EASL Clinical Practice Guidelines

The standard of care up to 2014

The primary goal of HCV therapy is to cure the infection. A sustained virological response (SVR) is defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion. The infection is cured in more than 99% of patients who achieve an SVR. The SVR is generally associated with resolution of liver disease in patients without cirrhosis. Patients with cirrhosis remain at risk of life-threatening complications; however hepatic fibrosis may regress and the risk of complications such as hepatic failure and portal hypertension is reduced. Recent data suggest that the risk of HCC and all-cause mortality is significantly reduced, but not eliminated, in cirrhotic patients who clear HCV compared to untreated patients and non-sustained virological responders [[2], [3]]. HCV may also affect neurocognition and effective viral suppression is associated with reversal of cerebral magnetic resonance abnormalities [4].

Until 2011, the combination of pegylated interferon (PegIFN)-α and ribavirin for 24 or 48 weeks was the approved treatment for chronic hepatitis C [5]. With this regimen, patients infected with HCV genotype 1 had SVR rates of approximately 40% in North America and 50% in Western Europe. Higher SVR rates were achieved in patients infected with HCV genotypes 2, 3, 5, and 6 (up to about 80%, and higher for genotype 2 than for genotypes 3, 5, and 6) and intermediate SVR rates were achieved in those with HCV genotype 4 [6].

In 2011, telaprevir and boceprevir were licensed for use in HCV genotype 1 infection. These two drugs are first-wave, first-generation direct-acting antivirals (DAAs). Both target the HCV NS3-4A serine protease and are thus referred to as protease inhibitors. Both telaprevir and boceprevir must be administered in combination with PegIFN-α and ribavirin. In the Phase III trials of boceprevir and telaprevir in HCV genotype 1 treatment-naïve patients, triple therapy regimens achieved higher SVR rates than PegIFN-α and ribavirin dual therapy, of the order of 65% to 75% [[7], [8], [9], [10]]. However, the side effect profiles of these triple combination therapies and the costs per SVR in patients with advanced hepatic fibrosis are such that they should ideally no longer be used in patients infected with HCV genotype 1, as soon as other, more efficacious and better tolerated options are available.

Three new HCV DAAs have been licensed in the EU in 2014, for use as part of combination therapies for HCV infection. Sofosbuvir, a pangenotypic nucleotide analogue inhibitor of HCV RNA-dependent RNA polymerase, has been approved in January 2014. Simeprevir, a second-wave, first-generation NS3-4A protease inhibitor active against genotypes 1 and 4 has been approved in May 2014. Daclatasvir, a pangenotypic NS5A inhibitor, has been approved in August 2014.

Each of these three DAAs can be used as a component of a triple combination regimen with PegIFN-α and ribavirin, yielding SVR rates of 60–100% according to the DAA used, the HCV genotype, the presence of detectable pre-existing amino acid substitutions conferring resistance to the DAA used and the severity of liver disease. Although these combinations are better tolerated than triple combination including telaprevir or boceprevir, their side effect profiles and management remain challenging because of the use of PegIFN-α and of ribavirin.

With three new HCV DAAs approved, IFN-free combinations were broadly used across Europe in 2014, initially as part of early access programs, essentially in patients with advanced liver disease (fibrosis METAVIR score F3 or F4). The combination of sofosbuvir and ribavirin is indicated in patients infected with HCV genotypes 2 (12 weeks) or 3 (24 weeks), yielding SVR rates of the order of 80–95%. The IFN-free combination of sofosbuvir and simeprevir, with or without ribavirin, was used based on the results of the small-size Phase II COSMOS study in patients infected with genotype 1 who achieved SVR in 93–100% of cases [11]. Recent preliminary real-life data from the US showed SVR rates slightly below those in the COSMOS trial in patients with genotype 1 infection: 82% SVR12 in the TRIO study, 89% SVR4 in the TARGET study [[12], [13]]. The combination of sofosbuvir and daclatasvir, with or without ribavirin, has also been widely used in patients with advanced liver disease throughout Europe, based on the results of a Phase II study in patients infected with genotype 1 reporting SVR rates between 95% and 100% [14]. This combination was well tolerated over the course of therapy in the trial, and real-life data are awaited.

The panel recognises the heterogeneity of per capita incomes and health insurance systems across Europe and in other regions, and therefore the possible necessity to continue to utilise regimens with PegIFN-α and ribavirin, with or without the first-wave, first-generation protease inhibitors telaprevir or boceprevir. However, the advent of new DAAs implies that these regimens are not recommended in 2015. It is hoped that the publication of up-to-date recommendations will guide reimbursement (and discounting of drug costs) in order to harmonize treatments across different countries and regions.