EASL Clinical Practice Guidelines: Management of hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide [[1]Lavanchy D. The global burden of hepatitis C.Liver Int. 2009; 29: 74-81Crossref PubMed Scopus (737) Google Scholar]. The long-term hepatic impact of HCV infection is highly variable, from minimal changes to chronic hepatitis, extensive fibrosis, and cirrhosis with or without hepatocellular carcinoma (HCC). The number of chronically infected persons worldwide may exceed 200 million, but most of them have no knowledge of their infection or of the ensuing hepatic condition. Clinical care for patients with HCV-related liver disease has advanced considerably during the last two decades, as a result of growing knowledge about the mechanisms of the disease, remarkable developments in diagnostic procedures, and advances in therapeutic and preventative approaches. Still, various aspects are not yet completely resolved. These EASL Clinical Practice Guidelines (CPGs) are intended to assist physicians and other healthcare providers, as well as patients and interested individuals, in the clinical decision-making process by describing optimal management of patients with acute and chronic HCV infections. These guidelines apply to therapies that are approved at the time of their publication. Several new therapeutic options have completed phase III development for patients infected with HCV genotype 1 and are currently awaiting licensing and approval in Europe and the United States. Therefore, the EASL CPGs on the management of HCV infection will be updated on a regular basis upon approval of additional novel therapies. It is estimated that approximately 130–210 million individuals, i.e. 3% of the world population, are chronically infected with HCV [1Lavanchy D. The global burden of hepatitis C.Liver Int. 2009; 29: 74-81Crossref PubMed Scopus (737) Google Scholar, 2Shepard C.W. Finelli L. Alter M.J. Global epidemiology of hepatitis C virus infection.Lancet Infect Dis. 2005; 5: 558-567Abstract Full Text Full Text PDF PubMed Scopus (1648) Google Scholar]. The prevalence varies markedly from one geographic area to another and within the population assessed. In Western Europe, HCV prevalence ranges from 0.4% to 3%. It is higher in Eastern Europe and the Middle East, where the numbers are not precisely known [[3]Esteban J.I. Sauleda S. Quer J. The changing epidemiology of hepatitis C virus infection in Europe.J Hepatol. 2008; 48: 148-162Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. Egypt has the highest worldwide prevalence, with 9% countrywide and up to 50% in certain rural areas, due to specific modes of infection [[4]Kamal S.M. Nasser I.A. Hepatitis C genotype 4: what we know and what we don’t yet know.Hepatology. 2008; 47: 1371-1383Crossref PubMed Scopus (159) Google Scholar]. Prior to the 1990’s, the principal routes of HCV infection were via blood transfusion, unsafe injection procedures, and intravenous drug use. These modes of acquisition are estimated to account for approximately 70% of cases in industrialized countries. Screening of blood products for HCV by means of enzyme immunoassays and, in a number of European countries, nucleic acid testing, has virtually eradicated transfusion-transmitted hepatitis C. Currently, new HCV infections are primarily due to intravenous or nasal drug use, and to a lesser degree to unsafe medical or surgical procedures. Parenteral transmission via tattooing or acupuncture with unsafe materials is also implicated in occasional transmissions. The risk of perinatal and of heterosexual transmission is low, while recent data indicate that promiscuous male homosexual activity is related to HCV infection [[5]van de Laar T.J.W. Matthews G.V. Prins M. Danta M. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection.AIDS. 2010; 24: 1799-1812Crossref PubMed Scopus (111) Google Scholar]. Six HCV genotypes, numbered 1–6, and a large number of subtypes have been described [[6]Simmonds P. Bukh J. Combet C. Deleage G. Enomoto N. Feinstone S. et al.Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes.Hepatology. 2005; 42: 962-973Crossref PubMed Scopus (960) Google Scholar]. They originated from diverse areas in Africa and Asia, and some of them have spread widely throughout the world. Genotype 1 (subtypes 1a and 1b) is by far the most prevalent genotype worldwide, with a higher prevalence of 1b in Europe and 1a in the US. Genotype 3a is highly prevalent in European intravenous drug users [[3]Esteban J.I. Sauleda S. Quer J. The changing epidemiology of hepatitis C virus infection in Europe.J Hepatol. 2008; 48: 148-162Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. This group is currently experiencing an increasing incidence and prevalence of infections related to HCV genotype 4. Genotype 2 is found in clusters in the Mediterranean region, while 5 and 6 are more rarely found [[7]Antaki N. Craxi A. Kamal S. Moucari R. Van der Merwe S. Haffar S. et al.The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.Liver Int. 2010; 30: 342-355Crossref PubMed Scopus (103) Google Scholar]. Acute HCV infection is asymptomatic in 50–90% of cases. Failure to spontaneously eradicate infection occurs in 50–90% of cases according to the route of transmission, the presence of symptomatic hepatitis, and to the age at which infection occurred [8Santantonio T. Wiegand J. Gerlach J.T. Acute hepatitis C: current status and remaining challenges.J Hepatol. 2008; 49: 625-633Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 9Wiegand J. Deterding K. Cornberg M. Wedemeyer H. Treatment of acute hepatitis C: the success of monotherapy with (pegylated) interferon alpha.J Antimicrob Chemother. 2008; 62: 860-865Crossref PubMed Scopus (37) Google Scholar]. In Europe, HCV infection is responsible for about 10% of cases of acute hepatitis [[3]Esteban J.I. Sauleda S. Quer J. The changing epidemiology of hepatitis C virus infection in Europe.J Hepatol. 2008; 48: 148-162Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar]. The incidence of acute HCV infection has decreased and is now about 1/100,000 subjects per year, but this figure is probably underestimated because it may exclude asymptomatic infections. Chronic infection is associated with variable degrees of hepatic inflammation and fibrosis progression, regardless of HCV genotype and of viral load. Only exceptionally does it resolve spontaneously. Liver disease progression takes place over several decades, and is accelerated in the presence of cofactors such as alcohol consumption, diabetes mellitus (to which HCV itself appears to predispose), older age of acquisition, human immunodeficiency virus (HIV) coinfection, or coinfection with other hepatotropic viruses. Depending on the presence of co-factors, between 10% and 40% of patients with chronic HCV infection will develop cirrhosis [[10]Afdhal N.H. The natural history of hepatitis C.Semin Liver Dis. 2004; 24: 3-8Crossref PubMed Google Scholar]. Death related to the complications of cirrhosis may occur, at an incidence of approximately 4% per year, whereas HCC occurs in this population at an estimated incidence of 1–5% per year [[11]Thompson C.J. Rogers G. Hewson P. Wright D. Anderson R. Cramp M. et al.Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.Health Technol Assess. 2007; 11: 1-206Google Scholar]. Patients diagnosed with HCC have a 33% probability of death during the first year [12Yang J.D. Roberts L.R. Hepatocellular carcinoma: a global view.Nat Rev Gastroenterol Hepatol. 2010; 7: 448-458Crossref PubMed Scopus (391) Google Scholar, 13Bartosch B. Thimme R. Blum H.E. Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis.J Hepatol. 2009; 51: 810-820Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. HCV infection has become the leading cause of primary liver cancers in Europe. Based on models from France to predict the death rates due to HCV-related HCC, the peak mortality related to HCV infection is ahead of us [[14]Deuffic-Burban S. Deltenre P. Louvet A. Canva V. Dharancy S. Hollebecque A. et al.Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France.J Hepatol. 2008; 49: 175-183Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar] and currently available therapies are expected to have a modest impact on the mortality rate [[15]Deuffic-Burban S. Babany G. Lonjon-Domanec I. Deltenre P. Canva-Delcambre V. Dharancy S. et al.Impact of pegylated interferon and ribavirin on morbidity and mortality in patients with chronic hepatitis C and normal aminotransferases in France.Hepatology. 2009; 50: 1351-1359Crossref PubMed Scopus (27) Google Scholar]. These results probably also apply to most other European countries. Extrahepatic manifestations including cryoglobulinaemia, lichen planus, porphyria cutanea tarda, lymphocytic sialoadenitis, and membranous glomerulonephritis may occur. There is an association between non-Hodgkin lymphoma and hepatitis C infection [[16]Zignego A.L. Craxi A. Extrahepatic manifestations of hepatitis C virus infection.Clin Liver Dis. 2008; 12 (ix): 611-636Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Diagnosis of chronic HCV infection is based on the presence of both anti-HCV antibodies, detected by enzyme immunoassays, and HCV RNA, detected by molecular assays. HCV RNA testing is essential for the management of HCV therapy [[17]Chevaliez S. Pawlotsky J.M. Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes.Best Pract Res Clin Gastroenterol. 2008; 22: 1031-1048Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. The most recent assays are based on the use of real-time polymerase chain reaction (PCR). They can detect minute amounts of HCV RNA (down to 10 international units (IU)/ml) and accurately quantify HCV RNA levels up to approximately 107 IU/ml. Their dynamic range of quantification adequately covers the clinical needs for diagnosis and monitoring [18Vermehren J. Kau A. Gartner B.C. Gobel R. Zeuzem S. Sarrazin C. Differences between two real-time PCR-based hepatitis C virus (HCV) assays (RealTime HCV and Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for RNA detection and quantification.J Clin Microbiol. 2008; 46: 3880-3891Crossref PubMed Scopus (61) Google Scholar, 19Chevaliez S. Bouvier-Alias M. Pawlotsky J.M. Performance of the Abbott Real-Time PCR assay using m2000(sp) and m2000(rt) for hepatitis C virus RNA quantification.J Clin Microbiol. 2009; 47: 1726-1732Crossref PubMed Scopus (38) Google Scholar, 20Fytili P. Tiemann C. Wang C. Schulz S. Schaffer S. Manns M.P. et al.Frequency of very low HCV viremia detected by a highly sensitive HCV-RNA assay.J Clin Virol. 2007; 39: 308-311Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. When new drugs such as direct acting antivirals become available, high sensitivity levels will become of major importance for characterization of virological responses and treatment decisions and it will be necessary to redefine how low-range HCV RNA results are reported. HCV genotype and subtype can be determined via various methods, including direct sequence analysis, reverse hybridization, and genotype-specific real-time PCR [[17]Chevaliez S. Pawlotsky J.M. Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes.Best Pract Res Clin Gastroenterol. 2008; 22: 1031-1048Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. The available commercial assays have been shown to accurately identify the six HCV genotypes. However, assays targeting the 5′ noncoding region of the HCV genome fail to differentiate HCV subtypes 1a and 1b in a substantial proportion of patients. Correct subtype identification, the importance of which may increase once new direct acting antivirals will be available, therefore, requires sequence or reverse hybridization-based methods targeting segments other than the 5′ noncoding region [[21]Chevaliez S. Bouvier-Alias M. Brillet R. Pawlotsky J.M. Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug development and future clinical practice.PLoS One. 2009; 4: e8209Crossref PubMed Scopus (69) Google Scholar]. Assessment of the severity of hepatic fibrosis is important in decision making in chronic hepatitis C treatment and prognosis. Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis [22Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Abstract Full Text PDF PubMed Scopus (2880) Google Scholar, 23Desmet V.J. Gerber M. Hoofnagle J.H. Manns M. Scheuer P.J. Classification of chronic hepatitis: diagnosis, grading and staging.Hepatology. 1994; 19: 1513-1520Crossref PubMed Google Scholar]. The shortcomings of biopsy have been highlighted in recent years and alternate non-invasive methods have been developed and extensively evaluated in patients with chronic HCV infection. They include serological markers and transient elastography [24Poynard T. Ngo Y. Munteanu M. Thabut D. Massard J. Moussalli J. et al.Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies.Antiviral Therapy. 2010; 15: 617-631Crossref PubMed Scopus (34) Google Scholar, 25Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis.J Viral Hepat. 2009; 16: 300-314Crossref PubMed Scopus (102) Google Scholar]. Their performance, when used alone or together, has been reported to be comparable with liver biopsy [24Poynard T. Ngo Y. Munteanu M. Thabut D. Massard J. Moussalli J. et al.Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies.Antiviral Therapy. 2010; 15: 617-631Crossref PubMed Scopus (34) Google Scholar, 25Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis.J Viral Hepat. 2009; 16: 300-314Crossref PubMed Scopus (102) Google Scholar]. Both non-invasive methods have been shown to accurately identify patients with mild fibrosis or cirrhosis. They are less able to discriminate moderate and severe fibrosis. Several independent genome-wide association studies have demonstrated that host polymorphisms located upstream of the IL28B (interferon lambda 3) gene are associated with sustained virological response to treatment with pegylated interferon alpha in combination with ribavirin [26Ge D.L. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (2354) Google Scholar, 27Tanaka Y. Nishida N. Sugiyama M. Kurosaki M. Matsuura K. Sakamoto N. et al.Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.Nat Genet. 2009; 41: 1105-1109Crossref PubMed Scopus (1524) Google Scholar, 28Suppiah V. Moldovan M. Ahlenstiel G. Berg T. Weltman M. Abate M.L. et al.IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.Nat Genet. 2009; 41: 1100-1174Crossref PubMed Scopus (1330) Google Scholar, 29Rauch A. Kutalik Z. Descombes P. Cai T. Di Iulio J. Mueller T. et al.Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.Gastroenterology. 2010; 138 (1345.e1–7): 1338-1345Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar]. These polymorphisms are also associated with spontaneous clearance of acute HCV infection, in particular in asymptomatic patients [30Thomas D.L. Thio C.L. Martin M.P. Qi Y. Ge D. O’hUigin C. et al.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.Nature. 2009; 461: 798-801Crossref PubMed Scopus (1297) Google Scholar, 31Tillmann H.L. Thompson A.J. Patel K. Wiese M. Tenckhoff H. Nischalke H.D. et al.A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice.Gastroenterology. 2010; 139: 1586-1592Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar]. The distribution of IL28B polymorphisms varies between different populations worldwide and helps to explain heterogeneity in response to interferon-based treatments in different ethnic or racial groups [[30]Thomas D.L. Thio C.L. Martin M.P. Qi Y. Ge D. O’hUigin C. et al.Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.Nature. 2009; 461: 798-801Crossref PubMed Scopus (1297) Google Scholar]. Determination of IL28B polymorphisms may be useful to identify a patient’s likelihood of response to treatment with pegylated interferon alpha and ribavirin; however, the predictive value is low. Other genetic variants may also bear some correlation with disease progression in response to treatment. The primary goal of HCV therapy is to cure the infection, which results in eliminating detectable circulating HCV after cessation of treatment. Sustained virological response (SVR), is defined as an undetectable HCV RNA level (<50 IU/ml) 24 weeks after treatment withdrawal. SVR is generally associated with resolution of liver disease in patients without cirrhosis. Patients with cirrhosis remain at risk of life-threatening complications; particularly, HCC may occur even after viral infection has been eradicated. The combination of pegylated interferon (IFN)-α and ribavirin is the approved and well accepted standard-of-care (SoC) for chronic hepatitis C [32Ghany M.G. Strader D.B. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374Crossref PubMed Scopus (1954) Google Scholar, 33McCaughan G.W. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection.J Gastroenterol Hepatol. 2007; 22: 615-633Crossref PubMed Scopus (117) Google Scholar, 34de Bruijne J. Buster E.H.C.J. Gelderblom H.C. Brouwer J.T. de Knegt R.J. van Erpecum K.J. et al.Treatment of chronic hepatitis C virus infection – Dutch national guidelines.Netherlands J Med. 2008; 66: 311-322PubMed Google Scholar, 35Italian Association for the study of the liver, Italian Society of infectious td, Italian Society for the study of sexually transmitted diseases. Practice guidelines for the treatment of hepatits C: recommendations from AISF/SIMIT/SIMAST. Dig Liver Dis 2010;42:81–91.Google Scholar, 36Sarrazin C. Berg T. Ross R.S. Schirmacher P. Wedemeyer H. Neumann U. et al.Prophylaxis, diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on the management of HCV infection.Z Gastroenterol. 2010; 48: 289-351Crossref PubMed Scopus (111) Google Scholar]. In patients infected with HCV genotype 1, SVR rates after SoC are on the order of 40% in North America and 50% in Western Europe in most trials. The SVR rates are considerably higher in patients infected with HCV genotypes 2, 3, 5, and 6 (on the order of 80% and are higher for genotype 2 than genotypes 3, 5, and 6). The results of therapy for genotype 4 infected patients approximate those for genotype 1 or are slightly better in HCV genotype 4 infected patients [[7]Antaki N. Craxi A. Kamal S. Moucari R. Van der Merwe S. Haffar S. et al.The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.Liver Int. 2010; 30: 342-355Crossref PubMed Scopus (103) Google Scholar]. Two pegylated IFN-α molecules can be used in combination with ribavirin, i.e. pegylated IFN-α2a and pegylated IFN-α2b. The pharmacokinetics of these compounds differs. A large-scale post-approval US trial comparing various schedules of administration of pegylated IFN-α2a and IFN-α2b with ribavirin in patients infected with HCV genotype 1 showed no significant difference between the tested strategies [[37]McHutchison J.G. Lawitz E.J. Shiffman M.L. Muir A.J. Galler G.W. McCone J. et al.Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.New Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (886) Google Scholar]. In contrast, two Italian trials in patients infected with HCV genotypes 1, 2, 3, and 4 showed some benefit, mostly in genotype 1 patients, in favor of pegylated IFN-α2a in combination with ribavirin [38Rumi M.G. Aghemo A. Prati G.M. D’Ambrosio R. Donato M.F. Soffredini R. et al.Randomized study of peginterferon-alpha 2a plus ribavirin vs peginterferon-alpha 2b plus ribavirin in chronic hepatitis C.Gastroenterology. 2010; 138: 108-115Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 39Ascione A. De Luca M. Tartaglione M.T. Lampasi F. Di Costanzo G.G. Lanza A.G. et al.Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.Gastroenterology. 2010; 138: 116-122Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. Although efficacy is still debated, there is currently no conclusive evidence that one pegylated IFN-α should be preferred to the other one as first-line therapy. A large number of drugs for HCV are at various stages of preclinical and clinical development [[40]Shiffman M.L. Treatment of hepatitis C in 2011: what can we expect?.Curr Gastroenterol Rep. 2010; 12: 70-75Crossref PubMed Scopus (12) Google Scholar]. New therapeutic strategies aim toward higher efficacy, shortened treatment, easier administration, and improved tolerability and patient adherence. Phase III studies have recently been reported for two NS3/4 protease inhibitors, telaprevir and boceprevir, in combination with pegylated IFN-α and ribavirin in both naïve and non-responder patients infected with HCV genotype 1 [41Bacon B.R. Gordon S.C. Lawitz E. Marcellin P. Vierling J.M. Zeuzem S. et al.HCV RESPOND-2 final results: high sustained virologic response among genotype1 previous nonresponders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus PegIntron/ribavirin.Hepatology. 2010; 52: 430ACrossref PubMed Scopus (59) Google Scholar, 42Jacobson I.M. McHutchison J.G. Dusheiko G.M. Di Bisceglie A.M. Reddy R. Bzowej N.H. et al.Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of Phase 3 ADVANCE study.Hepatology. 2010; 52: 427AGoogle Scholar, 43Poordad F. McCone J. Bacon B.R. Bruno S. Manns M.P. Sulkowski M.S. et al.Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-naive patients with hepatitis C (HCV) genotype 1: SPRINT-2 final results.Hepatology. 2010; 52: 402ACrossref Scopus (26) Google Scholar, 44Sherman K.E. Flamm S.L. Afdhal N.H. Nelson D.R. Sulkowski M.S. Everson G.T. et al.Telaprevir in combination with peginterferon alfa2b and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: final results of Phase 3 ILLUMINATE study.Hepatology. 2010; 52: 401ACrossref PubMed Scopus (5) Google Scholar]. These triple therapies are likely to be approved by the EMA and the FDA in late 2011, and to radically change treatment strategies for patients with chronic hepatitis due to HCV genotype 1 in countries that will have access to them (see Section 4.18). Other direct acting antiviral drugs are at earlier stages of clinical development, including additional protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase, NS5A inhibitors, and cyclophilin inhibitors. IFN-sparing regimens, with or without ribavirin, are also currently being tested. These EASL CPGs have been developed by a CPG Panel of experts chosen by the EASL Governing Board; the recommendations were peer-reviewed by external expert reviewers and approved by the EASL Governing Board. The CPGs were established using data collected from PubMed and Cochrane database searches before December 2010. The CPGs have been based as far as possible on evidence from existing publications, and, if evidence was unavailable, the experts personal experience and opinion. Where possible, the level of evidence and recommendation are cited. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The strength of recommendations thus reflects the quality of underlying evidence. The principles of the GRADE system have been enunciated. The quality of the evidence in the CPG has been classified in one of three levels: high (A), moderate (B) or low (C). The GRADE system offers two grades of recommendation: strong (1) or weak (2) (Table 1). The CPGs thus consider the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted.Table 1Evidence grading used in the EASL HCV Clinical Practice Guidelines (adapted from the GRADE system). Open table in a new tab The HCV CPG Panel has considered the following questions:–How should acute and chronic hepatitis C be diagnosed?–What are the goals and endpoints of treatment?–What are the results of current therapies and the predictors of response?–How should patients be assessed before therapy?–What are the contra-indications to therapy?–Who should be treated?–What first-line treatment should be prescribed?–How should treatment be managed?–How should treatment be tailored to the virological response?–How can success rates of SoC be improved?–How should patients with SVR be followed?–What should be offered to non-sustained responders to SoC?–How should patients with severe liver disease be treated?–How should special groups of patients be treated?–How should we treat patients with acute hepatitis C?–How should untreated patients and non-sustained responders be followed?–What are the perspectives of new treatments? Diagnosis of HCV infection is based on detection of anti-HCV antibodies by enzyme immunoassay and detection of HCV RNA by a sensitive molecular method (lower limit of detection <50 IU/ml), ideally a real-time PCR assay. The diagnosis of chronic hepatitis C is based on the detection of HCV infection (positive anti-HCV antibodies and HCV RNA) in a patient with signs of chronic hepatitis. Rarely, in profoundly immunosuppressed patients, anti-HCV antibodies are not detected and HCV RNA is present alone. Recommendations(1)A detailed history and physical examination is essential (A2) and patients should be queried about alcohol consumption (A1).(2)Diagnosis of HCV infection is based on detection of anti-HCV antibodies by EIA and HCV RNA by a sensitive molecular method (A1).(3)For the diagnosis of acute hepatitis C, HCV RNA testing is required since HCV RNA appears before anti-HCV antibodies may be detectable (A2).(4)Anti-HCV positive, HCV RNA negative patients with acute hepatitis should be retested a few weeks later (B2).(5)Anti-HCV and HCV RNA positivity does not differentiate acute hepatitis C from exacerbation of chronic hepatitis C or from acute hepatitis from other causes in a patient with chronic hepatitis C (B2).(6)Chronic hepatitis C should be proven by the presence of both anti-HCV antibodies and HCV RNA (A1).(7)Immunosuppressed patients may require a test for HCV RNA if hepatitis is present but anti-HCV antibodies are undetectable (B2). There are currently no vaccines available for the prevention of HCV infection [[45]Torresi J. Johnson D. Wedemeyer H. Progress in the development of preventive and therapeutic vaccines for hepatitis C virus.J Hepatol. 2011; PubMed Google Scholar]. Thus, HCV transmission can only be avoided by education and strict adherence to hygienic standards. The risk for HCV transmission is usually related to the level of HCV viral load. Genetic factors may also contribute to the susceptibility for HCV infection. Seroconversion to anti-HCV occurs in less than 1% of occupational exposures to HCV [[46]Kubitschke A. Bahr M.J. Aslan N. Bader C. Tillmann H.L. Sarrazin C. et al.Induction of hepatitis C virus (HCV)-specific T cells by needle stick injury in the absence of HCV-viraemia.Eur J Clin Invest. 2007; 37: 54-64Crossref PubMed Scopus (28) Google Scholar]. In addition, medical treatment still represents a risk factor for HCV transmission even in Western countries [47Deterding K. Wiegand J. Gruner N. Wedemeyer H. Medical procedures as a risk factor for HCV infection in developed countries: do we neglect a significant problem in medical care?.J Hepatol. 2008; 48: 1019-1020Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 48Martinez-Bauer E. Forns X. Armelles M. Planas R. Sola R. Vegara M. et al.Hospital admission is a relevant source of hepatitis C virus acquisition in Spain.J. Hepatol. 2008; : 48Google Scholar]. Acute HBV and HAV superinfection may take a more severe course in patients with chronic hepatitis C although conflicting data have been published [49Helbling B. Renner E.L. Kammerlander R. Acute hepatitis A in patients with chronic hepatitis C.Ann Intern Med. 1999; 131: 314Crossref PubMed Google Scholar, 50Hasle G. Hoel T. Jensenius M. Mortality of hepatitis A in adults with hepatitis C antibodies.Lancet. 1998; 351: 1888Abstract Full Text Full Text PDF PubMed Google Scholar, 51Deterding K. Tegtmeyer B. Cornberg M. Hadem J. Potthoff A. Boker K.H. et al.Hepatitis A virus infect