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IFN-free regimens are the only options in HCV-monoinfected and in HIV-coinfected patients with decompensated (Child-Pugh B or C) cirrhosis, with or without an indication for liver transplantation, and in patients after liver transplantation because of their virological efficacy, ease of use, safety and tolerability (
GuidelinesEASL Recommendations on Treatment of Hepatitis C 2018
Introduction
Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide.1 The long-term natural history of HCV infection is highly variable. The hepatic injury can range from minimal histological changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC). There are approximately 71 million chronically infected individuals worldwide,[1], [2] many of whom are unaware of their infection, with important variations according to the geographical area. Clinical care for patients with HCV-related liver disease has advanced considerably during the last two decades, thanks to an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention.
The primary goal of HCV therapy is to cure the infection, i.e. to achieve a sustained virological response (SVR) defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion. An SVR corresponds to a cure of the HCV infection, with a very low chance of late relapse. An SVR is generally associated with normalisation of liver enzymes and improvement or disappearance of liver necroinflammation and fibrosis in patients without cirrhosis. Patients with advanced fibrosis (METAVIR score F3) or cirrhosis (F4) remain at risk of life-threatening complications. However, hepatic fibrosis may regress and the risk of complications such as hepatic failure and portal hypertension is reduced after an SVR. Recent data suggest that the risk of HCC and liver-related mortality is significantly reduced, but not eliminated, in patients with cirrhosis who clear HCV compared to untreated patients and non-sustained virological responders, especially in the presence of cofactors of liver morbidity, such as the metabolic syndrome, harmful alcohol consumption and/or concurrent hepatitis B virus (HBV) infection.[3], [4], [5], [6], [7], [8], [9] HCV is also associated with a number of extra-hepatic manifestations and viral elimination induces reversal of most of them with reduction of all-cause mortality.[10], [11], [12], [13], [14], [15], [16]
These EASL Recommendations on Treatment of Hepatitis C are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process, by describing the current optimal management of patients with acute and chronic HCV infections. These recommendations apply to therapies that have been approved by the European Medicines Agency and other national European agencies at the time of their publication.
Section snippets
Methodology
These EASL recommendations have been prepared by a panel of experts chosen by the EASL Governing Board. The recommendations are primarily based on evidence from existing publications and presentations at international meetings. In the absence of such evidence, the experts’ personal experiences and opinions have been considered. Wherever possible, the level of evidence and recommendation are cited. The evidence and recommendations have been graded according to the Grading of Recommendations
Diagnosis of acute and chronic hepatitis C
Anti-HCV antibodies are detectable in serum or plasma by enzyme immunoassay (EIA) in the vast majority of patients with HCV infection, but EIA results may be negative in early acute hepatitis C and in profoundly immunosuppressed patients. Following spontaneous or treatment-induced viral clearance, anti-HCV antibodies persist in the absence of HCV RNA, but may decline and finally disappear in some individuals.[18], [19], [20]
The diagnosis of acute and chronic HCV infection is based on the
Screening for chronic hepatitis C
A major barrier to HCV elimination still results from the fact that a substantial proportion of patients with chronic HCV infection are unaware of their infection, with large variations across different regions, countries and risk populations. In addition, accurate HCV prevalence and incidence data are needed to analyse the magnitude of the pandemic in different regions and to design public health interventions. Thus, HCV screening is required to identify infected individuals and engage them in
Goals and endpoints of HCV therapy
The goal of therapy is to cure HCV infection in order to: (i) prevent the complications of HCV-related liver and extra-hepatic diseases, including hepatic necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death; (ii) improve quality of life and remove stigma; (iii) prevent onward transmission of HCV.
The endpoint of therapy is an SVR, defined by undetectable HCV RNA in serum or plasma 12 weeks (SVR12) or 24 weeks (SVR24) after the
Pre-therapeutic assessment
Liver disease severity must be assessed, and baseline virological parameters that will be useful for tailoring therapy should be determined.
Contraindications to therapy
Contraindications to treatment with a DAA are few. The use of certain cytochrome P450 (CYP)/P-glycoprotein (P-gp) inducing agents (such as carbamazepine and phenytoin) are contraindicated with all regimens, due to the risk of significantly reduced concentrations of DAA and therefore high risk of virological failure. Other concomitant medicine-related contraindications are discussed below. Treatment regimens comprising an NS3-4A protease inhibitor, such as ritonavir-boosted paritaprevir,
Indications for treatment: who should be treated?
All treatment-naïve and -experienced patients with HCV infection, who are willing to be treated and who have no contraindications for treatment, should be treated.
Treatment must be considered without delay in patients with significant fibrosis (METAVIR score F2 or F3) or cirrhosis (METAVIR score F4), including decompensated cirrhosis; patients with clinically significant extra-hepatic manifestations (e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune
Available drugs in Europe in 2018
The HCV drugs available in Europe are listed in this paragraph and in Table 3. Their known pharmacokinetic profiles and how this impacts drug-drug interactions are presented. For a more comprehensive listing of drug-drug interactions, see Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G, and www.hep-druginteractions.org for a comprehensive list of over 700 co-medications. For additional information on the disposition of individual DAAs, refer to the Summary of Product
Treatment of chronic hepatitis C, including patients without cirrhosis and patients with compensated (Child-Pugh A) cirrhosis
In 2018 and onwards, because of their virological efficacy, ease of use, safety and tolerability, interferon (IFN)-free, ribavirin-free, DAA-based regimens are the best options in HCV-infected patients without cirrhosis (and in those with compensated [Child-Pugh A] and decompensated [Child-Pugh B and C] cirrhosis), including “treatment-naïve” patients (defined as patients who have never been treated for their HCV infection) and “treatment-experienced“ patients (defined as patients who were
Simplified treatment of chronic hepatitis C with pangenotypic drug regimens in patients without cirrhosis and in patients with compensated (Child-Pugh A) cirrhosis
With the approval of highly efficacious, safe and well-tolerated combination regimens, improving access to anti-HCV therapy has become a worldwide priority. However, many obstacles remain that reduce global benefit from the new IFN-free, ribavirin-free combination regimens. They include the numbers of infected individuals, the cost of biological tests, the amount of information needed to inform treatment decisions, and the relative complexity of the treatment strategies shown in the previous
Treatment of patients with severe liver disease with or without an indication for liver transplantation and patients in the post-liver transplant setting
IFN-free, DAA-based regimens are the most suitable options for patients with decompensated (Child-Pugh B or C) liver disease. Protease inhibitors are contraindicated for this group.
HBV coinfection
In patients with HCV-HBV coinfection, the HBV DNA level is often low or undetectable, although it may fluctuate widely, and HCV is usually the main driver of chronic inflammatory activity. Patients should be carefully characterized for the replicative status of both HBV and HCV, and the presence of hepatitis D virus infection should be ascertained. When HCV RNA is present, HCV infection should be treated following the same rules as applied to HCV monoinfected patients.
There is a potential risk
Retreatment of patients who failed after a double combination of pegylated IFN-α and ribavirin, a triple combination of pegylated IFN-α, ribavirin and sofosbuvir, or a double combination of sofosbuvir and ribavirin
Treatment of patients who failed to achieve SVR after treatment with pegylated IFN-α and ribavirin, pegylated IFN-α, ribavirin and sofosbuvir, or sofosbuvir and ribavirin (“treatment-experienced” patients, as defined above) is described in the general recommendations (Table 7, Table 8).
Retreatment of patients who failed after a protease inhibitor- and/or NS5A inhibitor-containing regimen
Preliminary data suggest that retreatment can be optimised based on RAS testing.263 The RASs that have been shown to confer reduced susceptibility to the corresponding drug class in vitro and/or that have been
Treatment of acute hepatitis C
Most patients with acute hepatitis C are asymptomatic, but a high rate of chronicity is expected (50–90%). Symptomatic disease with jaundice, female gender, a young age, and genetic polymorphisms in the region upstream of the IL28B (recently renamed IFN lambda-3, IFNL3) gene have been associated with spontaneous viral clearance, but none of these parameters accurately predicts spontaneous resolution at the individual level.
Patients with acute hepatitis C should be considered for antiviral
Treatment monitoring
Treatment monitoring includes monitoring of treatment efficacy, of safety and side effects and of drug-drug interactions.
Measures to improve treatment adherence
Full adherence to all drugs is associated with high SVR rates. In contrast, suboptimal exposure to therapy is associated with a risk of virological breakthrough or post-treatment relapse and the selection of RASs. Simple measures to enhance adherence to treatment should thus be implemented.
Before starting antiviral therapy, patients must be instructed about the daily schedule and the rare side effects to be expected during treatment. Evidence exists for directly observed therapy for patients on
Post-treatment follow-up of patients who achieve an SVR
In patients without cirrhosis who achieve an SVR, the HCV infection can be considered as definitively cured. Patients with pre-existing cofactors for liver disease (notably, history of excessive alcohol drinking, obesity and/or type 2 diabetes) should be carefully and periodically subjected to a thorough clinical assessment, as needed.
Patients with advanced fibrosis (METAVIR score F3) and patients with cirrhosis (F4) who achieve an SVR should remain under surveillance for HCC every 6 months by
Follow-up of untreated patients and of patients with treatment failure
Untreated patients with chronic hepatitis C and those who failed to respond to previous treatment should be regularly followed. The reason(s) for non-treatment and treatment failure should be clearly documented. Untreated patients should be assessed every 1 to 2 years with a non-invasive method.41 Patients with advanced fibrosis (METAVIR score F3) and cirrhosis should undergo specific ultrasound surveillance every 6 months. Untreated patients with chronic hepatitis C and those who failed prior
Conflict of interest
Jean-Michel Pawlotsky: Grant and research support: Abbott, Abbvie and Gilead; Advisory Boards: Abbott, Abbvie, Gilead and Merck; Speaking and teaching: Abbott, Abbvie, Gilead and Merck. Alessio Aghemo: Grant and research support: Abbvie and Gilead; Advisory Boards: Abbvie, Alfasigma, Bristol-Myers Squibb, Gilead, Janssen and Merck; Speaking and teaching: Abbvie, Bristol-Myers Squibb, Gilead and Merck.
Marina Berenguer: Grant and research support: Gilead; Advisory Boards: Abbvie, Gilead,
Acknowledgments
The panel is grateful to Laurent Castéra for his contribution to Table 2, and to Slim Fourati for his contribution to Table 9. We would like to thank the reviewers of this Clinical Practice Guideline for their time and critical reviewing: EASL Governing Board, Jordan Feld, Thomas Berg and Graham Foster.
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