Simeprevir Plus Sofosbuvir Experienced, Genotype 1 Patients

Recommended Regimens by evidence level and alphabetically for:

Genotype 1, Simeprevir Plus Sofosbuvir Treatment-experienced Patients


Deferral of treatment is recommended, pending availability of data, for patients with HCV genotype 1 infection, regardless of subtype, in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed (no prior NS5A treatment), who do not have cirrhosis, and do not have reasons for urgent retreatment. IIb, C
Testing for resistance-associated substitutions that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended for patients with HCV genotype 1 infection, regardless of subtype, in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed (no prior NS5A treatment), who have compensated cirrhosis, or have reasons for urgent retreatment. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. II, C
When using nucleotide-based (eg, sofosbuvir) dual DAA therapy a treatment duration of 24 weeks is recommended, and weight-based ribavirin, unless contraindicated, should be added. II, C
If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. In these settings treatment duration ranges from 12 weeks to 24 weeks (see text), and weight-based ribavirin, unless contraindicated, are recommended. II, C
For decompensated cirrhosis, please refer to the appropriate section.

Simeprevir + sofosbuvir failures

Data suggest that approximately 5% to 10% of patients without cirrhosis and with HCV genotype 1 infection treated for 12 weeks with simeprevir plus sofosbuvir will experience treatment failure, typically due to viral relapse (Kwo, 2015). Failure rates in patients with cirrhosis treated for 24 weeks with this regimen are limited; however, treatment failure appears to be more common in persons infected with HCV genotype 1a and those with cirrhosis. Data from the OPTIMIST-1 and -2 studies indicate that treatment failure following a regimen of simeprevir plus sofosbuvir is associated with resistance to simeprevir and cross-resistance to other HCV NS3 protease inhibitors such as paritaprevir, telaprevir, and boceprevir; grazoprevir cross-resistance may also occur in the setting of D168 or A156 substitutions (Kwo, 2015); (Lawitz, 2017). On the other hand, only a single patient developed the signature sofosbuvir RAS S282T in the OPTIMIST trials supporting the rare occurrence of this substitution in clinical practice.

Data on retreatment of simeprevir plus sofosbuvir failures are extremely limited. Interim data from a cohort of 31 patients who had failed simeprevir plus sofosbuvir therapy indicated reasonable response rates to 12-24 weeks of ledipasvir/sofosbuvir therapy with or without ribavirin (Gonzales, 2015). In the subset of patients with SVR12 data available, 85% SVR12 was achieved in non-cirrhotic patients and 91% in cirrhotic patients. Given the lack of a standardized treatment approach and heterogeneous nature of the population, conclusions on the optimal retreatment regimen cannot be drawn.

Retreatment approach and potential regimens
(including other NS5A regimen containing failures)

For patients with cirrhosis or other patients who require retreatment urgently, testing for RASs that confer decreased susceptibility to NS3 protease inhibitors (eg, Q80K) and to NS5A inhibitors should be performed using commercially available assays prior to selecting the next HCV treatment regimen. For patients with no NS5A inhibitor RASs detected, retreatment with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir, both with ribavirin, for 24 weeks is recommended. For patients who have NS5A inhibitor RASs detected and who do not have NS3 inhibitor RASs detected, treatment with simeprevir, sofosbuvir, and ribavirin for 24 weeks is recommended. For patients who have both NS3 and NS5A inhibitor RASs detected there are several small studies that provide some insight on salvage regimens. Limited data suggest a retreatment approach based on sofosbuvir combined with either elbasvir/grazoprevir or PrOD may be efficacious (Lawitz, 2015e); (Poordad, 2015a). In a retreatment arm of the C-SWIFT study, 23 patients who had failed shorter courses of elbasvir/grazoprevir plus sofosbuvir were retreated with 12 weeks of this combination plus weight-based ribavirin. In a per protocol analysis a 100% SVR12 rate was achieved (23/23), including SVR in 9/9 patients with dual NS3 and NS5A RASs (Lawitz, 2015e). A second phase II study of 22 patients, including 14 PrOD failures, evaluated retreatment with 12-24 weeks of PrOD plus sofosbuvir. Treatment duration and ribavirin usage were determined by cirrhosis status, HCV RNA response on therapy, and genotype subtype. SVR12 data was available on 15 patients with 14/15 (93%) attaining SVR12. Based on these limited data, patients with dual NS3 and NS5A class RASs may be retreated with elbasvir/grazoprevir plus sofosbuvir with weight-based ribavirin for 12 weeks or PrOD plus sofosbuvir for 12 weeks in genotype 1b and 24 weeks with weight-based ribavirin in those with genotype 1a. If these regimens are unavailable, retreatment should be conducted in a clinical trial setting, as an appropriate treatment regimen cannot be recommended at this time. Another approach in patients with prior non-response to NS5A-containing therapy has been studied in genoptype 1, 2, and 3 patients who did not respond to velpatasvir-containing regimens including sofobuvir/velpatasvir and sofosbuvir/velpatasvir/GS-9857 (Gane, 2016). Retreatment with sofosbuvir/velpatasvir with ribavirin for 24 weeks yielded high overall response rates (91% or 59/65). Among genotype 1 patients, 97% (33/34) achieved SVR. Baseline NS5A RASs did not appear to effect SVR rates. In 34 genotype 1 patients, 6 patients had NS5A RASs prior to retreatment, all of whom achieved SVR. Although data are extremely limited, retreatment with sofosbuvir/velpatasvir + ribavirin for 24 weeks should be considered in genotype 1 patients who have not responded to prior NS5A-based therapy, especially if there is urgency for treatment.

Last update: 
April 12, 2017

Additional Reading:    HIV/HCV Coinfection    Renal Impairment    Acute Infection