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EASL 2016: Grazoprevir/ Elbasvir Superior to Sofosbuvir Plus Pegylated Interferon

New research has demonstrated the clear superiority of an oral combination of direct-acting antivirals (DAAs) over a regimen that combines a DAA with pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus (HCV) infection. Results from the C-EDGE Head-to-Head study were presented at the recent EASL International Liver Congress in Barcelona.

[Produced in collaboration with infohep.org]

Study participants were randomized to receive the DAA combination of grazoprevir/elbasvir (Zepatier) or the DAA sofosbuvir (Sovaldi) plus pegylated interferon and ribavirin. The grazoprevir/elbasvir combination was shown to have superior efficacy and safety.

Until recently, therapy for hepatitis C consisted of up to 48 weeks of treatment with pegylated interferon and ribavirin. This therapy was associated with modest cure rates (sustained virological response 12 weeks after completion of therapy, or SVR12) and high rates of adverse events. The addition of the DAA sofosbuvir to a pegylated interferon/ribavirin backbone improved SVR rates compared to pegylated interferon/ribavirin alone, but was also associated with the unfavorable safety profile of pegylated interferon/ribavirin.

Treatment with sofosbuvir and pegylated interferon/ribavirin is no longer recommended as a preferred option in World Health Organization guidelines or in U.S. guidelines for treatment of hepatitis C, but it remains an option for first-line treatment in the 2015 guidelines issued by the European Association for the Study of the Liver (EASL).

Further advances in research mean that hepatitis C therapy consisting entirely of oral DAAs is now a reality. This treatment could offer the high efficacy of combinations consisting of a DAA plus pegylated interferon/ribavirin but with a much improved safety profile.

Merck's grazoprevir is a HCV NS3/4A protease inhibitor and elbasvir is a HCV NS5A inhibitor. Together, they provide once-daily, fixed-dose oral therapy for the treatment of patients with HCV genotypes 1 or 4. The combination has been licensed in the U.S. and is marketed as Zepatier; it awaits regulatory review and marketing approval in the European Union.

Investigators designed a study to directly compare the efficacy and safety of grazoprevir/elbasvir versus sofosbuvir/pegylated interferon/ribavirin.

The study was randomized, multi-site, and open-label. Both treatment naive- and treatment-experienced individuals were eligible for recruitment.

A total of 255 patients were recruited. Over half (54%) were women, the mean age was 48 years, 99% were white, 78% had IL28B non-CC genotypes associated with a less favorable response to interferon-based treatment, 67% had a baseline viral load above 800,000 IU/mL, 82% had harder-to-treat HCV genotype 1b infection, and 75% were previously untreated.

Treatment lasted 12 weeks. The primary efficacy end-point was the proportion of patients achieving SVR12. The investigators analyzed data to see if grazoprevir/elbasvir had both non-inferior and superior efficacy compared to sofosbuvir/pegylated interferon/ribavirin.

In terms of efficacy, overall 99.2% of patients treated with the all-DAA combination had SVR12 compared to 90.5% of patients in the sofosbuvir/pegylated interferon/ribavirin arm. The difference in efficacy was 8.7% (95% CI 3.6%-15.3%). This showed both the non-inferiority and superiority of the grazoprevir/elbasvir regimen.

Analysis of outcomes by HCV genotype showed that all patients with genotype 1a infection achieved SVR12, regardless of randomization. However, grazoprevir/elbasvir had superior efficacy compared to the pegylated interferon/ribavirin-containing regimen among patients with genotype 1b (99% vs 90.4%) and genotype 4 (100% vs 60%).

When efficacy was analyzed according to specific patient characteristics, the analysis showed that grazoprevir/elbasvir was associated with significantly better outcomes in men, IL28B non-CC patients, people with a higher baseline HCV viral load, and individuals with a previous null response to hepatitis C therapy.

Patients taking the all-DAA combination were significantly less likely to experience a serious drug-related adverse event or to have a low neutrophil count or hemoglobin level compared to people treated with sofosbuvir/pegylated interferon/ribavirin. Approximately half (54%) of patients taking grazoprevir/elbasvir and 93% of patients treated with sofosbuvir/pegylated interferon/ribavirin experienced 1 or more adverse event; rates of the drug-related adverse events were 25% and 91%, respectively.

The investigators concluded that the DAA combination of grazoprevir/elbasvir has superior efficacy and safety compared to sofosbuvir/pegylated interferon/ribavirin for the treatment of patients with HCV genotype 1 or 4 infection.

5/26/16

Reference

J Sperl, G Horvath, W Halota, et al. C-EDGE Head-to-Head: efficacy and safety of elbasvir and grazoprevir compared with sofosbuvir/pegylated interferon/ribavirin: a phase 3 randomized controlled trial. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract PS002.

Other Sources

EASL. Newly approved all-oral hep C combination drug found more effective in head-to-head comparison. Press release. April 14, 2016.

Merck. Merck’s ZEPATIER (Elbasvir and Grazoprevir) Showed Superiority on Efficacy and Safety Endpoints Compared to Sofosbuvir Plus Peginterferon and Ribavirin Treatment Regimen in Phase 3 Trial. Press release. April 14, 2016.