Elbasvir/grazoprevir superior to sofosbuvir and pegylated interferon/ribavirin

Michael Carter
Published:
10 May 2016

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. The study was presented to the recent International Liver Congress in Barcelona.

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

Until recently, therapy for HCV infection 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 – 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 unfavourable safety profile of pegylated interferon/ribavirin.

Glossary

IL28B

An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.

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

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

Elbasvir is a HCV NS5A inhibitor and grazoprevir is a HCV NS3/4A protease inhibitor. They provide once-daily, fixed dose oral therapy for the treatment of patients with HCV genotype 1 or 4 infection. The combination has been licensed in the United States and is marketed as Zepatier; it awaits regulatory review and marketing approval in the European Union.

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

The study was randomised, multi-site and open-label.

Both treatment naïve- and treatment-experienced individuals were eligible for recruitment.

Treatment lasted twelve weeks. The primary efficacy end-point was the proportion of patients achieving a SVR12.

The investigators analysed data to see if elbasvir/grazoprevir had both non-inferior and superior efficacy to sofosbuvir/pegylated interferon/ribavirin.

A total of 255 patients were recruited. Over half (54.1%) were women, the mean age was 48 years, 99% were white, 77.6% had IL28B non-CC genotypes associated with a less favourable response to interferon-based treatment, 67.1% had a baseline viral load above 800,000 iu/ml, 82% had genotype 1b infection and 75% were previously untreated.

In terms of efficacy, overall 99.2% of patients treated with the all DAA combination had a 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 elbasvir/grazoprevir regimen.

Analysis of outcomes by HCV genotype showed that all patients with genotype 1a infection achieved a SVR12, regardless of randomization. However, elbasvir/grazoprevir 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%) infection.

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

Patients taking the all-DAA combination were significantly less likely to experience a serious drug-related adverse event (p < 0.001), have a low neutrophil count (p < 0.001) or haemoglobin (p < 0.001) compared to patients treated with sofosbuvir/pegylated interferon/ribavirin. Approximately half (54%) of patients taking elbasvir/grazoprevir and 93% of patients treated with sofosbuvir/pegylated interferon/ribavirin experienced one or more adverse event; rates of the drug-related adverse events were 25% and 91%, respectively.

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

Reference

Sperl J et al. C-EDGE: HEAD 2 HEAD. Efficacy and safety of elbasvir/grazoprevir versus sofosbuvir/pegylated interferon/ribavirin (PR) in treatment-naïve and prior PR treatment failure subjects with chronic HCV GT1 or 4 infection. International Liver Congress, Barcelona, 2016.