HCV New Drugs

Safety and Efficacy of Elbasvir/Grazoprevir in Patients with Hepatitis C Virus Infection and Compensated Cirrhosis: an Integrated Analysis
Ira M. Jacobson, Eric Lawitz, Paul Y. Kwo, Christophe Hézode, Cheng-Yuan Peng, Anita Y.M. Howe, Peggy Hwang, Janice Wahl, Michael Robertson, Eliav Barr, Barbara A. Haber

DOI: http://dx.doi.org/10.1053/j.gastro.2017.01.050

Abstract
Background & Aims
Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials.

Methods
We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12–18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA below 15 IU/mL.

Results
Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135/138) and 88.9% (48/54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients who achieved an SVR12 (90.3%, 28/31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74/81). All (49/49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks achieved SVR12, and 93.9% (46/49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared to patients with genotype 1b or 4 infections—particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated variants (RAVs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RAVs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RAVs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8/11) and 98% (96/98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RAVs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% of patients (6/264) receiving elbasvir/grazoprevir. Serious adverse events were reported in 3.0% of patients (8/264) and no patient had a decompensation-related event.

Conclusion
In an analysis of data from 6 clinical trials, we found rates of SVR12 to range from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RAVs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and need for ribavirin in patients with HCV genotype 1a infection.

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