVR) is associated with a median 2‐point reduction in MELD score, a lower incidence of decompensation over 12 months post‐SVR, and a 30% chance of delisting . In the European study coordinated by Belli et al., and involving 11 European centres, 38/142 treated patients were delisted .…”

“…Overall, a sustained virological response (SVR) is associated with a median 2-point reduction in MELD score, a lower incidence of decompensation over 12 months post-SVR, and a 30% chance of delisting. [172][173][174][175][176][177][178] In the European study coordinated by Belli et al, and involving 11 European centres, 38/142 treated patients were delisted. 165 In the Italian ITACOPS study, viral eradication was associated with a better liver function in about half of 224 patients treated.…”