The Potential Role of Simeprevir for the Treatment of Hepatitis C

Cristina del Barrio Gascón; Maria Buti


Future Virology. 2015;10(2):67-75. 

In This Article

IFN-free SMV Regimens

SMV has been evaluated in two IFN-free combination therapies for genotype 1: in combination with an NS5b polymerase inhibitor, sofosbuvir and with daclatasvir (DCV; an NS5a inhibitor). Both combinations have been evaluated in Phase II studies. On November 6, 2014, the combination of SMV and sofosbuvir was approved in the United States for the treatment of chronic hepatitis C genotype 1 infection.[24]

SMV in Combination With Sofosbuvir in an IFN-free Regimen

SMV can be used in combination with sofosbuvir to treat patients with an IFN-free regimen. The basis for the use of this combination is the Phase II COSMOS trial, an open-label study investigating the safety and efficacy of the two drugs, with or without RBV for either 12 or 24 weeks. The first cohort enrolled 80 genotype 1 previous null responders to IFN/RBV treatment, with METAVIR F0-F2 fibrosis.[25] In the 12-week arm, SVR12 by intent to treat analysis was observed in 96% of patients receiving SMV/sofosbuvir plus RBV and 93% receiving the combination without RBV.[25] The 24-week arm had SVR12 results of 79% with RBV and 93% without RBV.[25]

The second cohort of this trial consisted of 87 treatment-naive patients and prior null responders with METAVIR F3-F4 fibrosis. The overall SVR12 in the 12-week arm was 93% with or without RBV, while in the 24-week arm it was 93% and 100%, respectively. In all patients, HCV RNA level was less than 25 IU/ml by week 4. All three relapsers in cohort 2, two of whom had cirrhosis (one treatment-naive, one treatment-experienced), received 12 weeks of treatment, raising the possibility that 24 weeks may confer slightly higher SVR rates in the cirrhotic population. All the relapses occurred between week 4 and 8 after treatment discontinuation (Table 2).

Approximately 50% of patients with genotype 1a in the study had the Q80K polymorphism at baseline. The three relapsers in the first cohort and one of the three relapsers in the second had Q80K and all of them had a relapse between week 4 and 8 of treatment discontinuation.

In summary, patients with genotype 1a and Q80K had an SVR12 rate of 81% in cohort 1 and 96% in cohort 2, compared with 97 and 95% of genotype 1a patients without Q80K. The impact of Q80K in this IFN-free regimen seems minimal, but it should be confirmed in the currently ongoing Phase III trials.

New data on the use of SMV with sofosbuvir in the clinical practice have been reported. A study based in USA, the TRIO Health Network, collects prescription data patients with chronic hepatitis C treated with sofosbuvir-based regimens from academic and community medical centers. A total of 1211 hepatitis C patients were included and the primary analysis was focused on 955 patients treated with 12-week regimens. Among these regimen, 320 patients received sofosbuvir plus SMV, with or without RBV for 12 weeks. Nearly a third had liver cirrhosis. About 40% were treatment-experienced, of whom two-thirds were relapsers or partial responders and a third were prior null responders; 20% had previously been treated with HCV protease inhibitors. The intent-to-treat SVR 12 rates with sofosbuvir plus SMV with or without RBV were 82% and per protocol 90% per protocol. In patients with cirrhosis, SVR rates were of 75%.[26] Another study performed in USA, the TARGET trial included a large number of patients with chronic hepatitis C infected by genotype 1 and treated with sofosbuvir and SMV with or without for 12 weeks Preliminary results show an SVR 4 rate of 89% in 222 patients being SVR rates higher in patients without cirrhosis in those with cirrhosis.[27] These studies confirm that in a large, real-life population, the results observed in the in the Cosmos study.

SMV in Combination With DCV

SMV has also been evaluated in combination with DCV, an inhibitor of the NS5a replication complex. The combination was tested in the LEAGUE-1 study, a Phase II study in naive patients and null responders infected by genotype 1b. The DCV dose used was 30 mg q.d., a lower dose than has been submitted for approval, in combination with SMV with or without RBV. 104 naive patients and 43 prior null responders to PEG-IFN/RBV were included. Between 11 and 39% of patients had liver cirrhosis. Patients were randomized 1:1 to receive 12 weeks of SMV + DCV or SMV + DCV + RBV. Completers at week 12 were rerandomized 1:1 to stop therapy or continue an additional 12 weeks with the same regimen. In an intention to treat analysis, SVR12 in naive patients was 85% for the DCV + SMV combination and 75% for DCV + SMV + RBV, whereas in null responders the rates were 65% and 95%, respectively.[28]

Regarding treatment duration, prolongation to 24 weeks did not offer any enefit in regimens including RBV for 12 weeks. However, in SMV + DCV regimens without RBV, efficacy was 81% at 12 weeks and 89% at 24 weeks in naive patients and 83% and 50%, respectively, in null responders. SVR rates were higher in noncirrhotic patients than in those with cirrhosis, with the exception of SMV + DCV + RBV in null responders.

The all-oral combination regimen of DCV 30 mg q.d. (low dose) plus SMV with or without RBV achieved SVR rates of 75–85% in treatment-naive patients.