Page 2 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 2
Clinical Practice Guidelines
EASL Recommendations on Treatment of Hepatitis C 2015
European Association for the Study of the Liver ⇑
Introduction neurocognition and effective viral suppression is associated with
reversal of cerebral magnetic resonance abnormalities [4].
Hepatitis C virus (HCV) infection is one of the main causes of
chronic liver disease worldwide [1]. The long-term impact of Until 2011, the combination of pegylated interferon (PegIFN)-
HCV infection is highly variable, ranging from minimal histologi-
cal changes to extensive fibrosis and cirrhosis with or without a and ribavirin for 24 or 48 weeks was the approved treatment
hepatocellular carcinoma (HCC). The number of chronically
infected persons worldwide is estimated to be about 160 million, for chronic hepatitis C [5]. With this regimen, patients infected
but most are unaware of their infection. The implementation of with HCV genotype 1 had SVR rates of approximately 40% in
extended criteria for screening for HCV is a subject of major North America and 50% in Western Europe. Higher SVR rates
debate among different stakeholders. Clinical care for patients were achieved in patients infected with HCV genotypes 2, 3, 5,
with HCV-related liver disease has advanced considerably during and 6 (up to about 80%, and higher for genotype 2 than for geno-
the last two decades, thanks to an enhanced understanding of the types 3, 5, and 6) and intermediate SVR rates were achieved in
pathophysiology of the disease, and because of developments in those with HCV genotype 4 [6].
diagnostic procedures and improvements in therapy and
prevention. In 2011, telaprevir and boceprevir were licensed for use in
HCV genotype 1 infection. These two drugs are first-wave, first-
These EASL Recommendations on Treatment of Hepatitis C are generation direct-acting antivirals (DAAs). Both target the HCV
intended to assist physicians and other healthcare providers, as NS3-4A serine protease and are thus referred to as protease inhi-
well as patients and other interested individuals, in the clinical bitors. Both telaprevir and boceprevir must be administered in
decision-making process by describing the current optimal man-
agement of patients with acute and chronic HCV infections. These combination with PegIFN-a and ribavirin. In the Phase III trials
recommendations apply to therapies that have been approved in
the European Union at the time of their publication. of boceprevir and telaprevir in HCV genotype 1 treatment-naïve
patients, triple therapy regimens achieved higher SVR rates than
The standard of care up to 2014
PegIFN-a and ribavirin dual therapy, of the order of 65% to 75%
The primary goal of HCV therapy is to cure the infection. A sus-
tained virological response (SVR) is defined as undetectable [7–10]. However, the side effect profiles of these triple com-
HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment bination therapies and the costs per SVR in patients with
completion. The infection is cured in more than 99% of patients advanced hepatic fibrosis are such that they should ideally no
who achieve an SVR. The SVR is generally associated with res- longer be used in patients infected with HCV genotype 1, as soon
olution of liver disease in patients without cirrhosis. Patients as other, more efficacious and better tolerated options are
with cirrhosis remain at risk of life-threatening complications; available.
however hepatic fibrosis may regress and the risk of com-
plications such as hepatic failure and portal hypertension is Three new HCV DAAs have been licensed in the EU in 2014, for
reduced. Recent data suggest that the risk of HCC and all-cause use as part of combination therapies for HCV infection.
mortality is significantly reduced, but not eliminated, in cirrhotic Sofosbuvir, a pangenotypic nucleotide analogue inhibitor of
patients who clear HCV compared to untreated patients and non- HCV RNA-dependent RNA polymerase, has been approved in
sustained virological responders [2,3]. HCV may also affect January 2014. Simeprevir, a second-wave, first-generation NS3-
4A protease inhibitor active against genotypes 1 and 4 has been
Received 25 March 2015; accepted 25 March 2015 approved in May 2014. Daclatasvir, a pangenotypic NS5A inhibi-
Coordinator: Jean-Michel Pawlotsky; Panel members: Alessio Aghemo (EASL tor, has been approved in August 2014.
governing board), David Back, Geoffrey Dusheiko, Xavier Forns, Massimo Puoti,
Christoph Sarrazin. Each of these three DAAs can be used as a component of a tri-
⇑ Correspondence: EASL Office, 7 rue Daubin, CH 1203 Geneva, Switzerland.
Tel.: +41 22 807 0360; fax: +41 22 328 0724. ple combination regimen with PegIFN-a and ribavirin, yielding
E-mail address: easloffice@easloffice.eu
SVR rates of 60–100% according to the DAA used, the HCV geno-
type, the presence of detectable pre-existing amino acid sub-
stitutions 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-a 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 dis-
ease (fibrosis METAVIR score F3 or F4). The combination of sofos-
buvir and ribavirin is indicated in patients infected with HCV
EASL Recommendations on Treatment of Hepatitis C 2015
European Association for the Study of the Liver ⇑
Introduction neurocognition and effective viral suppression is associated with
reversal of cerebral magnetic resonance abnormalities [4].
Hepatitis C virus (HCV) infection is one of the main causes of
chronic liver disease worldwide [1]. The long-term impact of Until 2011, the combination of pegylated interferon (PegIFN)-
HCV infection is highly variable, ranging from minimal histologi-
cal changes to extensive fibrosis and cirrhosis with or without a and ribavirin for 24 or 48 weeks was the approved treatment
hepatocellular carcinoma (HCC). The number of chronically
infected persons worldwide is estimated to be about 160 million, for chronic hepatitis C [5]. With this regimen, patients infected
but most are unaware of their infection. The implementation of with HCV genotype 1 had SVR rates of approximately 40% in
extended criteria for screening for HCV is a subject of major North America and 50% in Western Europe. Higher SVR rates
debate among different stakeholders. Clinical care for patients were achieved in patients infected with HCV genotypes 2, 3, 5,
with HCV-related liver disease has advanced considerably during and 6 (up to about 80%, and higher for genotype 2 than for geno-
the last two decades, thanks to an enhanced understanding of the types 3, 5, and 6) and intermediate SVR rates were achieved in
pathophysiology of the disease, and because of developments in those with HCV genotype 4 [6].
diagnostic procedures and improvements in therapy and
prevention. In 2011, telaprevir and boceprevir were licensed for use in
HCV genotype 1 infection. These two drugs are first-wave, first-
These EASL Recommendations on Treatment of Hepatitis C are generation direct-acting antivirals (DAAs). Both target the HCV
intended to assist physicians and other healthcare providers, as NS3-4A serine protease and are thus referred to as protease inhi-
well as patients and other interested individuals, in the clinical bitors. Both telaprevir and boceprevir must be administered in
decision-making process by describing the current optimal man-
agement of patients with acute and chronic HCV infections. These combination with PegIFN-a and ribavirin. In the Phase III trials
recommendations apply to therapies that have been approved in
the European Union at the time of their publication. of boceprevir and telaprevir in HCV genotype 1 treatment-naïve
patients, triple therapy regimens achieved higher SVR rates than
The standard of care up to 2014
PegIFN-a and ribavirin dual therapy, of the order of 65% to 75%
The primary goal of HCV therapy is to cure the infection. A sus-
tained virological response (SVR) is defined as undetectable [7–10]. However, the side effect profiles of these triple com-
HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment bination therapies and the costs per SVR in patients with
completion. The infection is cured in more than 99% of patients advanced hepatic fibrosis are such that they should ideally no
who achieve an SVR. The SVR is generally associated with res- longer be used in patients infected with HCV genotype 1, as soon
olution of liver disease in patients without cirrhosis. Patients as other, more efficacious and better tolerated options are
with cirrhosis remain at risk of life-threatening complications; available.
however hepatic fibrosis may regress and the risk of com-
plications such as hepatic failure and portal hypertension is Three new HCV DAAs have been licensed in the EU in 2014, for
reduced. Recent data suggest that the risk of HCC and all-cause use as part of combination therapies for HCV infection.
mortality is significantly reduced, but not eliminated, in cirrhotic Sofosbuvir, a pangenotypic nucleotide analogue inhibitor of
patients who clear HCV compared to untreated patients and non- HCV RNA-dependent RNA polymerase, has been approved in
sustained virological responders [2,3]. HCV may also affect January 2014. Simeprevir, a second-wave, first-generation NS3-
4A protease inhibitor active against genotypes 1 and 4 has been
Received 25 March 2015; accepted 25 March 2015 approved in May 2014. Daclatasvir, a pangenotypic NS5A inhibi-
Coordinator: Jean-Michel Pawlotsky; Panel members: Alessio Aghemo (EASL tor, has been approved in August 2014.
governing board), David Back, Geoffrey Dusheiko, Xavier Forns, Massimo Puoti,
Christoph Sarrazin. Each of these three DAAs can be used as a component of a tri-
⇑ Correspondence: EASL Office, 7 rue Daubin, CH 1203 Geneva, Switzerland.
Tel.: +41 22 807 0360; fax: +41 22 328 0724. ple combination regimen with PegIFN-a and ribavirin, yielding
E-mail address: easloffice@easloffice.eu
SVR rates of 60–100% according to the DAA used, the HCV geno-
type, the presence of detectable pre-existing amino acid sub-
stitutions 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-a 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 dis-
ease (fibrosis METAVIR score F3 or F4). The combination of sofos-
buvir and ribavirin is indicated in patients infected with HCV
