Page 3 - EASL Recommendations on Treatment of Hepatitis C 2014
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1. Introduction Hepatitis C virus (HCV) infection is one of the main causes of chronic The panel recognises the heterogeneity of per capita incomes liver disease worldwide [1]. The long-term impact of HCV infection is and health insurance systems across Europe and in other regions, highly variable, ranging from minimal histological changes to extensive and therefore the possible necessity to continue to utilise current fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC). standards of care with pegylated IFN-α and ribavirin, with or without The number of chronically infected persons worldwide is estimated the first-generation protease inhibitors telaprevir or boceprevir. to be about 160 million, but most are unaware of their infection. The However the advent of new DAAs implies that these regimens are implementation of extended criteria for screening for HCV, such as not considered optimal in 2014. It is hoped that the publication of up-to- targeting birth cohorts, is a subject of major debate among different date recommendations will guide reimbursement (and discounting of stakeholders. Clinical care for patients with HCV-related liver disease drug costs) in order to harmonize treatments across different countries has advanced considerably during the last two decades, thanks to an and regions. enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention. 3. Methodology These EASL Recommendations on Treatment of Hepatitis C are intended to assist physicians and other healthcare providers, as well These EASL Recommendations have been updated by a as patients and other interested individuals, in the clinical decision- panel of experts chosen by the EASL Governing Board. The making process by describing the optimal management of patients recommendations were approved by the EASL Governing Board. with acute and chronic HCV infections. These guidelines apply to The Recommendations have been based as far as possible therapies that will be approved within less than 6 months at the time on evidence from existing publications and presentations at of their publication. international meetings, and, if evidence was unavailable, the experts’ personal experiences and opinion. Where possible, the 2. The standard of care up to 2014 level of evidence and recommendation are cited. The evidence and recommendations in these guidelines have been graded The primary goal of HCV therapy is to cure the infection. A sustained according to the Grading of Recommendations Assessment, virological response (SVR) is defined as undetectable HCV RNA 12 Development and Evaluation (GRADE) system. The strength of weeks (SVR12) or 24 weeks (SVR24) after treatment completion. recommendations thus reflects the quality of underlying evidence. The infection is cured in more than 99% of patients who achieve The principles of the GRADE system have been enunciated an SVR. The SVR is generally associated with resolution of liver [26]. The quality of the evidence in the CPG has been classified disease in patients without cirrhosis. Patients with cirrhosis remain into one of three levels: high (A), moderate (B) or low (C). The at risk of life-threatening complications; however hepatic fibrosis may GRADE system offers two grades of recommendation: strong regress and the risk of complications such as hepatic failure and (1) or weak (2) (Table 1). The CPGs thus consider the quality of portal hypertension is reduced. More data is required to ascertain the evidence: the higher the quality of evidence, the more likely a lifetime residual risk of hepatocellular carcinoma after viral infection strong recommendation is warranted; the greater the variability in has been eradicated. values and preferences, or the greater the uncertainty, the more Until 2011, the combination of pegylated interferon (IFN)-α and likely a weaker recommendation is warranted. ribavirin for 24 or 48 weeks was the approved treatment for chronic hepatitis C [2]. With this regimen, patients infected with HCV genotype These recommendations are necessarily based on currently 1 had SVR rates of approximately 40% in North America and 50% in licenced drugs. Several major Phase III trials have been completed Western Europe. Higher SVR rates were achieved in patients infected and filing for licencing has been completed or is imminent. The with HCV genotypes 2, 3, 5, and 6 (up to about 80%, and higher for panel could not recommend treatments with these compounds, but genotype 2 than for genotypes 3, 5, and 6) and intermediate SVR provides a perspective at the end, given the likely importance of rates were achieved in those with HCV genotype 4 [3]. these imminent regimens under review. These Recommendations In 2011, telaprevir and boceprevir were licensed for use in HCV will be updated regularly, following approval of new drug regimens genotype 1 infection. These two drugs are first-wave, first-generation by the European Medicines Agency. direct-acting antivirals (DAAs). Both target the HCV NS3/4A serine protease and are thus referred to as protease inhibitors. Both telaprevir and boceprevir must be administered in combination with pegylated 4. Recommendations IFN-α and ribavirin. In the phase III trials of boceprevir and telaprevir in HCV genotype 1 treatment-naïve patients, triple therapy regimens 4.1. Diagnosis of acute and chronic hepatitis C achieved higher SVR rates than pegylated IFN-α/ribavirin dual therapy, of the order of 65% to 75% [4-7]. However, the side effect profiles of The diagnosis of acute and chronic HCV infection is based on the these triple combination therapies are not favourable, and the costs detection of HCV RNA by a sensitive molecular method (lower limit per SVR in patients with advanced hepatic fibrosis are such that of detection <15 international units [IU]/ml). Anti-HCV antibodies they should ideally no longer be used in patients infected with HCV are detectable by enzyme immunoassay (EIA) in the vast majority genotype 1, as soon as other, more efficacious and better-tolerated of patients with HCV infection, but EIA results may be negative options are available. in early acute hepatitis C and in profoundly immunosuppressed In addition to pegylated IFN-α and ribavirin, three new HCV DAAs patients. Following spontaneous or treatment-induced viral will be licenced in the EU in the first half of 2014, for use as part of clearance, anti-HCV antibodies persist in the absence of HCV RNA combination therapies for HCV infection. Sofosbuvir, a nucleotide but may decline and finally disappear in some individuals [8, 9]. analogue inhibitor of HCV RNA-dependent RNA polymerase, has The diagnosis of acute hepatitis C can be confidently made been approved in January 2014. Simeprevir, a second-wave, first- only if seroconversion to anti-HCV antibodies can be documented, generation NS3/4A protease inhibitor will be approved in May 2014. since there is no serological marker which proves that HCV Daclatasvir, an NS5A inhibitor, is likely to be approved in August or infection is in the de novo acquired acute phase. Not all patients September 2014. Other drugs may be approved later in 2014 or in with acute hepatitis C will be anti-HCV positive at diagnosis. In 2015 and an update of these guidelines will be provided when this these cases, acute hepatitis C can be suspected if the clinical is the case. signs and symptoms are compatible with acute hepatitis C (alanine 1
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