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
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.
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.
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.
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.
designed a study to compare the efficacy and safety of elbasvir/grazoprevir versus
The study was
randomised, multi-site and open-label.
naïve- and treatment-experienced individuals were eligible for recruitment.
twelve weeks. The primary efficacy end-point was the proportion of patients
achieving a SVR12.
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
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.
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.
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.