Page 3 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 3
Clinical Practice Guidelines limit of detection <15 international units [IU]/ml). Anti-HCV
antibodies are detectable by enzyme immunoassay (EIA) in the
genotypes 2 (12 weeks) or 3 (24 weeks), yielding SVR rates of the vast majority of patients with HCV infection, but EIA results
order of 80–95%. The IFN-free combination of sofosbuvir and may be negative in early acute hepatitis C and in profoundly
simeprevir, with or without ribavirin, was used based on the immunosuppressed patients. Following spontaneous or treat-
results of the small-size Phase II COSMOS study in patients ment-induced viral clearance, anti-HCV antibodies persist in the
infected with genotype 1 who achieved SVR in 93–100% of cases absence of HCV RNA but may decline and finally disappear in
[11]. Recent preliminary real-life data from the US showed SVR some individuals [16,17].
rates slightly below those in the COSMOS trial in patients with
genotype 1 infection: 82% SVR12 in the TRIO study, 89% SVR4 The diagnosis of acute hepatitis C can be confidently made
in the TARGET study [12,13]. The combination of sofosbuvir only if seroconversion to anti-HCV antibodies can be docu-
and daclatasvir, with or without ribavirin, has also been widely mented, since there is no serological marker which proves that
used in patients with advanced liver disease throughout HCV infection is in the de novo acquired acute phase. Not all
Europe, based on the results of a Phase II study in patients patients with acute hepatitis C will be anti-HCV-positive at
infected with genotype 1 reporting SVR rates between 95% and diagnosis. In these cases, acute hepatitis C can be suspected if
100% [14]. This combination was well tolerated over the course the clinical signs and symptoms are compatible with acute hep-
of therapy in the trial, and real-life data are awaited. atitis C (alanine aminotransferase [ALT] >10 times the upper limit
of normal, jaundice) in the absence of a history of chronic liver
The panel recognises the heterogeneity of per capita incomes disease or other causes of acute hepatitis, and/or if a likely recent
and health insurance systems across Europe and in other regions, source of transmission is identifiable. In all cases, HCV RNA can
and therefore the possible necessity to continue to utilise be detected during the acute phase although brief interludes of
undetectable HCV RNA may occur.
regimens with PegIFN-a and ribavirin, with or without the
The diagnosis of chronic hepatitis C is based on the detec-
first-wave, first-generation protease inhibitors telaprevir or tion of both anti-HCV antibodies and HCV RNA in the presence
boceprevir. However, the advent of new DAAs implies that these of biological or histological signs of chronic hepatitis. Since, in
regimens are not recommended in 2015. It is hoped that the pub- the case of a newly acquired HCV infection, spontaneous viral
lication of up-to-date recommendations will guide reimburse- clearance is very rare beyond 4 to 6 months of infection, the
ment (and discounting of drug costs) in order to harmonize diagnosis of chronic hepatitis C can be made after that time
treatments across different countries and regions. period.
Methodology Recommendations
These EASL recommendations have been prepared by a panel of • Anti-HCV antibodies are the first-line diagnostic test for
experts chosen by the EASL Governing Board. The recommenda- HCV infection (A1)
tions were approved by the EASL Governing Board. The recom-
mendations have been based as far as possible on evidence • In the case of suspected acute hepatitis C or in
from existing publications and presentations at international immunocompromised patients, HCV RNA testing should
meetings, and, if evidence was unavailable, the experts’ provide be part of the initial evaluation (A1)
personal experiences and opinion. Where possible, the level of
evidence and recommendation are cited. The evidence and • If anti-HCV antibodies are detected, HCV RNA should
recommendations have been graded according to the Grading be determined by a sensitive molecular method (A1)
of Recommendations Assessment, Development and Evaluation
(GRADE) system. The strength of recommendations thus reflects • Anti-HCV-positive, HCV RNA negative individuals
the quality of underlying evidence. The principles of the GRADE should be retested for HCV RNA three months later to
system have been enunciated [15]. The quality of the evidence confirm true convalescence (A1)
in the recommendations has been classified into one of three
levels: high (A), moderate (B) or low (C). The GRADE system Screening for chronic hepatitis C
offers two grades of recommendation: strong (1) or weak (2)
(Table 1). The recommendations thus consider the quality of evi- Because of the approval of highly efficacious new HCV treatment
dence: the higher the quality of evidence, the more likely a strong regimens, access to therapy must be broadened. A substantial
recommendation is warranted; the greater the variability in val- proportion of patients with chronic hepatitis C are unaware of
ues and preferences, or the greater the uncertainty, the more their infection. In addition, accurate HCV prevalence and inci-
likely a weaker recommendation is warranted. dence data are needed to analyse the magnitude of the pandemic
in different regions and to design public health interventions.
These recommendations are necessarily based on currently Thus, hepatitis C testing is required to identify infected persons
licensed drugs. They will be updated regularly, following approval and engage them in care and treatment, and targeted screening
of new drug regimens by the European Medicines Agency. for markers of HCV infection must be implemented. Groups at
higher risk of HCV infection can be identified, and should be
Recommendations tested. At-risk populations, that should be screened, depend on
the local epidemiology of HCV infection. In addition to EIAs, rapid
Diagnosis of acute and chronic hepatitis C
The diagnosis of acute and chronic HCV infection is based on the
detection of HCV RNA by a sensitive molecular method (lower
2
antibodies are detectable by enzyme immunoassay (EIA) in the
genotypes 2 (12 weeks) or 3 (24 weeks), yielding SVR rates of the vast majority of patients with HCV infection, but EIA results
order of 80–95%. The IFN-free combination of sofosbuvir and may be negative in early acute hepatitis C and in profoundly
simeprevir, with or without ribavirin, was used based on the immunosuppressed patients. Following spontaneous or treat-
results of the small-size Phase II COSMOS study in patients ment-induced viral clearance, anti-HCV antibodies persist in the
infected with genotype 1 who achieved SVR in 93–100% of cases absence of HCV RNA but may decline and finally disappear in
[11]. Recent preliminary real-life data from the US showed SVR some individuals [16,17].
rates slightly below those in the COSMOS trial in patients with
genotype 1 infection: 82% SVR12 in the TRIO study, 89% SVR4 The diagnosis of acute hepatitis C can be confidently made
in the TARGET study [12,13]. The combination of sofosbuvir only if seroconversion to anti-HCV antibodies can be docu-
and daclatasvir, with or without ribavirin, has also been widely mented, since there is no serological marker which proves that
used in patients with advanced liver disease throughout HCV infection is in the de novo acquired acute phase. Not all
Europe, based on the results of a Phase II study in patients patients with acute hepatitis C will be anti-HCV-positive at
infected with genotype 1 reporting SVR rates between 95% and diagnosis. In these cases, acute hepatitis C can be suspected if
100% [14]. This combination was well tolerated over the course the clinical signs and symptoms are compatible with acute hep-
of therapy in the trial, and real-life data are awaited. atitis C (alanine aminotransferase [ALT] >10 times the upper limit
of normal, jaundice) in the absence of a history of chronic liver
The panel recognises the heterogeneity of per capita incomes disease or other causes of acute hepatitis, and/or if a likely recent
and health insurance systems across Europe and in other regions, source of transmission is identifiable. In all cases, HCV RNA can
and therefore the possible necessity to continue to utilise be detected during the acute phase although brief interludes of
undetectable HCV RNA may occur.
regimens with PegIFN-a and ribavirin, with or without the
The diagnosis of chronic hepatitis C is based on the detec-
first-wave, first-generation protease inhibitors telaprevir or tion of both anti-HCV antibodies and HCV RNA in the presence
boceprevir. However, the advent of new DAAs implies that these of biological or histological signs of chronic hepatitis. Since, in
regimens are not recommended in 2015. It is hoped that the pub- the case of a newly acquired HCV infection, spontaneous viral
lication of up-to-date recommendations will guide reimburse- clearance is very rare beyond 4 to 6 months of infection, the
ment (and discounting of drug costs) in order to harmonize diagnosis of chronic hepatitis C can be made after that time
treatments across different countries and regions. period.
Methodology Recommendations
These EASL recommendations have been prepared by a panel of • Anti-HCV antibodies are the first-line diagnostic test for
experts chosen by the EASL Governing Board. The recommenda- HCV infection (A1)
tions were approved by the EASL Governing Board. The recom-
mendations have been based as far as possible on evidence • In the case of suspected acute hepatitis C or in
from existing publications and presentations at international immunocompromised patients, HCV RNA testing should
meetings, and, if evidence was unavailable, the experts’ provide be part of the initial evaluation (A1)
personal experiences and opinion. Where possible, the level of
evidence and recommendation are cited. The evidence and • If anti-HCV antibodies are detected, HCV RNA should
recommendations have been graded according to the Grading be determined by a sensitive molecular method (A1)
of Recommendations Assessment, Development and Evaluation
(GRADE) system. The strength of recommendations thus reflects • Anti-HCV-positive, HCV RNA negative individuals
the quality of underlying evidence. The principles of the GRADE should be retested for HCV RNA three months later to
system have been enunciated [15]. The quality of the evidence confirm true convalescence (A1)
in the recommendations has been classified into one of three
levels: high (A), moderate (B) or low (C). The GRADE system Screening for chronic hepatitis C
offers two grades of recommendation: strong (1) or weak (2)
(Table 1). The recommendations thus consider the quality of evi- Because of the approval of highly efficacious new HCV treatment
dence: the higher the quality of evidence, the more likely a strong regimens, access to therapy must be broadened. A substantial
recommendation is warranted; the greater the variability in val- proportion of patients with chronic hepatitis C are unaware of
ues and preferences, or the greater the uncertainty, the more their infection. In addition, accurate HCV prevalence and inci-
likely a weaker recommendation is warranted. dence data are needed to analyse the magnitude of the pandemic
in different regions and to design public health interventions.
These recommendations are necessarily based on currently Thus, hepatitis C testing is required to identify infected persons
licensed drugs. They will be updated regularly, following approval and engage them in care and treatment, and targeted screening
of new drug regimens by the European Medicines Agency. for markers of HCV infection must be implemented. Groups at
higher risk of HCV infection can be identified, and should be
Recommendations tested. At-risk populations, that should be screened, depend on
the local epidemiology of HCV infection. In addition to EIAs, rapid
Diagnosis of acute and chronic hepatitis C
The diagnosis of acute and chronic HCV infection is based on the
detection of HCV RNA by a sensitive molecular method (lower
2
