EASL Clinical Practice Guidelines

Context

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 prevalence, 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 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].

Six HCV genotypes, numbered 1–6, and a large number of subtypes have been described [6]. 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]. 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].

Natural history

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 [[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 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]. 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 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] and currently available therapies are expected to have a modest impact on the mortality rate [15]. 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].

Available tools for diagnosis, assessment of disease severity, and monitoring

Virological tools

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]. 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], [19], [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 hybridization, 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 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].

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 extensively evaluated in patients with chronic HCV infection. They include serological markers and transient elastography [[24], [25]]. Their performance, when used alone or together, has been 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.

Host genetics

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 [[26], [27], [28], [29]]. These polymorphisms are also associated with spontaneous clearance of acute HCV infection, in particular in asymptomatic patients [[30], [31]]. 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]. 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 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 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 [[32], [33], [34], [35], [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 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].

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]. 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 [[38], [39]]. 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]. 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 [[41], [42], [43], [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 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.