丙肝指南 EASL 2011

EASL Clinical Practice Guidelines: Management of hepatitis C virus infection European Association for the Study of the Liver 1 1. Introduction Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide [1]. The long-term hepatic impact of HCV infection is highly variable, from minimal changes to chronic hepatitis, extensive fibrosis, and cirrhosis with or with- out 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 dec- ades, 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 physiciansandotherhealthcareproviders, aswell aspatients 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 thera- peutic options have completed phase III development for patients infectedwith 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. 2. Context 2.1. Epidemiology and public health burden It is estimated that approximately 130–210 million individuals, i.e. 3% of the world population, are chronically infected with HCV [1,2]. 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]. Egypt has the highest worldwide preva- lence, with 9% countrywide and up to 50% in certain rural areas, due to specific modes of infection [4]. 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 prod- ucts for HCV by means of enzyme immunoassays and, in a num- ber 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 proce- dures. 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]. Six HCV genotypes, numbered 1–6, and a large number of sub- types have been described [6]. They originated from diverse areas in Africa and Asia, and some of them have spread widely through- out 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]. 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]. 2.2. Natural history AcuteHCV 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 symptom- atic hepatitis, and to the age at which infection occurred [8,9]. In Europe, HCV infection is responsible for about 10% of cases of acute hepatitis [3]. 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 Journal of Hepatology 2011 vol. 55 j 245–264 Received 24 February 2011; accepted 24 February 2011 1 Correspondence: EASL Office, 7 rue des Battoirs, CH 1205 Geneva, Switzerland. Tel.: +41 22 807 0360; fax: +41 22 328 0724. E-mail address: easloffice@easloffice.eu Abbreviations: SoC, standard of care; TE, transient elastography; HCV, hepatitis C virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus; PCR, poly- merase chain reaction; EIA, enzyme immuno assay; INR, international normalized ratio. Clinical Practice Guidelines Panel: Contributors: Antonio Craxì (Coordinator), Jean-Michel Pawlotsky (EASL Governing Board), Heiner Wedemeyer (EASL Governing Board); Kristian Bjoro, Robert Flisiak, Xavier Forns, Mario Mondelli (Journal of Hepatology), Marcus Peck-Radosavljevic, William Rosenberg, Christoph Sarrazin. Reviewers: The EASL Governing Board, Ira Jacobson, Geoffrey Dusheiko. Clinical Practice Guidelines 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 immuno- deficiency virus (HIV) coinfection, or coinfection with other hepa- totropic viruses. Depending on the presence of co-factors, between 10% and 40% of patients with chronic HCV infection will develop cirrhosis [10]. 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]. Patients diagnosed with HCC have a 33% probability of death during the first year [12,13]. HCV infectionhasbecomethe leadingcauseofprimary liver can- cers 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] and currently available therapies are expected to have amodest impact on themortality rate [15]. These results probably also apply to most other European countries. Extrahepatic manifestations including cryoglobulinaemia, lichen planus, porphyria cutanea tarda, lymphocytic sialoadeni- tis, and membranous glomerulonephritis may occur. There is an association between non-Hodgkin lymphoma and hepatitis C infection [16]. 2.3. Available tools for diagnosis, assessment of disease severity, and monitoring 2.3.1. Virological tools Diagnosis of chronicHCV infection is based on the presence of both anti-HCVantibodies, detectedby enzyme immunoassays, andHCV RNA, detectedbymolecular assays.HCVRNA testing is essential for the management of HCV therapy [17]. 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 [18–20]. 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 hybridiza- tion, and genotype-specific real-time PCR [17]. The available commercial assays have been shown to accurately identify the six HCV genotypes. However, assays targeting the 50 noncoding region of theHCVgenome fail to differentiate HCV subtypes 1a and 1b in a substantial proportion of patients. Correct subtype iden- tification, 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 50 noncoding region [21]. 2.3.2. Assessment of liver disease severity 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 [22,23]. The shortcomings of biopsy have been highlighted in recent years and alternate non-invasive methods have been developed and exten- sively evaluated in patients with chronic HCV infection. They include serological markers and transient elastography [24,25]. Their performance,whenused aloneor together, hasbeen reported to be comparable with liver biopsy [24,25]. 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. 2.3.3. Host genetics Several independent genome-wide association studies have dem- onstrated that host polymorphisms located upstream of the IL28B (interferon lambda 3) gene are associated with sustained virolog- ical response to treatment with pegylated interferon alpha in combinationwith ribavirin [26–29]. Thesepolymorphismsare also associated with spontaneous clearance of acute HCV infection, in particular in asymptomatic patients [30,31]. The distribution of IL28Bpolymorphismsvaries betweendifferent populationsworld- wide and helps to explain heterogeneity in response to interferon- based treatments in different ethnic or racial groups [30]. 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. 2.4. The current standard of care and developing therapies. 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 treat- ment 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)-a and ribavirin is the approved and well accepted standard-of-care (SoC) for chronic hepatitis C [32–36]. 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 consider- ably 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]. Two pegylated IFN-a molecules can be used in combination with ribavirin, i.e. pegylated IFN-a2a and pegylated IFN-a2b. The pharmacokinetics of these compounds differs. A large-scale post-approval US trial comparing various schedules of adminis- tration of pegylated IFN-a2a and IFN-a2b with ribavirin in patients infected with HCV genotype 1 showed no significant dif- ference between the tested strategies [37]. 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-a2a in combination with ribavirin [38,39]. Although efficacy is still debated, there is currently no conclusive evidence that one pegylated IFN-a should be preferred to the other one as first-line therapy. Clinical Practice Guidelines 246 Journal of Hepatology 2011 vol. 55 j 245–264 A large number of drugs forHCVare at various stages of preclin- ical and clinical development [40]. New therapeutic strategies aim toward higher efficacy, shortened treatment, easier administra- tion, and improved tolerability and patient adherence. Phase III studies have recently been reported for two NS3/4 protease inhib- itors, telaprevir and boceprevir, in combination with pegylated IFN-a and ribavirin in both naïve and non-responder patients infected with HCV genotype 1 [41–44]. 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 prote- ase inhibitors, nucleoside/nucleotide analogues and non-nucleo- side 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. 3. Methodology 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 col- lected from PubMed and Cochrane database searches before December 2010. The CPGs have beenbased as far as possible on evi- dence 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 andrecommendations in theseguidelineshavebeengradedaccord- ing 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 evi- dence 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) orweak (2) (Table 1). The CPGs thus consider the quality of evidence: the higher the quality of evidence, themore likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncer- tainty, the more likely a weaker recommendation is warranted. 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? 4. Guidelines 4.1. Diagnosis of acute and chronic hepatitis C Diagnosis of HCV infection is based on detection of anti-HCV anti- bodies 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 con- sumption (A1). Table 1. Evidence grading used in the EASL HCV Clinical Practice Guidelines (adapted from the GRADE system). Evidence Notes Notes High quality Further research is very unlikely to change our confidence in the estimate of effect A Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate B Low quality Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertain C Recommendation Strong Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost 1 Weak Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption 2 JOURNAL OF HEPATOLOGY Journal of Hepatology 2011 vol. 55 j 245–264 247 (2) Diagnosis of HCV infection is based on detection of anti- HCV antibodies by EIA and HCV RNA by a sensitive molec- ular method (A1). (3) For the diagnosis of acute hepatitis C, HCV RNA testing is required since HCV RNA appears before anti-HCV antibod- ies 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). 4.1.1. Prevention of HCV transmission and vaccination against HAV and HBV There are currently no vaccines available for the prevention of HCV infection [45]. 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 occupa- tional exposures to HCV [46]. In addition, medical treatment still represents a risk factor for HCV transmission even in Western countries [47,48]. Acute HBV and HAV superinfection may take a more severe course in patients with chronic hepatitis C although conflicting data have been published [49–53]. The risk for sexual transmission of HCV is very low although recent data indicate that promiscuous male homosexual activity is related to HCV infection [5]. The vertical transmission rate of HCV is low (1–6%). Transmission might be higher for girls than for boys and in HIV-positive mothers [54] with high HCV viral load. Recommendations (1) Persons who experienced an injury with an HCV-contami- nated needle should be tested for HCV RNA within 4 weeks. Anti-HCV and ALT testing should be performed after 12 and 24 weeks (B2). (2) HCV infected persons should not share potentially blood- contaminated tools such as shavers, scissors, tooth brushes, or needles with any other person (A1). (3) Medical health professionals should be tested for anti- HCV. HCV RNA-positive health professionals should avoid activities with an increased risk of accidental puncture or break of skin or mucosa (C2). (4) Family members of HCV-infected patients