Hepatitis C-Salvage Study Grazoprevir and Elbasvir Plus Ribavirin: Final 24-week Follow-up Results

C-SALVAGE: Final 24-week Follow-up Results
Posted on September 17, 2015

Non-cross-resistant drugs are needed for salvage therapy of patients with chronic hepatitis C virus infection who do not achieve sustained virologic response on direct acting antiviral (DAA) regimens. The final follow-up week 24 results from the C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy), have been published in the journal Clinical Infectious Diseases (Buti M, et al. Clin Infect Dis. 2015 Sep 14. [Epub ahead of print]). 

In the C-SALVAGE study, an interferon free combination of grazoprevir (an NS3/4A protease inhibitor) and elbasvir (an NS5A inhibitor) with ribavirin was used to treat patients with chronic HCV genotype 1 infection who had previously failed triple therapy with pegylated interferon and ribavirin plus an earlier-generation protease inhibitor. Both SVR12 and SVR24 were achieved in all but 3 patients who had relapsed by or before follow-up week 8, yielding a durable response rate of 76 of 79 (96.2%), which likely reflects the cure rate.

The international, open-label, phase 2, C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) established that a non-cross-resistant protease inhibitor such as grazoprevir could be successfully used with a potent DAA of another class to treat patients harboring signature NS3 variants resistant to earlier protease inhibitors. The primary results were recently published in the Journal of Hepatology (Forns X, et al. J Hepatol. 2015;63:564–72).

• 79 patients (including 30 patients with genotype 1a infections [38%] and 34 patients with cirrhosis [43%]) were retreated with grazoprevir 100 mg/day and elbasvir 50 mg/day plus ribavirin after having failed at least 4 weeks of combination therapy with pegylated interferon and ribavirin (PR) plus either boceprevir, telaprevir, or simeprevir
• A total of 66 (84%) patients had a history of virologic failure.
• Despite a high prevalence of NS3 variants at baseline, the overall SVR rate at 12 weeks (SVR12) was 96.2% (76/79) due to 3 patients relapsing during the initial 8 weeks of post-therapy follow-up coincident with the emergence of NS3 ± NS5A RAVs

To exclude the unlikely possibility of late relapses, the correlation between SVR12 and durable viral suppression has been confirmed based on the results obtained at the final follow-up week 24. These results have been published in the journal Clinical Infectious Diseases (Buti M, et al. Clin Infect Dis. 2015 Sep 14. [Epub ahead of print]).

• 78 patients (99%) completed their final scheduled visit at follow-up week 24. One patient who had completed the prescribed course of treatment dropped out of the study at follow-up week 6 after relapsing 4 weeks after cessation of therapy.
• SVR24 was attained in 76 of 79 patients (96.2% [95% CI, 89.3%–99.2%]) overall, in 28 of 30 (93.3%) patients with genotype 1a infection, 63 of 66 (95.5%) patients with prior virologic failure, 33 of 36 (91.7%) patients with baseline NS3 and/or NS5 RAVs, and 32 of 34 (94.1%) patients with cirrhosis. No further relapses occurred subsequent to follow-up week 8, and undetectable HCV RNA levels were maintained in these 76 patients throughout the full 24 weeks of follow up.
• After removal of 9 patients for serious protocol violations during the treatment period, 68 of the 70 (97.1%) patients remaining in the primary per-protocol population achieved SVR24
• 3 patients relapsed during the initial 8 weeks of post-therapy follow-up, coincident with the emergence of NS3 ± NS5A RAVs
  • Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow up period, suggesting that virus persisted below the level of detection while on treatment
  • NS3_A156T (conferring >5 times increase in grazoprevir EC50 in vitro) emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients
  • NS5A_Y93H (conferring a >5 times increase in elbasvir EC50 in vitro) emerged in virus from 2 patients at relapse and persisted for the entire follow-up period

The authors concluded the following: “The combination of grazoprevir and elbasvir with ribavirin given orally for 12 weeks offers a new therapeutic option for patients who have failed treatment with pegylated interferon and ribavirin and an earlier protease inhibitor, even in the presence of NS3 variants detectable by population sequencing conferring resistance to the first generation of protease inhibitors. In treatment-naive patients, 12 weeks of grazoprevir/elbasvir without ribavirin produced a 95% SVR12 rate (Zeuzem S, et al. Ann Intern Med. 2015; 163:1–13); the contribution of ribavirin in treatment-experienced patients is being evaluated in a large phase 3 trial nearing completion. Unlike the transiently emergent NS3_A156T variant, NS5A_RAVs at relapse persisted for at least 24 weeks after cessation of therapy. If confirmed in larger numbers of patients, this finding could potentially have implications for the retreatment of the small number of patients who fail combination regimens containing an NS5A inhibitor.”

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