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EASL Recommendations on Treatment of Hepatitis C 2018

Published:April 09, 2018DOI:https://doi.org/10.1016/j.jhep.2018.03.026

      Summary

      Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention. These European Association for the Study of the Liver Recommendations on Treatment of Hepatitis C describe the optimal management of patients with acute and chronic HCV infections in 2018 and onwards.

      Introduction

      Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide.
      • Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
      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,
      • Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
      • European Union HCV Collaborators
      Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study.
      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.
      • Arase Y.
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      Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C.
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      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
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      • et al.
      Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population.
      • Kew M.C.
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      • et al.
      Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
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      • Bell B.P.
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      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.
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      • et al.
      Extrahepatic manifestations of chronic hepatitis C.
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      • Touscoz G.A.
      • et al.
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      • Mahale P.
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      • Hwang L.Y.
      • Brown E.L.
      • et al.
      The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection.
      • van der Meer A.J.
      • Berenguer M.
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      • Younossi Z.M.
      Hepatitis C infection: a systemic disease.
      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.

      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 Assessment, Development and Evaluation (GRADE) system.
      • Andrews J.
      • Guyatt G.
      • Oxman A.D.
      • Alderson P.
      • Dahm P.
      • Falck-Ytter Y.
      • et al.
      GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.
      The strength of recommendations reflects the quality of underlying evidence. The quality of the evidence in the recommendations has been classified into 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). Thus, the recommendations 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. The recommendations have been approved by the EASL Governing Board.
      Table 1Evidence grading used (adapted from the GRADE system).
      Evidence qualityNotesGrading
      HighFurther research is very unlikely to change our confidence in the estimate of effectA
      ModerateFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateB
      LowFurther 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 uncertainC
      RecommendationNotesGrading
      StrongFactors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost1
      WeakVariability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption2

      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.
      • Chevaliez S.
      • Pawlotsky J.M.
      Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes.
      • Kamili S.
      • Drobeniuc J.
      • Araujo A.C.
      • Hayden T.M.
      Laboratory diagnostics for hepatitis C virus infection.
      • Takaki A.
      • Wiese M.
      • Maertens G.
      • Depla E.
      • Seifert U.
      • Liebetrau A.
      • et al.
      Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.
      The diagnosis of acute and chronic HCV infection is based on the detection of HCV RNA in serum or plasma by a sensitive, exclusively qualitative, or both qualitative and quantitative, molecular method. An assay with a lower limit of detection ≤15 international units (IU)/ml is recommended. However, the vast majority of patients with an indication for anti-HCV therapy have an HCV RNA level above 50,000 IU/ml.
      • Terrault N.A.
      • Pawlotsky J.M.
      • McHutchison J.
      • Anderson F.
      • Krajden M.
      • Gordon S.
      • et al.
      Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy.
      There is an important need for diagnostic nucleic acid assays that are cheap (less than US$5-10) and thus applicable for large-scale diagnosis in low-to middle-income areas, as well as in specific settings in high-income countries. Such HCV RNA assays should have a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml). In such settings, the exceptionally low risk of a false-negative result with these assays, in a small percentage of infected individuals, is outweighed by the benefit of scaling up access to diagnosis and care to a larger population. Indeed, a study in patients with chronic hepatitis C due to HCV genotype 1 found only 4 patients out of 2,472 (0.16%) with an HCV RNA level below 1,000 IU/ml.
      • Ticehurst J.R.
      • Hamzeh F.M.
      • Thomas D.L.
      Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis.
      HCV core antigen in serum or plasma is a marker of HCV replication. Core antigen detection can be used instead of HCV RNA detection to diagnose acute or chronic HCV infection. HCV core antigen assays are less sensitive than HCV RNA assays (lower limit of detection equivalent to approximately 500 to 3,000 HCV RNA IU/ml, depending on the HCV genotype
      • Chevaliez S.
      • Feld J.
      • Cheng K.
      • Wedemeyer H.
      • Sarrazin C.
      • Maasoumy B.
      • et al.
      Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen.
      • Chevaliez S.
      • Soulier A.
      • Poiteau L.
      • Bouvier-Alias M.
      • Pawlotsky J.M.
      Clinical utility of hepatitis C virus core antigen quantification in patients with chronic hepatitis C.
      • Heidrich B.
      • Pischke S.
      • Helfritz F.A.
      • Mederacke I.
      • Kirschner J.
      • Schneider J.
      • et al.
      Hepatitis C virus core antigen testing in liver and kidney transplant recipients.
      ). As a result, the HCV core antigen becomes detectable in serum or plasma a few days after HCV RNA in patients with acute hepatitis C. In rare cases, the core antigen is undetectable in the presence of HCV RNA.
      • Freiman J.M.
      • Tran T.M.
      • Schumacher S.G.
      • White L.F.
      • Ongarello S.
      • Cohn J.
      • et al.
      Hepatitis C core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis.
      The diagnosis of acute hepatitis C can only be made confidently if recent seroconversion to anti-HCV antibodies can be documented, since there is no serological marker which establishes that HCV infection is in the de novo acquired acute phase. Not all patients with acute hepatitis C will be anti-HCV antibody-positive at diagnosis. In these cases, acute hepatitis C can be suspected if the clinical signs and symptoms are compatible with acute hepatitis (alanine aminotransferase [ALT] level >10 times the upper limit of normal, and/or jaundice) in the absence of a history of chronic liver disease or other causes of acute hepatitis, and/or if a likely recent source of transmission is identifiable. In all cases, HCV RNA (or HCV core antigen) can be detected during the acute phase, although their levels may vary widely and there may be interludes (up to several weeks) of undetectable HCV RNA (or HCV core antigen). Thus, HCV RNA-negative (or HCV core antigen-negative) individuals should be retested for HCV RNA (or HCV core antigen) 12 and 24 weeks after a negative result to confirm definitive clearance.
      HCV reinfection can occur after spontaneous or treatment-induced HCV clearance, essentially if patients at high risk of infection are re-exposed. Reinfection is defined by the reappearance of HCV RNA (or HCV core antigen) after an SVR and the demonstration that infection is caused by a different HCV strain (different genotype or distantly related strain by phylogenetic analysis if the genotype is the same). Reinfection should be suspected in cases of a post-SVR12 or -SVR24 recurrence of HCV infection, if risk behaviours have continued.
      The diagnosis of chronic hepatitis C is based on the detection of both anti-HCV antibodies and HCV RNA (or HCV core antigen). Spontaneous viral clearance rarely occurs beyond 4 to 6 months after a newly acquired infection,
      • Bulteel N.
      • Sarathy P.P.
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      • Mills P.R.
      • et al.
      Factors associated with spontaneous clearance of chronic hepatitis C virus infection.
      so the diagnosis of chronic hepatitis C can be made after this time period.
      • All patients with suspected HCV infection should be tested for anti-HCV antibodies in serum or plasma as first-line diagnostic test (A1).
      • In the case of suspected acute hepatitis C, in immunocompromised patients and in patients on haemodialysis, HCV RNA testing in serum or plasma should be part of the initial evaluation (A1).
      • If anti-HCV antibodies are detected, HCV RNA should be determined by a sensitive molecular method with a lower limit of detection ≤15 IU/ml (A1).
      • In low- and middle-income countries, and in specific settings in high-income countries, a qualitative HCV RNA assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) can be used to provide broad affordable access to HCV diagnosis and care (B2).
      • Anti-HCV antibody-positive, HCV RNA-negative individuals should be retested for HCV RNA 12 and 24 weeks later to confirm definitive clearance (A1).
      • HCV core antigen in serum or plasma is a marker of HCV replication that can be used instead of HCV RNA to diagnose acute or chronic HCV infection when HCV RNA assays are not available and/or not affordable (A1).

      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 care and treatment.
      Different screening strategies have been implemented in different regions, based on the local epidemiology. Groups at higher risk of HCV infection can be identified and should be tested. In regions where the majority of patients belong to a well-defined age group, birth cohort testing has proven efficacious, with limitations.
      • Chhatwal J.
      • Wang X.
      • Ayer T.
      • Kabiri M.
      • Chung R.T.
      • Hur C.
      • et al.
      Hepatitis C disease burden in the United States in the era of oral direct-acting antivirals.
      • Pawlotsky J.M.
      The end of the hepatitis C burden: really?.
      Systematic one-time testing has been recommended in countries with high endemicity and/or with the goal of complete eradication. The optimal regional or national screening approaches should be determined.
      Screening for HCV infection is based on the detection of anti-HCV antibodies. In addition to EIAs, rapid diagnostic tests (RDTs) can be used to screen for anti-HCV antibodies. RDTs use various matrices, including serum and plasma, but also fingerstick capillary whole blood or oral (crevicular) fluid, facilitating screening without the need for venipuncture, tube centrifugation, freezing and skilled labour. RDTs are simple to perform at room temperature without specific instrumentation or extensive training.
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      • Laperche S.
      • et al.
      Prospective assessment of rapid diagnostic tests for the detection of antibodies to hepatitis C virus, a tool for improving access to care.
      • Khuroo M.S.
      • Khuroo N.S.
      • Khuroo M.S.
      Diagnostic accuracy of point-of-care tests for hepatitis C virus infection: a systematic review and meta-analysis.
      • Shivkumar S.
      • Peeling R.
      • Jafari Y.
      • Joseph L.
      • Pant Pai N.
      Accuracy of rapid and point-of-care screening tests for hepatitis C: a systematic review and meta-analysis.
      If anti-HCV antibodies are detected, the presence of HCV RNA (or alternatively HCV core antigen if HCV RNA assays are not available and/or not affordable) should be determined to identify patients with ongoing infection. Currently, most laboratories use a two-step approach that includes phlebotomy and an antibody test in step 1, and phlebotomy and a test for HCV RNA in step 2. As a result, a substantial fraction of patients with anti-HCV antibodies never receive confirmatory HCV RNA testing. Therefore, reflex testing for HCV RNA should be applied whenever possible when anti-HCV antibodies are detected.
      • Chapko M.K.
      • Dufour D.R.
      • Hatia R.I.
      • Drobeniuc J.
      • Ward J.W.
      • Teo C.G.
      Cost-effectiveness of strategies for testing current hepatitis C virus infection.
      Dried blood spots can be used to collect whole blood specimens for EIA detection of anti-HCV antibodies in a central laboratory.
      • Poiteau L.
      • Soulier A.
      • Rosa I.
      • Roudot-Thoraval F.
      • Hezode C.
      • Pawlotsky J.M.
      • et al.
      Performance of rapid diagnostic tests for the detection of antibodies to hepatitis C virus in whole blood collected on dried blood spots.
      • Soulier A.
      • Poiteau L.
      • Rosa I.
      • Hezode C.
      • Roudot-Thoraval F.
      • Pawlotsky J.M.
      • et al.
      Dried blood spots: a tool to ensure broad access to hepatitis C screening, diagnosis, and treatment monitoring.
      • Tuaillon E.
      • Mondain A.M.
      • Meroueh F.
      • Ottomani L.
      • Picot M.C.
      • Nagot N.
      • et al.
      Dried blood spot for hepatitis C virus serology and molecular testing.
      A second spot on the same card can be used to test for HCV RNA, allowing for reflex testing to be performed in anti-HCV antibody-positive samples.
      A cartridge-based point-of-care HCV RNA assay has received World Health Organization (WHO) prequalification.
      • Grebely J.
      • Lamoury F.M.J.
      • Hajarizadeh B.
      • Mowat Y.
      • Marshall A.D.
      • Bajis S.
      • et al.
      Evaluation of the Xpert HCV Viral Load point-of-care assay from venepuncture-collected and finger-stick capillary whole-blood samples: a cohort study.
      Such assays have the potential to simplify testing algorithms, increase diagnosis rates, and facilitate linkage to treatment, especially in low- and middle-income areas and in difficult-to-reach populations, such as people who inject drugs (PWID). Depending upon relative costs, a direct test for HCV RNA and near-patient testing could be considered to replace screening based on anti-HCV antibody testing by the direct identification of viremic patients.
      • Screening strategies for HCV infection should be defined according to the local epidemiology of HCV infection, ideally within the framework of national plans (A1).
      • Screening strategies for HCV infection may include screening of populations at risk of infection, birth cohort testing, and general population testing in areas of intermediate to high seroprevalence (≥2%–5%) (B2).
      • Screening for HCV infection should be based on the detection of anti-HCV antibodies in serum or plasma by means of enzyme immunoassay (A1).
      • Anti-HCV antibody screening should be offered with linkage to prevention, care and treatment (A1).
      • Whole blood sampled on dried blood spots can be used as an alternative to serum or plasma obtained by venipuncture for anti-HCV antibody testing, after shipment to a central laboratory where the enzyme immunoassay will be performed (A2).
      • RDTs using serum, plasma, fingerstick whole blood or crevicular fluid (saliva) as matrices can be used instead of classical enzyme immunoassays at the patient’s care site to facilitate anti-HCV antibody screening and improve access to care (A2).
      • If anti-HCV antibodies are detected, the presence of HCV RNA, or alternatively HCV core antigen (if HCV RNA assays are not available and/or not affordable) in serum or plasma should be determined to identify patients with ongoing infection (A1).
      • Whole blood sampled on dried blood spots can be used as an alternative to serum or plasma obtained by venipuncture for HCV RNA testing, after shipment to a central laboratory where the molecular test will be performed (A2).
      • Reflex testing for HCV RNA in patients found to be anti-HCV antibody-positive should be applied to increase linkage to care (B1).
      • Anti-HCV antibody screening for HCV infection can be replaced by a point-of-care HCV RNA assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) or HCV core antigen testing, if such assays are available and the screening strategy proves to be cost-effective (C2).

      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 end of therapy, as assessed by a sensitive molecular method with a lower limit of detection ≤15 IU/ml. Both SVR12 and SVR24 have been accepted as endpoints of therapy by regulators in Europe and the United States, given that their concordance is >99%.
      • Martinot-Peignoux M.
      • Stern C.
      • Maylin S.
      • Ripault M.P.
      • Boyer N.
      • Leclere L.
      • et al.
      Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.
      In settings where sensitive HCV RNA assays are not available and/or not affordable, a qualitative assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) can be used to assess the virological response; in this case, the response should be assessed at week 24 post-treatment (SVR24).
      Long-term follow-up studies have shown that an SVR corresponds to a definitive cure of HCV infection in the vast majority of cases.
      • Swain M.G.
      • Lai M.Y.
      • Shiffman M.L.
      • Cooksley W.G.
      • Zeuzem S.
      • Dieterich D.T.
      • et al.
      A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin.
      Undetectable HCV core antigen 24 weeks after the end of therapy can be used as an alternative to HCV RNA testing to define the SVR24, respectively, in patients with detectable core antigen before treatment.
      • Chevaliez S.
      • Feld J.
      • Cheng K.
      • Wedemeyer H.
      • Sarrazin C.
      • Maasoumy B.
      • et al.
      Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen.
      • Chevaliez S.
      • Soulier A.
      • Poiteau L.
      • Bouvier-Alias M.
      • Pawlotsky J.M.
      Clinical utility of hepatitis C virus core antigen quantification in patients with chronic hepatitis C.
      • Freiman J.M.
      • Tran T.M.
      • Schumacher S.G.
      • White L.F.
      • Ongarello S.
      • Cohn J.
      • et al.
      Hepatitis C core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis.
      • Aghemo A.
      • Degasperi E.
      • De Nicola S.
      • Bono P.
      • Orlandi A.
      • D'Ambrosio R.
      • et al.
      Quantification of core antigen monitors efficacy of direct-acting antiviral agents in patients with chronic hepatitis C virus infection.
      In patients with advanced fibrosis (METAVIR score F3) and cirrhosis (F4), an SVR reduces the rate of decompensation and will also reduce, but not abolish, the risk of HCC.
      • Nahon P.
      • Bourcier V.
      • Layese R.
      • Audureau E.
      • Cagnot C.
      • Marcellin P.
      • et al.
      Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
      Thus, in these patients, surveillance for HCC must be continued.
      • 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 necro-inflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death; (ii) improve quality of life and remove stigma; and (iii) prevent onward transmission of HCV (A1).
      • The endpoint of therapy is undetectable HCV RNA in serum or plasma by a sensitive assay (lower limit of detection ≤15 IU/ml) 12 weeks (SVR12) or 24 weeks (SVR24) after the end of treatment (A1).
      • Undetectable HCV core antigen in serum or plasma 24 weeks (SVR24) after the end of treatment can be used as an alternative endpoint of therapy in patients with detectable HCV core antigen prior to therapy, if HCV RNA assays are not available and/or not affordable (A1).
      • Undetectable HCV RNA in serum or plasma 24 weeks (SVR24) after the end of treatment, using a qualitative HCV RNA assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml), can be used as an alternative endpoint of therapy in areas where sensitive HCV RNA assays are not available and/or not affordable (B1).
      • In patients with advanced fibrosis and cirrhosis, surveillance for HCC must be continued because an SVR will reduce, but not abolish, the risk of HCC (A1).

      Pre-therapeutic assessment

      Liver disease severity must be assessed, and baseline virological parameters that will be useful for tailoring therapy should be determined.

       Search for other causes of liver disease

      Other causes of chronic liver disease, or factors which are likely to affect the natural history or progression of liver disease and therapeutic choices, should be systematically investigated. All patients should be tested for other blood-borne viruses, particularly hepatitis B virus (HBV), and for human immunodeficiency virus (HIV). HBV and hepatitis A virus (HAV) vaccination should be proposed for patients who are not protected. Alcohol consumption should be assessed and quantified, and specific counselling to stop harmful alcohol consumption should be given. In addition, HCV may cause a variety of extra-hepatic manifestations which need to be considered in the work-up of HCV-infected patients. Thus, assessments should be carried out for possible comorbidities, including alcoholism, cardiac disease, renal impairment, autoimmunity, genetic or metabolic liver diseases (for instance genetic hemochromatosis, diabetes mellitus or obesity) and the possibility of drug-induced hepatotoxicity.

       Assessment of liver disease severity

      Assessment of liver disease severity is necessary prior to therapy. Identifying patients with cirrhosis (METAVIR score F4) or advanced (bridging) fibrosis (METAVIR score F3) is of particular importance, as the choice of treatment regimen and the post-treatment prognosis depend on the stage of fibrosis. Assessment of the stage of fibrosis is not required in patients with clinical evidence of cirrhosis. Patients with cirrhosis need to be assessed for portal hypertension, including oesophageal varices. Patients with advanced fibrosis and those with cirrhosis need continued post-treatment surveillance for HCC every 6 months. Since significant fibrosis may be present in patients with repeatedly normal ALT, evaluation of disease severity should be performed regardless of ALT levels.
      In chronic hepatitis C, non-invasive methods should be used instead of liver biopsy to assess liver disease severity prior to therapy. Liver stiffness measurement can be used to assess liver fibrosis and the presence of portal hypertension in patients with chronic hepatitis C. Consideration must be given to factors that may adversely affect its performance, such as obesity, high ALT levels, or post-prandial testing. Well-established panels of fibrosis biomarkers can also be applied. Both liver stiffness measurement and biomarkers perform well in the identification of cirrhosis or no fibrosis, but they perform less well in resolving intermediate degrees of fibrosis.
      • European Association for Study of the Liver
      Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis.
      Cut-offs used with common non-invasive markers to establish the different stages of fibrosis in patients with chronic hepatitis C prior to therapy are shown in Table 2.
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      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
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      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
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      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
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      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      In low- and middle-income countries, as well as in settings where treatment expands outside of specialty clinics, aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) are generally available, simple and cheap, and the information they provide is reliable. Notably, non-invasive tools should not be used to assess the fibrosis stage after therapy, as they are unreliable in this setting.
      Table 2Non-invasive marker cut-offs for prediction of stages of fibrosis, including F3 (advanced fibrosis) and F4 (cirrhosis).
      TestStage of fibrosisNumber of patientsCutoffAUROCSensitivitySpecificityPPVNPVRef.
      FibroScan®F3560 HCV-positive10 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.8372%80%62%89%
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      F41,855 HCV-positive13 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.90–0.9372–77%85–90%42–56%95–98%
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      ARFI (VTQ®)F32,691 (including 1,428 HCV-positive)1.60–2.17 m/s0.94

      (95% CI 0.91–0.95)
      84%

      (95% CI 80–88%)
      90%

      (95% CI 86–92%)
      n.a.n.a.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      F42,691 (including 1,428 HCV-positive)2.19–2.67 m/s0.91

      (95% CI 0.89–0.94)
      86%

      (95% CI 80–91%)
      84%

      (95% CI 80–88%)
      n.a.n.a.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      Aixplorer®F3379 HCV-positive9 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.9190%

      (95% CI 72–100%)
      77%

      (95% CI 78–92%)
      n.a.n.a.
      • Herrmann E.
      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      F4379 HCV-positive13 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.9386%

      (95% CI 74–95%)
      88%

      (95% CI 72–98%)
      n.a.n.a.
      • Herrmann E.
      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      Fibrotest®F41,579 (including 1,295 HCV-positive)0.740.82–0.8763–71%81–84%39–4093–94
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      FIB-4F42,297 HCV-positive1–45
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.


      3.25
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      0.87
      Median (range).
      (0.83–0.92)
      90%

      55%
      58%

      92%
      n.a.n.a.
      • Chou R.
      • Wasson N.
      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
      APRIF416,694 HCV-positive1.0
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.


      2.0
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      0.84
      Median (range).
      (0.54–0.97)
      77%

      48%
      75%

      94%
      n.a.n.a.
      • Chou R.
      • Wasson N.
      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
      APRI, aspartate aminotransferase to platelet ratio index; ARFI, acoustic radiation force impulse; AUROC, area under the receiver operating characteristic curve; FIB-4, fibrosis-4; n.a., not applicable; NPV, negative predictive value; PPV, positive predictive value.
      a Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      b Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      * Median (range).
      The combination of blood biomarkers or the combination of liver stiffness measurement and a blood test improve accuracy.
      • Castera L.
      • Sebastiani G.
      • Le Bail B.
      • de Ledinghen V.
      • Couzigou P.
      • Alberti A.
      Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C.
      • Castera L.
      • Vergniol J.
      • Foucher J.
      • Le Bail B.
      • Chanteloup E.
      • Haaser M.
      • et al.
      Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
      Liver biopsy may be required in cases of known or suspected mixed aetiologies (e.g. metabolic syndrome, alcoholism or autoimmunity).
      • The contribution of comorbidities to the progression of liver disease must be evaluated and appropriate corrective measures implemented (A1).
      • Liver disease severity must be assessed prior to therapy (A1).
      • Patients with cirrhosis must be identified, as their treatment regimen must be adjusted and post-treatment surveillance for HCC is mandatory (A1).
      • Post-treatment surveillance for HCC must also be performed in patients with advanced fibrosis (METAVIR score F3) (B1).
      • Fibrosis stage must be assessed by non-invasive methods initially, with liver biopsy reserved for cases where there is uncertainty or potential additional aetiologies (A1).
      • Renal function (creatinine/estimated glomerular filtration rate [eGFR]) should be ascertained (A1).
      • Extra-hepatic manifestations of HCV infection should be identified in case of symptoms (A1).
      • HBV and HAV vaccination should be proposed to patients who are not protected (A1).

       HCV RNA or HCV core antigen detection/quantification

      HCV RNA detection or detection/quantification in serum or plasma is indicated for patients who undergo antiviral treatment. HCV RNA assessment should be made by a reliable sensitive assay, and HCV RNA levels should be expressed in IU/ml.
      HCV core antigen detection and quantification by means of EIA can be performed when HCV RNA tests are not available and/or not affordable. HCV core antigen quantification should be made with a reliable assay and core antigen levels should be expressed in fmol/L.

       HCV genotype determination

      Together with prior treatment experience and the presence of cirrhosis, the HCV genotype, including genotype 1 subtype (1a or 1b), is still useful to tailor the treatment regimen and its duration. Genotyping/subtyping should be performed with an assay that accurately discriminates subtype 1a from 1b, i.e. an assay using the sequence of the 5′ untranslated region plus a portion of another genomic region, generally the core-coding or the NS5B-coding regions.
      • 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.
      The most widely used method is based on reverse hybridization with the line probe assay. A kit based on deep sequencing will soon be available.
      • Rodriguez C.
      • Soulier A.
      • Demontant V.
      • Poiteau L.
      • Mercier-Darty M.
      • Bouvier-Alias M.
      • et al.
      A novel standardized deep sequencing-based assay for hepatitis C virus genotype determination.
      With pan-genotypic HCV drug regimens, it is possible to treat individuals without identifying their HCV genotype and subtype. This may be particularly useful in regions where virological tests are not available or their cost exceeds that of antiviral treatment, or to simplify therapy in other regions, in order to improve access to care.

       HCV resistance testing

      No standardized tests for resistance of HCV to approved drugs are available as purchasable kits. Resistance testing mostly relies on in-house techniques based on population sequencing (Sanger sequencing) or deep sequencing.
      • Fourati S.
      • Pawlotsky J.M.
      Virologic tools for HCV drug resistance testing.
      A limited number of laboratories have made such tests available in Europe and elsewhere. HCV resistance testing may be technically difficult, in particular for genotypes other than 1 and 4, and the performances of the available in-house assays vary widely. A kit based on deep sequencing is currently at the developmental stage.
      Access to reliable HCV resistance testing is limited and there is no consensus on the techniques, interpretation and reporting of these tests. In addition, highly efficacious treatments are now available for patients with detectable pre-existing resistance-associated substitutions (RASs) at baseline. Thus, systematic testing for HCV resistance prior to treatment in direct-acting antiviral (DAA) drug-naïve individuals is not recommended.
      • Pawlotsky J.M.
      Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens.
      The current EASL recommendations suggest treatment regimens that do not necessitate any resistance testing prior to first-line therapy. In areas where these regimens are not available or not reimbursed, physicians who have easy access to reliable resistance tests can use these results to guide their decisions, according to the EASL Recommendations for Treatment of Hepatitis C 2016.
      • European Association for the Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2016.
      • HCV RNA detection and quantification in serum or plasma should be made by a sensitive assay with a lower limit of detection of ≤15 IU/ml (A1).
      • In low- and middle-income countries and in specific settings in high-income countries, a qualitative HCV RNA assay with a lower limit of detection of ≤1,000 IU/ml can be used if more sensitive quantitative assays are not available and/or not affordable (B1).
      • If HCV RNA testing is not available and/or not affordable, HCV core antigen detection and quantification by EIA can be used as a surrogate marker of HCV replication (A1).
      • The HCV genotype and genotype 1 subtype (1a or 1b) must be assessed prior to treatment initiation to determine the choice of therapy and its duration, among other parameters (A1).
      • Treatment with new pangenotypic regimens can be initiated without knowledge of the genotype and subtype in areas where genotype determination is not available and/or not affordable, or to simplify treatment access (B1).
      • Testing for HCV resistance prior to treatment is not recommended (B1).
      • In areas where only regimens that require optimisation based on pre-treatment resistance testing are available, and physicians have easy access to a reliable test that evaluates HCV resistance to NS5A inhibitors (spanning amino acids 24 to 93), these analyses can guide decisions, as specified in the EASL Recommendations for Treatment of Hepatitis C 2016 (B2).

      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, grazoprevir, glecaprevir or voxilaprevir, must not be used in patients with Child-Pugh B or C decompensated cirrhosis, because of the substantially higher protease inhibitor concentrations in these patients and the related risk of toxicity.
      Sofosbuvir should be used with caution in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) if no alternative treatment option is available, as the pharmacokinetics and safety of sofosbuvir-derived metabolites in patients with severe renal dysfunction are still being ascertained.
      • 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 (A1).
      • Treatment regimens comprising a protease inhibitor must not be used in patients with Child-Pugh B or C decompensated cirrhosis or in patients with previous episodes of decompensation (A1).
      • In patients with an eGFR <30 ml/min/1.73 m2, sofosbuvir should only be used if no alternative treatment approved for use in patients with severe renal impairment is available (B1).

      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 complex-related nephropathy and non-Hodgkin B-cell lymphoma); patients with HCV recurrence after liver transplantation; patients at risk of a rapid evolution of liver disease because of concurrent comorbidities (non-liver solid organ or stem cell transplant recipients, HBV coinfection, diabetes); and individuals at high risk of transmitting HCV PWIDs, men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, haemodialysis patients, incarcerated individuals). PWIDs and men who have sex with men with high-risk sexual practices should be made aware of the risk of reinfection and should apply preventive measures after successful treatment.
      Patients with decompensated cirrhosis and an indication for liver transplantation with a MELD score ≥18–20 will benefit from transplantation first and antiviral treatment after transplantation, because the probability of significant improvement in liver function and delisting is low.
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr, R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease.
      • Manns M.
      • Samuel D.
      • Gane E.J.
      • Mutimer D.
      • McCaughan G.
      • Buti M.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
      • Coilly A.
      • Pageaux G.P.
      • Houssel-Debry P.
      • Duvoux C.
      • Radenne S.
      • De Ledinghen V.
      • et al.
      Improving liver function and delisting of patients awaiting liver transplantation for HCV cirrhosis: do we ask too much to DAAs?.
      • Belli L.S.
      • Berenguer M.
      • Cortesi P.A.
      • Strazzabosco M.
      • Rockenschaub S.R.
      • Martini S.
      • et al.
      Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study.
      • Chhatwal J.
      • Samur S.
      • Kues B.
      • Ayer T.
      • Roberts M.S.
      • Kanwal F.
      • et al.
      Optimal timing of hepatitis C treatment for patients on the liver transplant waiting list.
      • Pascasio J.M.
      • Vinaixa C.
      • Ferrer M.T.
      • Colmenero J.
      • Rubin A.
      • Castells L.
      • et al.
      Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.
      However, patients with a MELD score ≥18–20 with a waiting time before transplantation expected to be more than 6 months can be treated for their HCV infection.
      Treatment is generally not recommended in patients with limited life expectancy because of non–liver-related comorbidities.
      • All patients with HCV infection must be considered for therapy, including treatment-naïve patients and individuals who failed to achieve SVR after prior treatment (A1).
      • Treatment should be considered without delay in patients with significant fibrosis or cirrhosis (METAVIR score F2, F3 or F4), including compensated (Child-Pugh A) and decompensated (Child-Pugh B or C) cirrhosis, in patients with clinically significant extra-hepatic manifestations (e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune complex-related nephropathy and non-Hodgkin B-cell lymphoma), in patients with HCV recurrence after liver transplantation, in patients at risk of a rapid evolution of liver disease because of concurrent comorbidities (non-liver solid organ or stem cell transplant recipients, HBV coinfection, diabetes) and in individuals at risk of transmitting HCV (PWID, men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, haemodialysis patients, incarcerated individuals) (A1).
      • Patients with decompensated (Child-Pugh B or C) cirrhosis and an indication for liver transplantation with a MELD score ≥18–20 should be transplanted first and treated after transplantation (B1).
      • If the waiting time on a liver transplant list is more than 6 months, patients with decompensated (Child-Pugh B or C) cirrhosis with a MELD score ≥18–20 can be treated before transplantation, although the clinical benefit for these patients is not well established (B2).
      • Treatment is generally not recommended in patients with limited life expectancy due to non-liver-related comorbidities (B2).

      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 Characteristics.
      Table 3HCV DAAs approved in Europe in 2018 and recommended in this document.
      ProductPresentationPosology
      Pangenotypic drugs or drug combinations
       SofosbuvirTablets containing 400 mg of sofosbuvirOne tablet once daily
       Sofosbuvir/velpatasvirTablets containing 400 mg of sofosbuvir and 100 mg of velpatasvirOne tablet once daily
       Sofosbuvir/velpatasvir/

      voxilaprevir
      Tablets containing 400 mg of sofosbuvir, 100 mg of velpatasvir and 100 mg of voxilaprevirOne tablet once daily
       Glecaprevir/pibrentasvirTablets containing 100 mg of glecaprevir and 40 mg of pibrentasvirThree tablets once daily
      Genotype-specific drugs or drug combinations
       Sofosbuvir/ledipasvirTablets containing 400 mg of sofosbuvir and 90 mg of ledipasvirOne tablet once daily
       Paritaprevir/ombitasvir/ritonavirTablets containing 75 mg of paritaprevir, 12.5 mg of ombitasvir and 50 mg of ritonavirTwo tablets once daily
       DasabuvirTablets containing 250 mg of dasabuvirOne tablet twice daily (morning and evening)
       Grazoprevir/elbasvirTablets containing 100 mg of grazoprevir and 50 mg of elbasvirOne tablet once daily
      DAA, direct-acting antiviral; HCV, hepatitis C virus.
      Table 4ADrug-drug interactions between HCV DAAs and antiretroviral drugs.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      *Known or anticipated increase in tenofovir concentrations in regimens containing tenofovir disoproxil fumarate. Caution and frequent renal monitoring.
      Table 4BDrug-drug interactions between HCV DAAs and illicit/recreational drugs or drugs of abuse.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4CDrug-drug interactions between HCV DAAs and lipid lowering drugs.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4DDrug-drug interactions between HCV DAAs and central nervous system drugs.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4EDrug-drug interactions between HCV DAAs and cardiovascular drugs.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4FDrug-drug interactions between HCV DAAs and immunosuppressants.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4GDrug-drug interactions between HCV DAAs and antiplatelets and anticoagulants.
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Notes: Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice. The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.

       Sofosbuvir

      Sofosbuvir should be administered at the dose of 400 mg (one tablet) once per day, with or without food. Approximately 80% of sofosbuvir is renally excreted, whereas 15% is excreted in faeces. The majority of the sofosbuvir dose recovered in urine is the dephosphorylation-derived nucleoside metabolite GS-331007 (78%), while 3.5% is recovered as sofosbuvir. Renal clearance is the major elimination pathway for GS-331007, with a large part actively secreted. Thus, currently, no sofosbuvir dose recommendation can be given for patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) or with end-stage renal disease because of higher exposures (up to 20-fold) of GS-331007. However, there is accumulating evidence on safe use of sofosbuvir-based regimens in patients with an eGFR <30 ml/min/1.73 m2, including patients on haemodialysis.
      • Desnoyer A.
      • Pospai D.
      • Le M.P.
      • Gervais A.
      • Heurgue-Berlot A.
      • Laradi A.
      • et al.
      Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C.
      Sofosbuvir exposure is not significantly changed in patients with mild liver impairment, but it is increased 2.3-fold in those with moderate liver impairment.
      Sofosbuvir is well tolerated over 12 to 24 weeks of administration. The most common adverse events (≥20%) observed in combination with ribavirin were fatigue and headache. Slight elevations of creatine kinase, amylase and lipase without clinical impact were also observed.
      Sofosbuvir is not metabolised by cytochrome P450, but is transported by P-gp. Drugs that are potent P-gp inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with known inducers of P-gp, such as rifampicin, carbamazepine, phenytoin or St. John’s wort. Other potential interactions may occur with rifabutin, rifpentine and modafinil. No significant drug-drug interactions have been reported in studies with the antiretroviral agents emtricitabine, tenofovir, rilpivirine, efavirenz, darunavir/ritonavir and raltegravir, and there are no potential drug-drug interactions with other antiretrovirals.
      Sofosbuvir-based regimens are contraindicated in patients who are being treated with the anti-arrhythmic amiodarone because of the risk of life-threatening arrhythmias. Indeed, bradycardia has been observed within hours to days of starting the DAA, but cases have been observed up to 2 weeks after initiating HCV treatment. The mechanism of interaction and the role of other co-medications (e.g. β-blockers) is still unclear, although a number of potential mechanisms have been proposed involving P-gp inhibition, protein binding displacement and direct effects of sofosbuvir and/or other DAAs on cardiomyocytes or ion channels. Toxicity is likely the result of a combination of mechanisms. Because of the long half-life of amiodarone, an interaction is possible for several months after discontinuation of amiodarone. If the patient has no cardiac pacemaker in situ, waiting 3 months after discontinuing amiodarone before starting a sofosbuvir-based regimen is recommended. Sofosbuvir-containing regimens have also been implicated in cardiac toxicity in the absence of amiodarone, but this remains controversial. In the absence of specific drug-drug interaction data, caution should be exercised with antiarrhythmics other than amiodarone.

       Sofosbuvir and ledipasvir

      Sofosbuvir and ledipasvir are available in a two-drug fixed-dose combination containing 400 mg of sofosbuvir and 90 mg of ledipasvir in a single tablet. The recommended dose of the combination is one tablet taken orally once daily with or without food.
      Biliary excretion of unchanged ledipasvir is the major route of elimination with renal excretion being a minor pathway (accounting for approximately 1%), whereas sofosbuvir is principally excreted renally, as noted above. Following administration of sofosbuvir/ledipasvir, the median terminal half-lives of sofosbuvir and its predominant metabolite GS-331007 were 0.5 and 27 h, respectively. Neither sofosbuvir nor ledipasvir are substrates for hepatic uptake transporters; GS-331007 is not a substrate for renal transporters.
      Ledipasvir plasma exposure (area under the curve [AUC]) was similar in patients with severe hepatic impairment and control patients with normal hepatic function. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to ledipasvir.
      While no dose adjustment of sofosbuvir and ledipasvir is required for patients with mild or moderate renal impairment, the safety of the sofosbuvir-ledipasvir combination has not been assessed in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) or end-stage renal disease requiring haemodialysis, but there is growing evidence of acceptable risk-benefit.
      • Lawitz E.
      • Landis C.S.
      • Maliakkal B.J.
      • Bonacini M.
      • Ortiz-Lasanta G.
      • Zhang J.
      • et al.
      Safety and efficacy of treatment with once-daily ledipasvir/sofosbuvir (90/400 mg) for 12 weeks in genotype 1 HCV-infected patients with severe renal impairment.
      Relative to patients with normal renal function (eGFR >80 ml/min/1.73 m2), the sofosbuvir AUC was 61%, 107% and 171% higher in patients with mild, moderate and severe renal impairment, while the GS-331007 AUC was 55%, 88% and 451% higher, respectively. Thus, no dose adjustment is required for patients with mild or moderate renal impairment, but no dose recommendation can currently be given for patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) or with end-stage renal disease. Pangenotypic drug combinations that are not cleared by the kidney are available, thus obviating the need for sofosbuvir-based regimens where appropriate drugs are available.
      The most common adverse reactions reported with this combination were fatigue and headache.
      Since the combination contains ledipasvir and sofosbuvir, any interactions identified with the individual drugs will apply to the combination. The potential (limited) interactions with sofosbuvir have been previously outlined. Since both ledipasvir and sofosbuvir are transported by intestinal P-gp and breast cancer resistance protein (BCRP), any co-administered drugs that are potent P-gp inducers will not only decrease sofosbuvir but also ledipasvir plasma concentrations, leading to reduced therapeutic effect. Although co-administration with drugs that inhibit P-gp and/or BCRP may increase the exposure of sofosbuvir and ledipasvir, clinical consequences are unlikely.
      Ledipasvir may also be the perpetrator of drug interactions by inhibiting P-gp and/or BCRP, potentially increasing the intestinal absorption of co-administered drugs. Thus, caution is warranted with well-studied P-gp substrates such as digoxin and dabigatran, but also potentially with other drugs which are, in part, transported by these proteins (e.g. aliskerin, amlodipine, buprenorphine, carvedilol, cyclosporine). Co-administration of amiodarone with sofosbuvir/ledipasvir is contraindicated because of a serious risk of symptomatic or even fatal bradycardia or asystole (see above, mechanism of interaction is unknown). The use of rosuvastatin is also not recommended (because of potential inhibition of hepatic OATP by ledipasvir) and interactions with other statins cannot be excluded. It is important to monitor carefully for statin-related adverse reactions. Since ledipasvir solubility decreases as pH increases, drugs that increase gastric pH (antacids, H2-receptor antagonists, proton pump inhibitors) are likely to decrease concentrations of ledipasvir. H2-receptor antagonists can be given simultaneously or 12 h apart at a dose not exceeding that equivalent to famotidine 40 mg and proton pump inhibitors can be given simultaneously, at a dose comparable to omeprazole 20 mg (Table 5). Real-world data have suggested slightly reduced SVR rates in patients receiving high-dose proton pump inhibitors, reinforcing the need for caution when treating patients on such drugs with sofosbuvir and ledipasvir.
      • Terrault N.A.
      • Zeuzem S.
      • Di Bisceglie A.M.
      • Lim J.K.
      • Pockros P.J.
      • Frazier L.M.
      • et al.
      Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response.
      Table 5Dose equivalence among proton pump inhibitors and H2 antagonists.
      Drug familyDrugDose
      Proton pump inhibitors

      (dose equivalent to omeprazole 20 mg once daily)
      Omeprazole20 mg once daily
      Lansoprazole30 mg once daily
      Esomeprazole20 mg once daily
      Pantoprazole40 mg once daily
      Rabeprazole20 mg once daily
      H2 antagonists

      (dose equivalent to famotidine 20 mg twice daily)
      Famotidine20 mg twice daily
      Ranitidine150 mg twice daily
      Cimetidine300 mg three-four times daily
      Nizatidine150 mg twice daily
      The proton pump inhibitor doses shown in the Table are considered equivalent. The H2 antagonist doses shown in the Table are considered equivalent.
      Sofosbuvir/ledipasvir may be given with all antiretrovirals. However, because of an increase in tenofovir disoproxil fumarate (TDF) concentrations when a pharmacokinetic enhancer (ritonavir or cobicistat) is present in an antiretroviral regimen, these combinations (i.e. atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, elvitegravir/cobicistat, atazanavir/cobicistat, darunavir/cobicistat, all in combination with tenofovir disoproxil fumarate/emtricitabine) should be used with caution, with frequent renal monitoring if other alternatives are not available. The interaction is not mitigated by staggering administration by 12 h. Tenofovir levels are also increased in efavirenz-containing regimens and caution is required. The recent approval of tenofovir alafenamide (TAF), which results in considerably lower plasma tenofovir levels, means that there is less concern about an interaction leading to increased tenofovir exposure.

       Sofosbuvir and velpatasvir

      Sofosbuvir and velpatasvir are available in a two-drug fixed-dose combination containing 400 mg of sofosbuvir and 100 mg of velpatasvir in a single tablet. The recommended dose of the combination is one tablet taken orally once daily with or without food.
      Velpatasvir is metabolised in vitro by CYP2B6, CYP2C8 and CYP3A4. However, because of the slow turnover, the vast majority of drug in plasma is the parent drug. Importantly, velpatasvir is transported by P-gp and BCRP and, to a limited extent, by organic anion transporting polypeptide (OATP) 1B1. Biliary excretion of the parent drug is the major route of elimination. The median terminal half-life of velpatasvir following administration of sofosbuvir and velpatasvir is approximately 15 h.
      Velpatasvir plasma exposure (AUC) is similar in subjects with moderate and severe hepatic impairment compared to subjects with normal hepatic function. Cirrhosis (including decompensated cirrhosis) has no clinically relevant effect on velpatasvir exposure in a population pharmacokinetic analysis in HCV-infected individuals.
      The pharmacokinetics of velpatasvir were studied in HCV-negative patients with severe renal impairment (eGFR <30 ml/min/1.73 m2). Relative to individuals with normal renal function, velpatasvir AUC was 50% higher, which was not considered to be clinically relevant.
      The safety assessment of sofosbuvir and velpatasvir was based on pooled phase III data. Headache, fatigue and nausea were the most commonly reported adverse events, at as similar frequency to placebo-treated patients.
      Because of the disposition profile of velpatasvir, there are some contraindications in relation to co-medications. Drugs that are potent P-gp or potent CYP inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, St John’s wort) are contraindicated, because of the decrease in sofosbuvir and/or velpatasvir exposure with the potential loss in efficacy. However, there are also drugs that are moderate P-gp or CYP inducers (such as modafinil) which can reduce velpatasvir exposure. Currently, this combination would not be recommended with sofosbuvir and velpatasvir.
      Similar to ledipasvir, there is some concern about the inhibition of P-gp and/or BCRP by velpatasvir, such that there is an increase in exposure of a co-medication that is a substrate for these transporters. Current thinking is that the sofosbuvir and velpatasvir combination may be co-administered with P-gp, BCRP, OATP and CYP substrates, but there clearly needs to be some caution with co-medications that have a narrow therapeutic window and in which an increase in drug exposure could potentially have clinical consequences. The colour coding for sofosbuvir/velpatasvir in Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G reflects this (e.g. for digoxin, dabigatran, ticagrelor, carvedilol, amlodipine, diltiazem, aliskiren).
      Like ledipasvir, the solubility of velpatasvir decreases as pH increases. Therefore, it is important to be aware of the recommendations concerning the co-administration of antacids, H2-receptor antagonists and proton pump inhibitors. For most patients, proton pump inhibitors should be avoided during sofosbuvir/velpatasvir treatment. If considered necessary, sofosbuvir/velpatasvir should be given with food and taken 4 hours before the proton pump inhibitor, at a maximum dose comparable to omeprazole 20 mg (Table 5).
      In HIV-HCV coinfected patients, sofosbuvir/velpatasvir may be given with most antiretrovirals, the exceptions being the inducing drugs efavirenz, etravirine and nevirapine. Efavirenz causes a 50% decrease in velpatasvir exposure. Sofosbuvir/velpatasvir also increases tenofovir exposure by inhibiting P-gp. This means that patients on a regimen containing TDF will need to be monitored for renal adverse events.

       Sofosbuvir, velpatasvir and voxilaprevir

      Sofosbuvir, velpatasvir and voxilaprevir are available in a three-drug fixed-dose combination containing 400 mg of sofosbuvir, 100 mg of velpatasvir and 100 mg of voxilaprevir in a single tablet. The recommended dose of the combination is one tablet taken orally once daily with food, as voxilaprevir plasma exposure (AUC) and maximum concentration (Cmax) were 112% to 435%, and 147% to 680% higher, respectively, in the presence of food.
      The specific pharmacokinetic information related to sofosbuvir and velpatasvir individually is discussed in previous sections. Voxilaprevir is metabolised in vitro by CYP3A4, with the vast majority of drug in plasma being the parent drug. Velpatasvir and voxilaprevir are both inhibitors of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3. Biliary excretion of the parent drug is the major route of elimination for voxilaprevir. The median terminal half-life of voxilaprevir following administration of sofosbuvir, velpatasvir and voxilaprevir is approximately 33 h.
      Population pharmacokinetic analysis of voxilaprevir in HCV-infected patients indicated that patients with compensated (Child-Pugh A) cirrhosis had 73% higher exposure of voxilaprevir than those without cirrhosis. Thus, no dose adjustment of sofosbuvir, velpatasvir and voxilaprevir is required for patients with compensated cirrhosis. The pharmacokinetics of single-dose voxilaprevir were also studied in patients with moderate and severe hepatic impairment (Child-Pugh B and C, respectively). Relative to patients with normal hepatic function, the voxilaprevir AUC was 3-fold and 5-fold higher in patients with moderate and severe hepatic impairment, respectively. Thus, the combination of sofosbuvir, velpatasvir and voxilaprevir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and contraindicated in those with severe hepatic impairment (Child-Pugh C).
      The pharmacokinetics of voxilaprevir were studied in HCV-negative patients with severe renal impairment (eGFR <30 ml/min/1.73 m2). Relative to subjects with normal renal function, voxilaprevir AUC was 71% higher in subjects with severe renal impairment, which was not considered to be clinically relevant.
      The safety data of sofosbuvir, velpatasvir and voxilaprevir was based on data from phase II and III clinical trials. Headache, diarrhoea and nausea were the most commonly reported adverse events. The risk of gastrointestinal side effects is greater than with the combination of sofosbuvir and velpatasvir alone.
      Because velpatasvir and voxilaprevir are both inhibitors of P-gp, BCRP, OATP1B1 and OATP1B3, co-administration of sofosbuvir, velpatasvir and voxilaprevir with medicinal products that are substrates of these transporters may increase the exposure of the co-medications. This means that those for which elevated plasma levels are associated with serious events are contraindicated and others may require dose adjustment or additional monitoring. Rosuvastatin is contraindicated because of a 19-fold increase in plasma exposure of the statin. As this effect is likely to be attributed more to the BCRP transporter, other drugs that are a BCRP substrate, including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, sulfasalazine and topotecan, are also not recommended. Dabigatran is contraindicated because of a near 3-fold increase in AUC. This is caused by P-gp inhibition by both velpatasvir and voxilaprevir. Other substrates of P-gp may need to be dose-adjusted or monitored for increased exposure, including digoxin, ticagrelor, carvedilol, diltiazem and aliskiren. Similar caution is required with OATP1B inhibitors, such as cyclosporin, as voxilaprevir plasma exposure increases 19-fold, or with OATP1B substrates, such as edoxaban, as voxilaprevir inhibition is expected to increase the exposure of the factor Xa inhibitor. Neither of these combinations are recommended.
      Concomitant use with medicinal products that are strong P-gp and/or strong CYP inducers such as rifampicin, rifabutin, St. John's wort, carbamazepine, phenobarbital or phenytoin are contraindicated due to the decrease in sofosbuvir, velpatasvir and/or voxilaprevir exposure with the potential loss in efficacy. However, there are also drugs that are moderate P-gp or CYP inducers (such as modafinil, efavirenz, oxcarbazepine and others) which can also reduce exposure of this DAA and are not currently recommended.
      For women of childbearing age, concomitant use with ethinylestradiol-containing contraception is contraindicated because of the risk of ALT elevations. Progestogen-containing contraception is allowed.
      The solubility of velpatasvir decreases as pH increases. Therefore it is important to be aware of the recommendations concerning the co-administration of antacids, H2-receptor antagonists and proton pump inhibitors. Proton pump inhibitors can be given with sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed doses comparable to omeprazole 20 mg (Table 5). Sofosbuvir/velpatasvir/voxilaprevir should be given with food and taken 4 hours before the proton pump inhibitor if possible.
      In HIV-HCV coinfected patients, sofosbuvir/velpatasvir/voxilaprevir is not recommended with the inducing drugs efavirenz, etravirine and nevirapine, and the protease inhibitors atazanavir/ritonavir and lopinavir/ritonavir. Caution is required with twice daily darunavir/ritonavir, darunavir/cobicistat and atazanavir/cobicistat as there are no data. Efavirenz causes a 50% decrease in velpatasvir exposure and atazanavir causes a 4-fold increase in voxilaprevir exposure. Sofosbuvir/velpatasvir/voxilaprevir also increases tenofovir exposure by inhibiting P-gp. This means that patients on a regimen containing TDF need to be monitored for renal adverse events.

       Ritonavir-boosted paritaprevir, ombitasvir and dasabuvir

      Paritaprevir is a protease inhibitor which is metabolised primarily by CYP3A4 and is given with a low dose of the CYP3A inhibitor ritonavir as a pharmacokinetic enhancer. This enables once daily administration and a lower dose than would be required without ritonavir. Ombitasvir is an NS5A inhibitor given in a fixed-dose combination with paritaprevir/ritonavir. The recommended dose of this combination is two tablets of ritonavir/paritaprevir/ombitasvir (50 mg/75 mg/12.5 mg per tablet) taken orally once daily with food. Dasabuvir is a non-nucleoside inhibitor of HCV RNA-dependent RNA polymerase administered in 250 mg tablets twice daily, in combination with ritonavir/paritaprevir/ombitasvir in genotype 1 patients.
      Paritaprevir is excreted predominantly into the faeces. Ombitasvir shows linear kinetics, and is predominantly eliminated in the faeces. Dasabuvir is metabolised in the liver, and its predominant metabolite is mainly cleared via biliary excretion and faecal elimination with minimal renal clearance.
      Pharmacokinetic results from hepatic impairment studies have shown that, in patients with severe hepatic impairment (Child-Pugh C), the AUC of paritaprevir was increased 9.5-fold, whereas ombitasvir was reduced 54% and dasabuvir was increased 3.3-fold. In Child-Pugh B, there is an increase in paritaprevir exposure of 62% with a decrease in ombitasvir of 30%. Thus, no dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A), but the combination of ritonavir-boosted paritaprevir and ombitasvir with or without dasabuvir should not be used in patients with moderate hepatic impairment (Child-Pugh B) or in those with severe hepatic impairment (Child-Pugh C).
      The AUC of paritaprevir was increased 45% in patients with severe renal impairment (creatinine clearance 15–29 ml/min), that of ritonavir 114%, and dasabuvir 50%. Currently, no dose adjustment is required for patients with mild, moderate or severe renal impairment. Paritaprevir, ombitasvir and dasabuvir can also be used in dialysis settings.
      The most common side effects reported with the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir were fatigue and nausea.
      Paritaprevir is primarily metabolised by CYP3A4, whereas dasabuvir is primarily metabolised by CYP2C8 and ombitasvir undergoes hydrolysis. However, both ombitasvir and dasabuvir can be metabolised by CYP3A4. Transporters seem to play an important role in the disposition of these drugs, with paritaprevir inhibiting OATP1B1/B3, P-gp and BCRP. Dasabuvir and ritonavir may also inhibit P-gp and BCRP. Given the metabolic profile of the drugs and the presence of ritonavir, there is a potential for many drug-drug interactions. A comprehensive drug-drug interaction programme has been undertaken based on regulatory guidance from both the European Medicines Agency and the US Food and Drug Administration. It is important to consider the drug interaction profile of the compounds as a combination (either with or without dasabuvir), because the drugs have mutual effects on each other.
      Ritonavir is a strong inhibitor of CYP3A4; thus, co-administration with drugs metabolised by this enzyme may result in markedly increased plasma concentrations. A number of drugs are contraindicated because elevated plasma exposure would lead to serious adverse events, including: alfuzosin, amiodarone, astemizole, terfenadine, cisapride, ergot derivatives, lovastatin, simvastatin, atorvastatin, oral midazolam, triazolam, quetiapine, quinidine, salmeterol, sildenafil when used for pulmonary arterial hypertension. Also contraindicated are enzyme inducers that might compromise virological efficacy, e.g. carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort, enzalutamide, and enzyme inhibitors that might increase paritaprevir exposure, e.g. azole antifungals, some macrolide antibiotics.
      In addition to the contraindications, there are other drugs where caution needs to be exercised and there may be a requirement for a dosage adjustment, altered timing of administration or additional monitoring. Drug interactions need to be carefully considered in the setting of coinfection with HIV. Atazanavir and darunavir should be taken without ritonavir and other protease inhibitors are contraindicated. Efavirenz, etravirine and nevirapine are contraindicated, and rilpivirine should be used cautiously with repeat ECG monitoring. The exposure of raltegravir and dolutegravir may be increased, but this is not linked to safety issues. Cobicistat-containing regimens should not be used because of the additional boosting effect.

       Grazoprevir and elbasvir

      Grazoprevir and elbasvir are available in a two-drug fixed-dose combination containing 100 mg of grazoprevir and 50 mg of elbasvir in a single tablet. The recommended dose of the combination is one tablet taken orally once daily with or without food.
      Grazoprevir and elbasvir are partially metabolised by CYP3A4, but no circulating metabolites are detected in plasma. The principal route of elimination is biliary and faecal with <1% recovered in urine. Grazoprevir is transported by P-gp and OATP1B1, while elbasvir is a substrate for P-gp. Both elbasvir (>99.9%) and grazoprevir (98.8%) are extensively bound to plasma proteins. The terminal half-life values are approximately 24 and 31 h, respectively.
      Pharmacokinetic data from hepatic impairment studies in non-HCV-infected individuals have demonstrated a decrease in elbasvir AUC in Child-Pugh A (40%), Child-Pugh B (28%) and Child-Pugh C (12%) cirrhosis. In contrast, grazoprevir exposure is increased in Child-Pugh A (70%), Child-Pugh B (5-fold) and Child-Pugh C (12-fold) cirrhosis. Based on these data, there is a contraindication for elbasvir/grazoprevir in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
      No dose adjustment is required in patients with mild, moderate or severe renal impairment (including patients on haemodialysis or peritoneal dialysis). There is an increase in elbasvir (65%) and grazoprevir (86%) exposure in non-HCV infected individuals with an eGFR <30 ml/min/1.73 m2, but this is not considered to be clinically significant.
      The safety of elbasvir/grazoprevir is based on phase II and III clinical studies with the most commonly reported adverse reactions being fatigue and headache. Rare cases (0.8%) of substantial ALT level elevations were reported, slightly more frequently in female, Asian and elderly patients. Less than 1% of subjects treated with elbasvir/grazoprevir with or without ribavirin discontinued treatment because of adverse events.
      Since elbasvir and grazoprevir are substrates of CYP3A and P-gp, inducers of these proteins such as efavirenz, etravirine, phenytoin, carbamazepine, bosentan, modafinil and St John’s wort may cause a marked decrease in plasma exposure of both DAAs and are therefore contraindicated. Strong inhibitors of CYP3A (e.g. boosted protease inhibitors, some azole antifungals), which may markedly increase plasma concentrations, are either contraindicated or not recommended. In addition to inhibition of CYP3A, grazoprevir plasma concentrations may also be markedly increased by inhibitors of OATP1B1 (including boosted protease inhibitors, cobicistat, cyclosporin, single-dose rifampicin). However, there is no effect of acid reducing agents on the absorption of either DAA.
      The potential for grazoprevir/elbasvir to affect other medications is relatively low, although grazoprevir is a weak CYP3A inhibitor (approximately 30% increase in midazolam exposure) and elbasvir a weak inhibitor of P-gp. There needs to be some caution when co-administering drugs that use CYP3A and P-gp in their disposition, especially in the presence of a narrow therapeutic index (e.g. tacrolimus, some statins, dabigatran, ticagrelor), or drugs with large ranges such a quetiapine, where those on higher doses may need additional monitoring, dose reduction and/or ECG.
      Based on the findings above, there are limitations on which antiretrovirals can be co-administered with elbasvir/grazoprevir. Currently the antiretrovirals that can be used are the nucleotide reverse transcriptase inhibitors abacavir, lamivudine, tenofovir (either as TDF or as TAF), emtricitabine, rilpivirine, raltegravir, dolutegravir and maraviroc (Table 4A).

       Glecaprevir and pibrentasvir

      Glecaprevir and pibrentasvir are available in a two-drug fixed-dose combination containing 100 mg of glecaprevir and 40 mg of pibrentasvir. The recommended dose is three tablets taken orally once daily with food, as glecaprevir plasma exposure increases 83%-163% in the presence of food compared to the fasted state.
      Biliary excretion is the major route of elimination for glecaprevir and pibrentasvir. The half-lives of glecaprevir and pibrentasvir are approximately 6 and 23 h, respectively.
      Population pharmacokinetic analysis in HCV-infected subjects showed that following administration of glecaprevir/pibrentasvir in HCV-infected individuals with compensated (Child-Pugh A) cirrhosis, exposure of glecaprevir was approximately 2-fold higher whilst pibrentasvir exposure was similar to patients without cirrhosis. When compared to patients with normal hepatic function, glecaprevir AUC was 33% higher in patients with compensated cirrhosis (Child-Pugh A), 100% higher in those with moderate hepatic impairment (Child-Pugh B), and increased to 11-fold in those with severe hepatic impairment (Child-Pugh C). Thus, glecaprevir/pibrentasvir is contraindicated in patients with Child-Pugh B or C.
      Glecaprevir/pibrentasvir was studied in HCV-negative individuals with mild, moderate, severe, or end-stage renal impairment not on dialysis and compared to subjects with normal renal function. The AUCs were increased by less than 56% in all patients, which was not clinically significant. Glecaprevir/pibrentasvir AUC was also similar with and without dialysis.
      The safety of pibrentasvir and glecaprevir was evaluated in phase II and III clinical trials. Headache and fatigue were the most commonly reported adverse events.
      Glecaprevir and pibrentasvir are inhibitors of P-gp, BCRP and OATP1B1 and OATP1B3. Co-administration with glecaprevir/pibrentasvir may increase the concentration of co-medications that are substrates of P-gp (e.g. dabigatran etexilate which is contraindicated because of a 2.4-fold increase in dabigatran exposure), BCRP (e.g. rosuvastatin which requires a dose reduction), or OATP1B1/3 (e.g. atorvastatin or simvastatin which are contraindicated). For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment should be considered.
      Glecaprevir/pibrentasvir concentrations may be decreased by strong P-gp and CYP3A inducing drugs such as rifampicin, carbamazepine, St. John's wort or phenytoin, leading to reduced therapeutic effect or loss of virologic response. Co-administration with these, or other potent inducers, is contraindicated. A similar effect cannot be ruled out with moderate inducers, such as oxcarbazepine and eslicarbazepine, and co-administration of these drugs is not recommended. Co-medications that inhibit P-gp and BCRP may increase plasma exposure of glecaprevir/pibrentasvir. Similarly OATP1B1/3 inhibitors, such as cyclosporin, darunavir and lopinavir, may also increase glecaprevir concentrations.
      The potential for glecaprevir/pibrentasvir to affect other medications is relatively low, although glecaprevir is a weak CYP3A inhibitor (approximately 27% increase in midazolam exposure). There needs to be some caution when co-administering drugs that use CYP3A in their disposition in the presence of a narrow therapeutic index (e.g. tacrolimus) or drugs with large ranges such a quetiapine, whereas patients on higher doses may need additional monitoring, dose reduction and/or ECG.
      For women of childbearing age, concomitant use with ethinylestradiol-containing contraception is contraindicated because of the risk of ALT elevations. Progestogen-containing contraception is allowed.
      Similar to other DAAs, the solubility of glecaprevir decreases as pH increases. Cmax of glecaprevir decreases on average by 64% when co-administered with omeprazole 40 mg. The license states that no dose changes are recommended. However, prescribing doses of omeprazole greater than 40 mg or equivalent (Table 5) with glecaprevir and pibrentasvir has not been studied and may lead to a greater decrease in glecaprevir concentrations.
      In HIV-HCV coinfected patients, because of the mechanisms described above, glecaprevir/pibrentasvir is contraindicated with atazanavir-containing regimens and is not recommended with other HIV protease inhibitors. Similarly, the inducing non-nucleoside reverse transcriptase inhibitors efavirenz, etravirine and nevirapine are not recommended because of an expected reduction in plasma exposure of glecaprevir/pibrentasvir. All other antiretroviral drugs can be co-administered, including cobicistat when used with integrase inhibitor elvitegravir.
      • Numerous and complex drug-drug interactions are possible with HCV DAAs. Therefore, a thorough drug-drug interaction risk assessment prior to starting therapy and before starting other medications during treatment is required in all patients undergoing treatment with DAAs, based on the prescribing information for each DAA (summary data on key interactions can be found in Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G in this document; a key internet resource is www.hep-druginteractions.org where recommendations are regularly updated) (A1).
      • Drug-drug interactions are a key consideration in treating HIV-HCV coinfected patients, and close attention must be paid to anti-HIV drugs that are contraindicated, not recommended or require dose adjustment with particular DAA regimens (A1).
      • Patients should be educated on the importance of adherence to therapy, following the dosing recommendations and reporting the use of other prescribed medications, over-the-counter medications, medications bought via the internet, and use of party or recreational drugs (A1).

      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 previously treated with pegylated IFN-α and ribavirin; pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin).
      Indications depend on the HCV genotype/subtype, the severity of liver disease, and/or prior therapy. The indications are the same in HCV-monoinfected and HIV-coinfected patients. However, treatment alterations or dose adjustments may be needed in the latter, owing to drug-drug interactions (see above and Table 4A).
      The panel recognises the heterogeneity of per capita incomes and health insurance systems across Europe and in other regions, and therefore the constraints that may necessitate continued utilisation of regimens described in previous versions of these recommendations but no longer recommended in 2018. In settings where none of the IFN-free, ribavirin-free options proposed in this document are available, options proposed in previous versions of these recommendations remain acceptable for patients likely to respond to these regimens until new DAAs become available and affordable; see prior EASL Recommendations on Treatment of Hepatitis C.
      • European Association for the Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2016.
      • European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      • European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      • European Association for Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2015.
      It is hoped that the publication of up-to-date recommendations will guide reimbursement and discounting of drug costs in order to harmonize access and treatments across different countries and regions.
      • IFN-free, ribavirin-free, DAA-based regimens must be used in HCV-infected patients without cirrhosis or with compensated (Child-Pugh A) 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 previously treated with pegylated IFN-α and ribavirin; or pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin), because of their virological efficacy, ease of use, safety and tolerability (A1).
      • The same IFN-free, ribavirin-free treatment regimens should be used in HIV-coinfected patients as in patients without HIV infection, as the virological results of therapy are identical. Treatment alterations or dose adjustments should be performed in case of interactions with antiretroviral drugs (A1).
      • Whenever possible (same treatment duration, equivalent SVR rates), combination regimens comprising two drugs are preferred to triple combination regimens, in order to minimize the risk of side effects and drug-drug interactions (B1).
      The IFN-free combination regimens that represent valuable options for each genotype/subtype are shown (Table 6). For each genotype/subtype, the available options are described below, followed by a summary of the data that support the given option, and summarised in Table 7, Table 8 for patients without cirrhosis and those with compensated (Child-Pugh A) cirrhosis, respectively.
      Table 6IFN-free, ribavirin-free combination treatment regimens available for treatment-naïve patients (defined as patients who have never been treated for their HCV infection) and treatment-experienced patients (defined as patients who were previously treated with pegylated IFN-α and ribavirin; pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin), without cirrhosis or with compensated (Child-Pugh A) cirrhosis, recommended for each HCV genotype/subtype in 2018 and onwards.
      DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      * Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens.
      a Treatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis.
      b Treatment-naïve and treatment-experienced patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/ml (5.9 Log10 IU/ml).
      c Treatment-naïve and treatment-experienced patients without cirrhosis.
      d Treatment-naïve and treatment-experienced patients with compensated (Child-Pugh A) cirrhosis.
      e Treatment-naïve patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with an HCV RNA level ≤800,000 IU/ml (5.9 Log10 IU/ml).
      Table 7Treatment recommendations for HCV-monoinfected or HCV/HIV-coinfected patients with chronic hepatitis C without 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 previously treated with pegylated IFN-α and ribavirin; pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin).
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      Table 8Treatment recommendations for HCV-monoinfected or HCV/HIV-coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) 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 previously treated with pegylated IFN-α and ribavirin; pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin).
      DAA, direct-acting antiviral; DSV, dasabuvir; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LDV, ledipasvir; OBV, ombitasvir; PIB, pibrentasvir; PTV, paritaprevir; r, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VOX: voxilaprevir.
      By convention, the combination regimens listed start with fixed-dose pangenotypic combinations, followed by genotype-specific combinations (two-drug combinations followed by three-drug combinations; sofosbuvir-based followed by sofosbuvir-free).

       Treatment of HCV genotype 1a infection

      Four treatment options are available in 2018 for patients infected with HCV genotype 1a (Table 6, Table 7, Table 8). These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/ledipasvir.
      • Grazoprevir/elbasvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 1a, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of grazoprevir (100 mg) and elbasvir (50 mg) in a single tablet administered once daily).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 1a, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-1 trial in patients with HCV genotype 1 infection (22% with cirrhosis, 66% treatment-naïve, 34% treatment-experienced, 44% of whom exposed to previous DAA) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks. An SVR12 was observed in 98% (206/210; one relapse) of patients infected with genotype 1a.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      These results were confirmed in real-world studies.
      • Tsai N.
      • Bacon B.
      • Curry M.
      • Dieterich D.
      • Flamm S.
      • Kowdley K.
      • et al.
      Utilization of DAA therapies ledipasvir/sofosbuvir and sofosbuvir/velpatasvir in patients with genotype 1 HCV: real-world experience from the TRIO network.
      • Landis C.S.
      • Sulkowski M.S.
      • Reau N.
      • Lutchman G.A.
      • Vainorius M.
      • Welzel T.M.
      • et al.
      Safety and efficacy of velpatasvir and sofosbuvir-based regimens for the treatment of HCV genotype 1–6: results of the HCV-TARGET study.
      In the ASTRAL-5 trial in treatment-naïve or treatment-experienced patients with or without cirrhosis infected with genotype 1a and coinfected with HIV, the SVR12 rate with the same regimen was 95% (63/66; 2 relapses).
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-lLabel, Phase 3 study.
      The triple combination of sofosbuvir, velpatasvir and voxilaprevir administered for 8 weeks failed to achieve non-inferiority compared to sofosbuvir/velpatasvir for 12 weeks in the POLARIS-2 phase III trial, which included approximately 20% of patients with cirrhosis and 25% of treatment-experienced patients. The SVR12 rates in patients infected with genotype 1a were 92% (155/169; 14 relapses) after 8 weeks of sofosbuvir/velpatasvir/voxilaprevir and 99% (170/172; one relapse) after 12 weeks of sofosbuvir/velpatasvir.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 Phase 3 randomized trials.
      Thus, the triple combination of sofosbuvir, velpatasvir and voxilaprevir for 8 weeks is not recommended in patients infected with HCV genotype 1a.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 1a without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (A1).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 1a with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of two phase III trials in patients with HCV genotype 1a infection. In ENDURANCE-1, the SVR12 rate was 98% (150/152; one virological breakthrough, one non-virological failure) in treatment-naïve or treatment-experienced patients without cirrhosis receiving 8 weeks of glecaprevir/pibrentasvir, including 13 patients who were HIV-coinfected.
      • Zeuzem S.
      • Foster G.R.
      • Wang S.
      • Asatryan A.
      • Gane E.
      • Feld J.J.
      • et al.
      Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection.
      Treatment-naïve and treatment-experienced genotype 1a-infected patients with compensated cirrhosis were studied in the EXPEDITION-1 trial. The SVR12 rate was 98% (47/48; one relapse) after 12 weeks of glecaprevir/pibrentasvir.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      • Treatment-naïve patients infected with HCV genotype 1a, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 weeks (A1).
      • Treatment-naïve patients infected with HCV genotype 1a without cirrhosis can be treated with the fixed-dose combination of sofosbuvir and ledipasvir for 8 weeks (B2).
      • The combination of sofosbuvir and ledipasvir is not recommended in treatment-experienced patients infected with genotype 1a (B1).
      Comments: This recommendation is based on the results of the three phase III trials ION-1, ION-3 and ION-4,
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • Lawitz E.
      • Gordon S.C.
      • Schiff E.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      • Naggie S.
      • Cooper C.
      • Saag M.
      • Workowski K.
      • Ruane P.
      • Towner W.J.
      • et al.
      Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1.
      on post hoc analyses of pooled data from phase II and III clinical trials and on real-world data reported at international medical conferences or published.
      In ION-1, treatment-naïve genotype 1a patients, including approximately 15% with compensated cirrhosis, achieved SVR12 in 98% (141/144; one relapse) of cases after 12 weeks of the fixed-dose combination of sofosbuvir and ledipasvir.
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      An integrated analysis of treatment-naïve genotype 1a patients with compensated cirrhosis treated with sofosbuvir/ledipasvir for 12 weeks in different phase II and III studies showed an overall SVR12 rate of 98% (84/86).
      • Reddy K.R.
      • Bourliere M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: an integrated safety and efficacy analysis.
      In ION-4, an open-label study in treatment-naïve or treatment-experienced genotype 1a patients with or without cirrhosis who were coinfected with HIV and received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir, the SVR12 rate was 96% (240/250; 8 relapses).
      • Naggie S.
      • Cooper C.
      • Saag M.
      • Workowski K.
      • Ruane P.
      • Towner W.J.
      • et al.
      Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1.
      In ION-3 in treatment-naïve genotype 1a patients without cirrhosis, the SVR12 rates were 93% (159/171; 10 relapses) with sofosbuvir/ledipasvir for 8 weeks and 95% (163/172; 2 relapses) with sofosbuvir/ledipasvir for 12 weeks.
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      These results were confirmed by real-world studies from Europe and the United States in the same subgroup of patients, showing similarly high SVR12 rates. One study showed that shortening sofosbuvir and ledipasvir treatment duration can be applied to patients with an HCV RNA <6,000,000 IU/ml (6.8 Log10 IU/ml) at baseline.
      • Wilson E.
      • Davitkov P.
      • Kwo P.Y.
      • Katkakuzhy S.
      • Qureshi K.
      • Sundaram V.
      • et al.
      Real-world effectiveness of 8 vs 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) in Blacks with HCV: a comparative analysis of clinical trials with real-world cohorts.
      A pooled analysis of patients from different real-world studies included 566 treatment-naïve genotype 1a-infected patients without cirrhosis; 527 of them were eligible to receive 8 weeks of sofosbuvir-ledipasvir, as per FDA labelling. The SVR12 rate was 98% (518/527; 9 relapses). Logistic regression analysis identified male sex, African-American origin and a fibrosis stage F3 as independent predictors of post-treatment relapse.
      • Kowdley K.V.
      • Sundaram V.
      • Jeon C.
      • Qureshi K.
      • Latt N.L.
      • Sahota A.K.
      • et al.
      8 weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection.
      The effect of F3 fibrosis was not confirmed in later studies.
      • Buggisch P.
      • Vermehren J.
      • Mauss S.
      • Gunther R.
      • Schott E.
      • Pathil A.
      • et al.
      Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C.
      • Kowdley K.V.
      • Sundaram V.
      • Jeon C.Y.
      • Qureshi K.
      • Latt N.L.
      • Sahota A.
      • et al.
      8 weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection.
      SVR12 rates of the same order as in the clinical trials were observed in patients with or without compensated cirrhosis in real-world studies from various continents.
      The combination of sofosbuvir and ledipasvir is not recommended in treatment-experienced patients infected with genotype 1a, because this regimen would require the addition of ribavirin, as explained in the EASL Recommendations for Treatment of Hepatitis C 2016.
      • European Association for the Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2016.
      • Treatment-naïve and treatment-experienced patients infected with genotype 1a, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, with an HCV RNA level ≤800,000 IU/ml (5.9 Log10 IU/ml) at baseline should be treated with the fixed-dose combination of grazoprevir and elbasvir for 12 weeks (B1).
      • The combination of grazoprevir and elbasvir is not recommended in patients infected with genotype 1a with an HCV RNA level >800,000 IU/ml (5.9 Log10 IU/ml) (A1).
      Comments: This recommendation is based on the results of three phase III trials and subsequent post hoc analyses of pooled phase II and III clinical trial data.
      In the C-EDGE-TN trial, in treatment-naïve patients infected with genotype 1a receiving grazoprevir and elbasvir for 12 weeks, the SVR12 rate was 92% (144/157; one breakthrough and 12 relapses), with compensated cirrhosis having no effect on SVR12 rate.
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial.
      In the open-label C-EDGE-COINFECTION trial, treatment-naïve patients coinfected with HIV with or without compensated cirrhosis were treated with grazoprevir and elbasvir for 12 weeks, with an SVR12 rate of 97% (139/144) in genotype 1a-infected patients.
      • Rockstroh J.K.
      • Nelson M.
      • Katlama C.
      • Lalezari J.
      • Mallolas J.
      • Bloch M.
      • et al.
      Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial.
      In a pooled efficacy analysis of treatment-naïve patients with genotype 1a infection from phase II and III trials treated with grazoprevir/elbasvir for 12 weeks, the SVR12 rate was 99% (121/122) in patients with an HCV RNA level ≤800,000 IU/ml, with no influence of pre-existing NS5A RASs at baseline on SVR (unpublished data provided to the panel by Merck).
      In treatment-experienced patients included in the C-EDGE-TE phase III trial, including approximately 30% of patients with compensated cirrhosis, the SVR12 rate in genotype 1a patients was 92% (55/60) after 12 weeks of grazoprevir/elbasvir.
      • Kwo P.
      • Gane E.J.
      • Peng C.Y.
      • Pearlman B.
      • Vierling J.M.
      • Serfaty L.
      • et al.
      Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection.
      In a pooled efficacy population of treatment-experienced patients with genotype 1a from phase II and III trials treated for 12 weeks, the SVR12 rate was 100% (14/14) in patients with an HCV RNA level ≤800,000 IU/ml (unpublished data provided to the panel by Merck).
      With this regimen, the SVR12 rate was impacted by the presence of NS5A RASs at baseline in treatment-naïve and treatment-experienced patients with an HCV RNA level >800,000 IU/ml (unpublished data provided to the panel by Merck). Therefore, because resistance testing is not recommended prior to therapy, this regimen is not recommended in patients with an HCV RNA level >800,000 IU/ml.

       Treatment of HCV genotype 1b infection

      Five treatment options are available in 2018 for patients infected with HCV genotype 1b (Table 6, Table 7, Table 8). These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/ledipasvir.
      • Grazoprevir/elbasvir.
      • Ombitasvir/paritaprevir/ritonavir and dasabuvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 1b, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of grazoprevir (100 mg) and elbasvir (50 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of ombitasvir (12.5 mg), paritaprevir (75 mg) and ritonavir (50 mg) in one single tablet (two tablets once daily with food), and dasabuvir (250 mg) (one tablet twice daily).
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-1 trial in patients with HCV genotype 1 infection (22% with cirrhosis, 66% treatment-naïve, 34% treatment-experienced, 44% of whom exposed to previous DAA) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks. An SVR12 was observed in 99% (117/118; one relapse) of patients infected with genotype 1b.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      In the ASTRAL-5 trial in HIV-coinfected patients, the SVR12 rate with the same regimen was 92% (11/12; no virological failure) in treatment-naïve or treatment-experienced patients without cirrhosis or with compensated cirrhosis infected with genotype 1b.
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-lLabel, Phase 3 study.
      These results were confirmed in real-world studies.
      • Tsai N.
      • Bacon B.
      • Curry M.
      • Dieterich D.
      • Flamm S.
      • Kowdley K.
      • et al.
      Utilization of DAA therapies ledipasvir/sofosbuvir and sofosbuvir/velpatasvir in patients with genotype 1 HCV: real-world experience from the TRIO network.
      • Landis C.S.
      • Sulkowski M.S.
      • Reau N.
      • Lutchman G.A.
      • Vainorius M.
      • Welzel T.M.
      • et al.
      Safety and efficacy of velpatasvir and sofosbuvir-based regimens for the treatment of HCV genotype 1–6: results of the HCV-TARGET study.
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (A1).
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of two phase III trials in patients with HCV genotype 1b infection. In ENDURANCE-1, the SVR12 rate was 100% (198/198) in treatment-naïve and treatment-experienced patients without cirrhosis receiving 8 weeks of glecaprevir/pibrentasvir, including two patients who were HIV-coinfected.
      • Zeuzem S.
      • Foster G.R.
      • Wang S.
      • Asatryan A.
      • Gane E.
      • Feld J.J.
      • et al.
      Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection.
      Treatment-naïve and treatment-experienced genotype 1b-infected patients with compensated cirrhosis were studied in the EXPEDITION-1 trial. The SVR12 rate was 100% (39/39) after 12 weeks of glecaprevir/pibrentasvir.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 weeks (A1).
      • Treatment-naïve patients infected with genotype 1b without cirrhosis can be treated with the fixed-dose combination of sofosbuvir and ledipasvir for 8 weeks (B1).
      Comments: This recommendation is based on the results of the four phase III trials ION-1, ION-2, ION-3 and ION-4
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • Lawitz E.
      • Gordon S.C.
      • Schiff E.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      • Naggie S.
      • Cooper C.
      • Saag M.
      • Workowski K.
      • Ruane P.
      • Towner W.J.
      • et al.
      Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1.
      and several post hoc analyses of pooled data from phase II and III clinical trials.
      In ION-1, treatment-naïve patients infected with HCV genotype 1b, including approximately 15% with compensated cirrhosis, achieved SVR12 in 100% (66/66) of cases after 12 weeks of the fixed-dose combination of sofosbuvir and ledipasvir.
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      An integrated analysis of genotype 1b patients with compensated cirrhosis treated with sofosbuvir/ledipasvir for 12 weeks in different phase II and III studies showed an overall SVR12 rate of 97% (72/74) in treatment-naïve and 96% (124/129) in treatment-experienced patients.
      • Reddy K.R.
      • Bourliere M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: an integrated safety and efficacy analysis.
      In ION-2, in treatment-experienced patients (previously treated with pegylated IFN-α and ribavirin, or with pegylated IFN-α, ribavirin and either telaprevir or boceprevir), including approximately 20% with cirrhosis, the SVR12 rate was 87% (20/23; 3 relapses) in patients infected with HCV genotype 1b.
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • Lawitz E.
      • Gordon S.C.
      • Schiff E.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      In ION-4, an open-label study in treatment-naïve and treatment-experienced genotype 1b patients with or without cirrhosis who were coinfected with HIV and received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir, the SVR12 rate was 96% (74/77; 3 relapses).
      • Naggie S.
      • Cooper C.
      • Saag M.
      • Workowski K.
      • Ruane P.
      • Towner W.J.
      • et al.
      Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1.
      In ION-3 in treatment-naïve patients without cirrhosis (F3 fibrosis was present in only 13% of patients with genotype 1 who underwent liver biopsy), the SVR12 rate was 98% (42/43; one relapse) after 8 weeks of sofosbuvir/ledipasvir in patients infected with genotype 1b.
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • Rossaro L.
      • Bernstein D.E.
      • Lawitz E.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      These results were confirmed by real-world studies from Europe and the United States in the same subgroup of patients, showing similarly high SVR12 rates. In a pooled analysis of patients from different real-world studies, the SVR12 rate after 8 weeks of sofosbuvir/ledipasvir as per FDA labelling was over 99% (235/237; 2 relapses) in genotype 1b patients.
      • Kowdley K.V.
      • Sundaram V.
      • Jeon C.
      • Qureshi K.
      • Latt N.L.
      • Sahota A.K.
      • et al.
      8 weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection.
      Similar SVR12 rates as those achieved in the clinical trials were observed in treatment-naïve and treatment-experienced patients with or without compensated cirrhosis in real-world studies from various continents.
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of grazoprevir and elbasvir for 12 weeks (A1).
      • Treatment-naïve patients infected with genotype 1b with F0-F2 fibrosis can be treated with the fixed-dose combination of grazoprevir and elbasvir for 8 weeks (B2).
      Comments: This recommendation is based on the results of four phase III trials, and subsequent post hoc analyses of pooled phase II and III clinical trial data, as well as of the STREAGER trial with a shorter treatment duration.
      In the C-EDGE-TN trial, in treatment-naïve patients infected with genotype 1b receiving grazoprevir and elbasvir for 12 weeks, the SVR12 rate was 99% (129/131; one relapse).
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial.
      In the C-CORAL trial, performed in Russia and the Asia-Pacific region, the SVR12 rate was 98% (382/389; 5 relapses).
      • Wei L.J.
      • Zhdanov K.
      • Burnevich E.
      • Sheen I.S.
      • Heo J.
      • Nguyen V.K.
      • et al.
      Efficacy and safety of elbasvir/grazoprevir in treatment-naïve patients with chronic HCV GT 1, GT 4 and GT 6 infection (C-CORAL): a Phase III randomized multinational clinical trial.
      In the open-label C-EDGE-COINFECTION trial, treatment-naïve patients coinfected with HIV with or without compensated cirrhosis were treated with grazoprevir and elbasvir for 12 weeks. The SVR12 rate was 95% (42/44) in genotype 1b-infected patients.
      • Rockstroh J.K.
      • Nelson M.
      • Katlama C.
      • Lalezari J.
      • Mallolas J.
      • Bloch M.
      • et al.
      Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial.
      In treatment-experienced patients included in the C-EDGE-TE phase III trial, in which approximately a third of patients had compensated cirrhosis, the SVR12 rate in genotype 1b patients was 100% (34/34) after 12 weeks of grazoprevir/elbasvir.
      • Kwo P.
      • Gane E.J.
      • Peng C.Y.
      • Pearlman B.
      • Vierling J.M.
      • Serfaty L.
      • et al.
      Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection.
      A pooled analysis of all phase II and III trials showed an SVR rate of 97% (1040/1070; 15 relapses and 15 virological failures) in patients infected with genotype 1b treated for 12 weeks with this regimen.
      • Zeuzem S.
      • Serfaty L.
      • Vierling J.
      • Cheng W.
      • George J.
      • Sperl J.
      • et al.
      The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection.
      In the STREAGER study, treatment-naïve genotype 1b-infected patients with a stage of fibrosis F0-F2 (excluding patients with advanced fibrosis or cirrhosis) treated with grazoprevir/elbasvir for 8 weeks achieved an SVR12 in 97% (66/68) of cases. Two patients relapsed post-treatment (updated data provided to the panel by Merck).
      • Abergel A.
      • Loustaud-Ratti V.
      • Di Martino V.
      • Gournay J.
      • Larrey D.G.
      • Fouchard-Hubert I.
      • et al.
      High efficacy and safety of the combination HCV regimen grazoprevir and elbasvir for 8 weeks in treatment-naive, non-severe fibrosis HCV GT1b-infected patients: interim results of the STREAGER study.
      • Treatment-naïve and treatment-experienced patients infected with genotype 1b, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the combination of ombitasvir, paritaprevir and ritonavir plus dasabuvir for 12 weeks (A1).
      • Treatment-naïve patients infected with genotype 1b with F0-F2 fibrosis can be treated with the combination of ombitasvir, paritaprevir and ritonavir plus dasabuvir for 8 weeks (B2).
      Comments: This recommendation is based on the results of several phase III trials. In the PEARL-3 trial, the SVR12 rate was 99% (207/209) in treatment-naïve patients without cirrhosis infected with subtype 1b receiving the triple combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir for 12 weeks.
      • Ferenci P.
      • Bernstein D.
      • Lalezari J.
      • Cohen D.
      • Luo Y.
      • Cooper C.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.
      In MALACHITE-1, the SVR12 rate in treatment-naïve patients without cirrhosis was 98% (81/83).
      • Dore G.J.
      • Conway B.
      • Luo Y.
      • Janczewska E.
      • Knysz B.
      • Liu Y.
      • et al.
      Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: the MALACHITE-I/II trials.
      In the TURQUOISE-1 study in treatment-naïve patients without cirrhosis coinfected with HIV-1 and stable on antiretroviral treatment containing atazanavir or raltegravir, SVR12 was achieved in 100% (7/7) of genotype 1b patients.
      • Wyles D.
      • Saag M.
      • Viani R.M.
      • Lalezari J.
      • Adeyemi O.
      • Bhatti L.
      • et al.
      TURQUOISE-I Part 1b: ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for hepatitis C virus infection in HIV-1 coinfected patients on darunavir.
      Finally, in the GARNET study, the SVR12 rate was 97% (161/166) in treatment-naïve patients with genotype 1b infection and no cirrhosis (METAVIR score F0 to F3) after 8 weeks of treatment with ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. Among the 15 patients with F3 fibrosis included in this study, two experienced a virological failure.
      • Welzel T.M.
      • Asselah T.
      • Dumas E.O.
      • Zeuzem S.
      • Shaw D.
      • Hazzan R.
      • et al.
      Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, Phase 3b trial.
      In treatment-experienced patients (pegylated IFN-α and ribavirin failures) without cirrhosis treated with this combination for 12 weeks in PEARL-2, SVR12 was achieved in 100% (95/95) of cases.
      • Andreone P.
      • Colombo M.G.
      • Enejosa J.V.
      • Koksal I.
      • Ferenci P.
      • Maieron A.
      • et al.
      ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection.
      In the TOPAZ-1 study, treatment-naïve and treatment-experienced patients without cirrhosis receiving the same regimen achieved SVR12 in 99% (738/745; 3 virological failures) of cases.
      • Agarwal K.
      • Dumas E.O.
      • Gaeta G.B.
      • Lee S.
      • Streinu-Cercel A.
      • Schott E.
      • et al.
      Long-term clinical outcomes in HCV genotype 1-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin: first interim safety and efficacy results from TOPAZ-I.
      A pooled analysis of several clinical trials showed a 99% SVR12 rate in 521 patients without cirrhosis (PEARL-2, PEARL-3, TOPAZ-2, MALACHITE-1).
      • Welzel T.M.
      • Isakov V.
      • Trinh R.
      • Streinu-Cercel A.
      • Dufour J.F.
      • Marinho R.T.
      • et al.
      Efficacy and safety of ombitasvir, paritaprevir/ritonavir and dasabuvir without ribavirin in patients with HCV genotype 1b with or without compensated cirrhosis: pooled analysis across 5 clinical trials.
      Similarly high SVR12 rates were achieved in Asian patients infected with genotype 1b with this combination.
      • Wei L.
      • Hou J.
      • Luo Y.
      • Heo J.
      • Chu C.J.
      • Duan Z.P.
      • et al.
      ONYX-I: safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir in Asian adults with genotype 1b chronic hepatitis C virus (HCV) infection. A randomized, double-blind, placebo-controlled study.
      In treatment-naïve and treatment-experienced patients with compensated cirrhosis included in the TURQUOISE-3 trial, SVR12 was achieved in 100% (60/60) of genotype 1b patients treated for 12 weeks with ritonavir-boosted paritaprevir, ombitasvir and dasabuvir.
      • Feld J.J.
      • Moreno C.
      • Trinh R.
      • Tam E.
      • Bourgeois S.
      • Horsmans Y.
      • et al.
      Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks.
      Similar SVR12 rates as those achieved in the clinical trials were observed in a large number of real-world studies from various continents.

       Treatment of HCV genotype 2 infection

      Two first-line treatment options are available for patients infected with HCV genotype 2 (Table 6, Table 7, Table 8). These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 2, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 2, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-2 trial in patients with HCV genotype 2 infection (14% with compensated cirrhosis, 86% treatment-naïve, 14% treatment-experienced) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin, showing SVR12 in 99% (133/134) of patients.
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      In ASTRAL-1, the SVR12 rate was 100% (104/104) in treatment-naïve (two-thirds) and treatment-experienced (one-third) patients, who included approximately 30% with cirrhosis.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      In the ASTRAL-5 trial in HIV-coinfected patients, the SVR12 rate with the same regimen was 100% (11/11) in genotype 2 patients.
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-lLabel, Phase 3 study.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 2 without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (A1).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 2 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (A1).
      Comments: This recommendation is in part based on the results of the phase II SURVEYOR-2 trial, showing an SVR12 rate of 98% (53/54; no virological failure) in treatment-naïve and treatment-experienced patients without cirrhosis infected with HCV genotype 2, receiving the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis.
      These results were confirmed in the CERTAIN-2 trial, showing an SVR rate of 98% (127/129, no virological failure) in Japanese patients infected with genotype 2, receiving the same treatment regimen for 8 weeks.
      • Toyoda H.
      • Chayama K.
      • Suzuki F.
      • Sato K.
      • Atarashi T.
      • Watanabe T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.
      In the EXPEDITION 2 trial, the SVR12 rate was 100% (12/12) after 8 weeks of glecaprevir/pibrentasvir in patients without cirrhosis with genotype 2 infection coinfected with HIV.
      • Rockstroh J.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 study.
      In the EXPEDITION-1 trial, 12 weeks of glecaprevir/pibrentasvir yielded SVR12 in 100% (31/31) of treatment-naïve or treatment-experienced genotype 2-infected patients with compensated cirrhosis.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      These results were confirmed in the CERTAIN-2 trial, showing an SVR rate of 100% (38/38) in Japanese patients with compensated cirrhosis infected with genotype 2 receiving the same treatment regimen for 12 weeks.
      • Toyoda H.
      • Chayama K.
      • Suzuki F.
      • Sato K.
      • Atarashi T.
      • Watanabe T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.

       Treatment of HCV genotype 3 infection

      Three first-line treatment options are available for patients infected with HCV genotype 3 (Table 6, Table 7, Table 8). These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/velpatasvir/voxilaprevir.
      • The following regimens are recommended for the treatment of patients infected with genotype 3, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg), velpatasvir (100 mg) and voxilaprevir (100 mg) in a single tablet administered once daily with food.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 3 without cirrhosis should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (A1).
      • The combination of sofosbuvir and velpatasvir is not recommended in treatment-naïve and treatment-experienced patients infected with HCV genotype 3 with compensated (Child-Pugh A) cirrhosis, because suboptimal results have been reported with this combination (B2).
      Comments: This recommendation is based on the results of the phase III ASTRAL-3 trial in patients with HCV genotype 3 infection (29% with compensated cirrhosis, 74% treatment-naïve, 26% treatment-experienced) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks. The SVR12 rates were 98% (160/163) in treatment-naïve patients without cirrhosis. Lower SVR12 rates were observed in patients who were treatment-experienced or had cirrhosis with this regimen: overall 90% (104/116; 12 virological failures); 93% (40/43) in treatment-naïve patients with compensated cirrhosis, 91% (31/34) in treatment-experienced patients without cirrhosis and 89% (33/37) in treatment-experienced patients with compensated cirrhosis.
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      Thus, the addition of a third drug to this regimen is necessary, at least in patients infected with genotype 3 with compensated cirrhosis, justifying the use of the triple combination of sofosbuvir, velpatasvir and voxilaprevir in this group (see below).
      In the ASTRAL-5 trial in HIV-coinfected patients, the SVR12 rate with the same regimen was 92% (11/12).
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-lLabel, Phase 3 study.
      • Treatment-naïve patients infected with HCV genotype 3, with no to moderate fibrosis (METAVIR score F0-F2), should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (A1).
      • Treatment-naïve patients infected with HCV genotype 3, with advanced fibrosis (METAVIR score F3), but without cirrhosis, can be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (B2).
      • Treatment-experienced patients infected with HCV genotype 3 without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (B1).
      • Treatment-naïve patients infected with HCV genotype 3 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (B1).
      • Treatment-experienced patients infected with HCV genotype 3 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 16 weeks (B1).
      Comments: This recommendation is based on the results of the phase III ENDURANCE-3 trial showing an SVR12 rate of 95% (149/157; 5 relapses, one virological breakthrough) in treatment-naïve patients without cirrhosis infected with HCV genotype 3 receiving the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks. However, only 17% of patients in this study had advanced fibrosis (METAVIR score F3), the remaining 83% having mild to moderate fibrosis (F0-F2).
      • Foster G.R.
      • Gane E.
      • Asatryam A.
      • Asselah T.
      • Ruane P.J.
      • Pol S.
      • et al.
      ENDURANCE-3: safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis.
      Thus, more data must be generated to strengthen the recommendation of 8 weeks of glecaprevir and pibrentasvir as the ideal treatment duration in treatment-naïve patients with advanced (F3) fibrosis.In the EXPEDITION-2 trial, the SVR12 rate was 100% (22/22) after 8 weeks of glecaprevir/pibrentasvir in patients with genotype 3 infection coinfected with HIV without cirrhosis.
      • Rockstroh J.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 study.
      An integrated analysis of phase II and III trials in patients infected with genotype 3 showed an SVR12 rate of 95% (198/208; 6 virological failures) after 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients infected with genotype 3 without cirrhosis.
      • Flamm S.L.
      • Wyles D.L.
      • Wang S.
      • Mutimer D.J.
      • Rockstroh J.K.
      • Horsmans Y.J.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic HCV genotype 3: an integrated Phase 2/3 analysis.
      In the same integrated analysis of phase II and III trials, the SVR12 rate after 12 weeks of glecaprevir/pibrentasvir in treatment-naïve patients with cirrhosis infected with genotype 3 was 97% (67/69; one virological breakthrough).
      • Flamm S.L.
      • Wyles D.L.
      • Wang S.
      • Mutimer D.J.
      • Rockstroh J.K.
      • Horsmans Y.J.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic HCV genotype 3: an integrated Phase 2/3 analysis.
      In the SURVEYOR-2 study, the SVR12 rates were 91% (20/22; 2 relapses) and 95% (21/22; 1 relapse) in treatment-experienced patients without cirrhosis treated for 12 or 16 weeks, respectively; they were 98% (39/40; no virological failure) in treatment-naïve patients with cirrhosis treated for 12 weeks and 96% (45/47; 2 virological failures) in treatment-experienced patients with cirrhosis treated for 16 weeks.
      • Wyles D.
      • Poordad F.
      • Wang S.
      • Alric L.
      • Felizarta F.
      • Kwo P.Y.
      • et al.
      Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized Phase 3 clinical trial.
      A pooled analysis of phase II and III clinical trials in patients infected with genotype 3 showed SVR12 rates of 96% (258/270) in treatment-naïve patients without cirrhosis treated for 12 weeks, 90% (44/49) in treatment-experienced patients without cirrhosis treated for 12 weeks, 96% (21/22) in treatment-experienced patients without cirrhosis treated for 16 weeks, 99% (64/65) in treatment-naïve patients with compensated cirrhosis treated for 12 weeks, and 94% (48/51) in treatment-experienced patients with compensated cirrhosis treated for 16 weeks.
      • Krishnan P.
      • Schnell G.
      • Tripathi R.
      • Ng T.
      • Reisch T.
      • Beyer J.
      • et al.
      Pooled resistance analysis in HCV genotype 1-6-infected patients treated with glecaprevir/pibrentasvir in Phase 2 and 3 clinical trials.
      Data with 12 weeks of treatment with glecaprevir and pibrentasvir in treatment-experienced patients with cirrhosis are needed.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 3 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir for 12 weeks (B2).
      Comments: This recommendation is based on the results of the POLARIS-2 and -3 phase III trials. In POLARIS-2, which included approximately three-quarters of treatment-naïve and one-quarter of treatment-experienced patients and approximately 20% of individuals with cirrhosis, the SVR12 rate was 99% (91/92; no virological failure) after 8 weeks of the triple combination of sofosbuvir, velpatasvir and voxilaprevir.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 Phase 3 randomized trials.
      In POLARIS-3, 8 weeks of the triple combination yielded a 96% SVR12 rate (106/110; 2 relapses) in treatment-naïve and treatment-experienced patients with compensated cirrhosis.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 Phase 3 randomized trials.
      Because genotype 3 is more difficult-to-cure than other genotypes, and in the absence of data with 12 weeks of therapy, it appears to be safer to treat patients with genotype 3 infection who have cirrhosis for 12 weeks with this combination.

       Treatment of HCV genotype 4 infection

      Four treatment options are available in 2018 for patients infected with HCV genotype 4 (Table 6, Table 7, Table 8). These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/ledipasvir.
      • Grazoprevir/elbasvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 4, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of grazoprevir (100 mg) and elbasvir (50 mg) in a single tablet administered once daily.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 4, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (A1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-1 trial in patients with HCV genotype 4 infection (23% with cirrhosis, 55% treatment-naïve, 45% treatment-experienced) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin, showing SVR12 in 100% (116/116) of patients.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      In the ASTRAL-5 trial in HIV-coinfected patients receiving the same treatment regimen, the SVR12 rate was 100% (4/4).
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-lLabel, Phase 3 study.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 4 without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (A1).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 4 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (A1).
      Comments: This recommendation is partly based on the results of the phase II SURVEYOR-2 trial showing an SVR12 rate of 93% (43/46; no virological failure) in treatment-naïve and treatment-experienced patients without cirrhosis infected with HCV genotype 4 receiving the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis.
      In ENDURANCE-4, genotype 4 patients without cirrhosis treated for 12 weeks achieved SVR in 99% (75/76; no virological failures) of cases,
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      whereas in EXPEDITION-1, 100% (16/16) of patients with cirrhosis infected with genotype 4 achieved SVR12.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      In the EXPEDITION 2 trial, the SVR12 rate was 100% (16/16) after 8 weeks of glecaprevir/pibrentasvir in patients with genotype 4 infection coinfected with HIV without cirrhosis.
      • Rockstroh J.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 study.
      • Treatment-naïve patients infected with HCV genotype 4, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 weeks (B1).
      • The combination of sofosbuvir and ledipasvir is not recommended in treatment-experienced patients infected with genotype 4 (B1).
      Comments: The SYNERGY trial assessed the efficacy and safety of the combination of sofosbuvir and ledipasvir in patients with genotype 4 infection. After 12 weeks of therapy, 95% (20/21; no virological failure) of them achieved an SVR.
      • Kohli A.
      • Kapoor R.
      • Sims Z.
      • Nelson A.
      • Sidharthan S.
      • Lam B.
      • et al.
      Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label Phase 2a cohort study.
      In another phase II trial, patients were treated with the combination of sofosbuvir and ledipasvir for 12 weeks. The SVR12 rates were 96% (21/22) in treatment-naïve and 91% (20/22) in treatment-experienced individuals; the split was 91% (31/34) in patients without cirrhosis and 100% (10/10) in those with cirrhosis.
      • Abergel A.
      • Metivier S.
      • Samuel D.
      • Jiang D.
      • Kersey K.
      • Pang P.S.
      • et al.
      Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection.
      • Treatment-naïve patients infected with genotype 4, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, with an HCV RNA level ≤800,000 IU/ml (5.9 Log10 IU/ml) at baseline should be treated with the fixed-dose combination of grazoprevir and elbasvir for 12 weeks (A1).
      • The combination of grazoprevir and elbasvir is not recommended in patients infected with genotype 4 who are treatment-naïve with an HCV RNA level >800,000 IU/ml (5.9 Log10 IU/ml), or treatment-experienced regardless of their baseline HCV RNA level (A1).
      Comments: This recommendation is based on the results of three phase III trials including a small number of patients infected with genotype 4 and on the analogy with data in patients infected with genotype 1. In the C-EDGE-TN trial, the SVR12 rate was 100% (18/18) in treatment-naïve patients infected with genotype 4 receiving grazoprevir and elbasvir for 12 weeks (including 12% with cirrhosis).
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial.
      In the open-label C-EDGE-COINFECTION trial, treatment-naïve patients with HCV genotype 4 coinfected with HIV, with or without compensated cirrhosis, were treated with grazoprevir and elbasvir for 12 weeks. The SVR12 rate was 96% (27/28; one relapse).
      • Rockstroh J.K.
      • Nelson M.
      • Katlama C.
      • Lalezari J.
      • Mallolas J.
      • Bloch M.
      • et al.
      Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial.
      In the C-CORAL trial, 3/3 treatment-naïve patients infected with genotype 4 achieved an SVR12 after 12 weeks of grazoprevir/elbasvir.
      • Wei L.J.
      • Zhdanov K.
      • Burnevich E.
      • Sheen I.S.
      • Heo J.
      • Nguyen V.K.
      • et al.
      Efficacy and safety of elbasvir/grazoprevir in treatment-naïve patients with chronic HCV GT 1, GT 4 and GT 6 infection (C-CORAL): a Phase III randomized multinational clinical trial.
      The SVR12 rate was 100% (11/11) in the C-EDGE CO-STAR trial in PWIDs on opioid substitution therapy receiving the same treatment regimen.
      • Dore G.J.
      • Altice F.
      • Litwin A.H.
      • Dalgard O.
      • Gane E.J.
      • Shibolet O.
      • et al.
      Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial.

       Treatment of HCV genotype 5 infection

      Three treatment options are available in 2018 for patients infected with HCV genotype 5 (Table 6, Table 7, Table 8). However, the number of patients infected with genotype 5 treated in all of the trials was limited, making it difficult to make strong recommendations once the data are broken down by cirrhosis and prior treatment. These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/ledipasvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 5, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg) in a single tablet administered once daily.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 5, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (B1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-1 trial in patients with HCV genotype 5 (14% with cirrhosis, 69% treatment-naïve, 31% treatment-experienced) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, showing SVR12 in 97% (34/35) of them.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 5 without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (B1).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 5 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (B1).
      Comments: This recommendation is based on the results of the phase II SURVEYOR-2 trial in which 2/2 patients without cirrhosis infected with HCV genotype 5 receiving the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks achieved an SVR12.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis.
      In ENDURANCE-4, genotype 5 patients without cirrhosis treated for 12 weeks achieved SVR in 100% (26/26) of cases,
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      whereas in EXPEDITION-1, 2/2 patients infected with genotype 5 with cirrhosis achieved SVR12.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      • Treatment-naïve patients infected with HCV genotype 5 without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the combination of sofosbuvir and ledipasvir for 12 weeks (B1).
      • The combination of sofosbuvir and ledipasvir is not recommended in treatment-experienced patients infected with genotype 5 (B1).
      Comments: In a phase II trial, 41 treatment-naïve and treatment-experienced patients infected with HCV genotype 5, including 9 with compensated cirrhosis, were treated with sofosbuvir and ledipasvir without ribavirin for 12 weeks: 95% (39/41) achieved SVR12.
      • Abergel A.
      • Asselah T.
      • Metivier S.
      • Kersey K.
      • Jiang D.
      • Mo H.
      • et al.
      Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.

       Treatment of HCV genotype 6 infection

      Three treatment options are available in 2018 for patients infected with HCV genotype 6 (Table 6, Table 7, Table 8). However, the number of patients infected with genotype 6 treated in all of the trials was limited, making it difficult to make strong recommendations once the data are broken down by cirrhosis and prior treatment. These options are considered equivalent, and their order of presentation does not indicate any superiority or preference, unless specified:
      • Sofosbuvir/velpatasvir.
      • Glecaprevir/pibrentasvir.
      • Sofosbuvir/ledipasvir.
      • The following regimens are recommended for the treatment of patients infected with genotype 6, according to the below recommendations (A1):
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • o
          the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in three tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • o
          the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg) in a single tablet administered once daily.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 6, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks (B1).
      Comments: This recommendation is based on the results of the phase III ASTRAL-1 trial in patients with HCV genotype 6 (15% with cirrhosis, 93% treatment-naïve, 17% treatment-experienced) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin, of whom 100% (41/41) achieved SVR12.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV gGenotype 1, 2, 4, 5, and 6 infection.
      These results were confirmed by a 97% (35/36; one relapse) SVR rate in a phase III trial in patients infected with genotype 6 from Singapore, Malaysia, Thailand and Vietnam.
      • Lim S.G.
      • Mohamed R.
      • Le P.
      • Tee H.P.
      • McNabb B.L.
      • Lu S.
      • et al.
      Safety and efficacy of sofosbuvir/velpatasvir in a genotype 1–6 HCV-infected population from Singapore, Malaysia, Thailand, and Vietnam: results from a Phase 3 clinical trial.
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 6 without cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks (B1).
      • Treatment-naïve and treatment-experienced patients infected with HCV genotype 6 with compensated (Child-Pugh A) cirrhosis should be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks (B1).
      Comments: This recommendation is partly based on the results of the phase II SURVEYOR-2 trial, showing an SVR12 rate of 90% (9/10; no virological failure) in treatment-naïve and treatment-experienced patients infected with HCV genotype 6 without cirrhosis, who received the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis.
      In ENDURANCE-4, genotype 6 patients without cirrhosis treated for 12 weeks achieved SVR in 100% (19/19) of cases,
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      whereas in EXPEDITION-1, 100% (7/7) of patients infected with genotype 6 with cirrhosis achieved SVR12.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      In the EXPEDITION 2 trial, the SVR12 rate was 3/3 after 8 weeks of glecaprevir/pibrentasvir in patients with genotype 6 infection and HIV coinfection without cirrhosis.
      • Rockstroh J.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 study.
      • Treatment-naïve patients infected with HCV genotype 6, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the combination of sofosbuvir and ledipasvir for 12 weeks (B1).
      • The combination of sofosbuvir and ledipasvir is not recommended in treatment-experienced patients infected with genotype 6 (B1).
      Comments: The combination of sofosbuvir and ledipasvir administered for 12 weeks without ribavirin, in treatment-naïve and treatment-experienced patients infected with genotype 6, yielded an SVR rate of 96% (24/25).
      • Gane E.J.
      • Hyland R.H.
      • An D.
      • Svarovskaia E.
      • Pang P.S.
      • Brainard D.
      • et al.
      Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection.

      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 chapter.
      The availability of new pangenotypic regimens now provides healthcare practitioners worldwide with the opportunity to considerably simplify, and thereby facilitate, treatment access while reducing its cost. Indeed, the use of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for 12 weeks in all patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis, including treatment-naïve or treatment-experienced patients (as defined above) is expected to yield an SVR12 rate above 95%. The only information needed to start treatment with one of these regimens is the presence of HCV replication (as assessed by HCV RNA or HCV core antigen testing, as described above) and possible drug-drug interactions. The presence of advanced fibrosis (F3) or cirrhosis (F4) must be checked prior to therapy as it will determine whether the patient needs post-treatment surveillance for HCC, provided that treatment for HCC is available. A simple non-invasive marker score, such as FIB-4 or APRI, can be used for that purpose (see above, Table 2). A universal duration of 12 weeks ensures that this information is not needed to choose the treatment regimen. However, if the information is available and reliable, the combination of glecaprevir and pibrentasvir can be used for 8 weeks instead of 12 weeks in treatment-naïve patients without cirrhosis.
      Licensed generic drugs and drugs agreed with the Medicines Patent Pool have been shown to generate similar results to the original compounds.
      • Freeman J.A.
      • Hill A.
      The use of generic medications for hepatitis C.
      The presence of the drug at the appropriate dosage must be verified by the provider and guaranteed to the prescriber and patient. Indeed, effective and safe generics are a crucial resource in resource-limited countries.
      • Simplified, pangenotypic anti-HCV treatment recommendations are now possible, thanks to the approval of highly efficacious, safe and well-tolerated pangenotypic anti-HCV drug regimens (B1).
      • Pre-treatment assessment can be limited to proof of HCV replication (presence of HCV RNA or of HCV core antigen in serum or plasma) and the assessment of the presence or absence of cirrhosis by means of a simple non-invasive marker (such as FIB-4 or APRI) that determines whether the patient needs post-treatment follow-up (B1).
      • Treatment-naïve and treatment-experienced patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis can be treated with either the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, or the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks without testing genotype (B1).
      • If cirrhosis can be reliably excluded by means of a non-invasive marker in treatment-naïve patients, the combination of glecaprevir and pibrentasvir can be administered for 8 weeks only (A1).
      • Generic drugs can be used, provided that quality controls are met and guaranteed by the provider (A1).
      • Possible drug-drug interactions should be carefully checked and dose modifications implemented when necessary (A1).
      • Given the high SVR12 rates expected with these regimens across all groups of patients if adherent, checking SVR12 12 weeks after the end of treatment is dispensable (B1).
      • Patients with high-risk behaviours and risk of reinfection should be tested for SVR12 and yearly thereafter whenever possible (B1).
      • In patients with advanced fibrosis (F3) or compensated cirrhosis (F4), post-SVR surveillance for the diagnosis of HCC and linkage to care must be provided when treatment for HCC is available (A1).

      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.
      • 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 (A1).
      • Protease inhibitor-containing regimens are contraindicated in patients with decompensated (Child-Pugh B or C) cirrhosis (A1).

       Patients with decompensated cirrhosis, no HCC, with an indication for liver transplantation

      Liver transplantation is the treatment of choice for patients with end-stage liver disease. Hepatitis C recurrence because of graft infection is universal after transplantation in the absence of prevention,
      • Garcia-Retortillo M.
      • Forns X.
      • Feliu A.
      • Moitinho E.
      • Costa J.
      • Navasa M.
      • et al.
      Hepatitis C virus kinetics during and immediately after liver transplantation.
      and the life of the graft and survival are reduced in patients with recurrent hepatitis C.
      Treatment of HCV infection pre-transplant in patients awaiting liver transplantation has two complementary goals: preventing liver graft infection after transplantation by achieving viral clearance, and stabilising or improving liver function before transplantation. In some regions, treatment of HCV infection increases access to marginal grafts which may not be made available to patients with ongoing HCV infection. Prevention of liver graft infection substantially facilitates post-transplant management. In addition, improvement of liver function denotes delisting of some patients.
      • Gane E.
      • Pilmore H.
      Management of chronic viral hepatitis before and after renal transplantation.
      However, with the exception of living-donor grafts, the duration of antiviral therapy is unpredictable in a patient on the waiting list, so the patient may be transplanted before the virus has been cleared. In addition, if delisted, the patient will keep a diseased liver with the risk of subsequent decompensation, HCC occurrence and death, potentially foregoing the opportunity to cure the liver disease and the infection, because cure of HCV infection can be achieved by therapy in the vast majority of patients after transplantation.
      The use of protease inhibitors is contraindicated in patients with Child-Pugh B and C decompensated cirrhosis, because of substantially higher drug exposure, which is associated with toxicities in these patients. Protease inhibitors should also not be used in patients with compensated cirrhosis and a history of prior decompensation, as cases of decompensation have been reported on treatment.
      • Wedemeyer H.
      • Craxi A.
      • Zuckerman E.
      • Dieterich D.
      • Flisiak R.
      • Roberts S.K.
      • et al.
      Real-world effectiveness of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: a meta-analysis.
      Thus, treatment of patients with decompensated cirrhosis on the transplant list should be based on the combination of sofosbuvir and an NS5A inhibitor, namely sofosbuvir/ledipasvir or sofosbuvir/velpatasvir. If these regimens are not available, the combination of sofosbuvir and daclatasvir remains an acceptable option, according to the EASL Recommendations for Treatment of Hepatitis C 2016.
      • European Association for the Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2016.
      In the SOLAR-1 trial, patients infected with genotype 1 or 4 with decompensated cirrhosis were treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 or 24 weeks with ribavirin. In Child-Pugh B patients, the SVR12 rates were 87% (26/30) and 89% (24/27) after 12 and 24 weeks of therapy, respectively; in Child-Pugh C patients, they were 86% (19/22) and 87% (20/23) after 12 and 24 weeks of therapy, respectively. The MELD and Child-Pugh scores improved in approximately half of treated patients.
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr, R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease.
      The design of the SOLAR-2 trial was identical in patients infected with genotype 1 or 4 with decompensated cirrhosis who received the same treatment regimens. The SVR12 rates were 87% (20/23) and 96% (22/23) after 12 and 24 weeks of therapy, respectively, in Child-Pugh B patients; they were 85% (17/20) and 78% (18/23) after 12 and 24 weeks of therapy, respectively, in Child-Pugh C patients. The MELD and Child-Pugh scores improved in approximately half of treated patients.
      • Manns M.
      • Samuel D.
      • Gane E.J.
      • Mutimer D.
      • McCaughan G.
      • Buti M.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
      The lower SVR rates in patients with decompensated cirrhosis as compared to patients with compensated cirrhosis in other studies were due to treatment discontinuations rather than virological failures. Despite the early improvement in MELD score, long-term data are limited to determine whether SVR is associated with clinical improvement in these patients.
      In a real-world study based on the United Kingdom early access program, patients with decompensated cirrhosis infected with HCV genotype 1 were treated with sofosbuvir and ledipasvir, or with sofosbuvir and daclatasvir, for 12 weeks with or without ribavirin. The SVR12 rates were: 85% (11/13) after 12 weeks of sofosbuvir and ledipasvir without ribavirin; 91% (136/149) after 12 weeks of sofosbuvir and ledipasvir with ribavirin; 50% (2/4) after 12 weeks of sofosbuvir and daclatasvir without ribavirin; and 88% (30/34) after 12 weeks of sofosbuvir and daclatasvir with ribavirin. However, in patients with decompensated cirrhosis infected with genotype 3, the SVR12 rates were 60% (3/5) after 12 weeks of sofosbuvir and daclatasvir without ribavirin and 71% (75/105) after 12 weeks of sofosbuvir and daclatasvir with ribavirin.
      • Foster G.R.
      • Irving W.L.
      • Cheung M.C.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • et al.
      Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.
      Approximately one-third of patients improved their MELD scores, one-third had no change, and one-third suffered deteriorating liver function 12 weeks after treatment. Improvement in MELD score was more frequent in treated than in untreated patients. The proportion of patients with at least one decompensating event during the study period (baseline to week 12 post-treatment) was reduced in the treated compared to untreated group, apart from the subgroup with a baseline MELD score ≥15. Rates of new decompensation in patients with recompensated disease at baseline were significantly lower in the treated cohort (4% vs. 10%).
      • Foster G.R.
      • Irving W.L.
      • Cheung M.C.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • et al.
      Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis.
      Longer-term follow-up of the same group of patients confirmed that treatment was clinically beneficial in patients with advanced liver disease.
      • Cheung M.C.M.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • McLauchlan J.
      • Mutimer D.J.
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      When considering the two SOLAR studies and the United Kingdom early access program study together, the proportion of patients who substantially improved their MELD scores after achieving SVR was modest. Only 24% (10/42) of patients with Child-Pugh B and 38% (13/34) of patients with Child-Pugh C cirrhosis had a MELD score improvement ≥3 points 12 weeks after the end of treatment when pooling results from SOLAR-1 and SOLAR-2. These results were comparable to those found in the United Kingdom early access program real-world study, showing MELD score improvements in only 17% (15/88) and 33% (3/9) of patients with Child-Pugh B and C cirrhosis, respectively.
      • Charlton M.R.
      • Cheung M.C.
      • Manns M.P.
      • Sajed N.
      • Troke P.
      • Spellman J.G.
      • et al.
      Ledipasvir/sofosbuvir + ribavirin (LDV/SOF + RBV) for 12 weeks in decompensated HCV genotype 1 patients: SOLAR-1 and -2 studies compared to a real-world dataset.
      In the ASTRAL-4 study, patients with Child-Pugh B decompensated cirrhosis infected with genotypes 1 to 4 were randomized to receive the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin, for 12 weeks with weight-based dosed ribavirin, or for 24 weeks without ribavirin. The SVR12 rates with these three treatment regimens, respectively, were: 88% (44/50), 94% (51/54) and 93% (51/55) in patients with genotype 1a infection; 89% (16/18), 100% (14/14) and 88% (14/16) in patients with genotype 1b infection; 100% (4/4), 100% (4/4) and 75% (3/4) in patients with genotype 2 infection; 50% (7/14), 85% (11/13) and 50% (6/12) in patients with genotype 3 infection; 100% (4/4), 100% (2/2) and 100% (2/2) in patients with genotype 4 infection. No arm with sofosbuvir, velpatasvir and ribavirin for 24 weeks was included in the study.
      • Curry M.P.
      • O'Leary J.G.
      • Bzowej N.
      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      Of the patients with a baseline MELD score <15, 51% (114/223) had an improved MELD score at week 12 post-treatment, 22% (49/223) had no change in their MELD score, and 27% (60/223) had a worse MELD score. Of the patients who had a baseline MELD score ≥15, 81% (22/27) had an improved MELD score, 11% (3/27) had no change in their MELD score, and 7% (2/27) had a worse MELD score.
      • Curry M.P.
      • O'Leary J.G.
      • Bzowej N.
      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      In these studies, the median MELD score improvement was 2 points (range: 1–17), not always followed by clinical improvement. Importantly, data are almost non-existent for patients with the most advanced forms of disease (Child-Pugh score >12 or MELD score >20), who were excluded from the studies.
      Several studies assessed whether achieving an SVR prior to liver transplantation would lead to patients being removed from the transplantation list. In a multicentre European real-world study of patients receiving IFN-free, DAA-based therapy followed for a median duration of 52 weeks (interquartile range 33–67), 40% (41/103) of patients were transplanted, whereas only 20% (21/103) were delisted and an additional 13% (13/103) were put on hold. Patients with lower MELD scores were more likely to be delisted, while the median MELD score evolved from 15.5 to 14.0 (p = 0.0008) from start of DAA therapy to 24 weeks afterwards.
      • Belli L.S.
      • Berenguer M.
      • Cortesi P.A.
      • Strazzabosco M.
      • Rockenschaub S.R.
      • Martini S.
      • et al.
      Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study.
      Among the 23.9% of patients who were delisted because of clinical improvement and followed-up for a median duration of 58 weeks, only 8.8% (3/34) had to be relisted because of re-decompensation. No HCC occurred.
      • Belli L.S.
      • Berenguer M.
      • Cortesi P.A.
      • Facchetti R.
      • Strazzabosco M.
      • Perricone G.
      • et al.
      Delisting of liver transplant candidates with chronic hepatitis C virus infection after viral eradication: outcome after delisting: a European study.
      In a French cohort study, including 18 transplant centres with a mean follow-up of 68 weeks (range: 12–95 weeks), 18% of patients (14/77) were delisted and 16% (12/77) improved.
      • Coilly A.
      • Pageaux G.P.
      • Houssel-Debry P.
      • Duvoux C.
      • Radenne S.
      • De Ledinghen V.
      • et al.
      Improving liver function and delisting of patients awaiting liver transplantation for HCV cirrhosis: do we ask too much to DAAs?.
      In a similar Spanish study, 24% (29/122) of patients were delisted after DAA-based therapy. No patients with a baseline MELD score >20 were delisted.
      • Pascasio J.M.
      • Vinaixa C.
      • Ferrer M.T.
      • Colmenero J.
      • Rubin A.
      • Castells L.
      • et al.
      Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.
      Overall, the short-term benefits observed must be balanced with the respective risks of death on the waiting list and likelihood of transplantation. A recent US study combining real data and modelling suggested that treating HCV before instead of after liver transplantation would only increase life expectancy in patients with a MELD score ≤23–27, depending on the United Network for Organ Sharing region. Above a MELD score of 20, the life expectancy benefit of treating before liver transplantation in the model was always less than one year, arguing for transplanting individuals with very severe disease prior to HCV therapy.
      • Chhatwal J.
      • Samur S.
      • Kues B.
      • Ayer T.
      • Roberts M.S.
      • Kanwal F.
      • et al.
      Optimal timing of hepatitis C treatment for patients on the liver transplant waiting list.
      Finally, pre-liver transplantation treatment was reported to be cost-effective for patients without HCC with a MELD score ≤20, while antiviral treatment after liver transplantation was cost-effective in patients with a MELD score >20.
      • Cortesi P.A.
      • Belli L.S.
      • Facchetti R.
      • Mazzarelli C.
      • Perricone G.
      • De Nicola S.
      • et al.
      The optimal timing of hepatitis C therapy in liver transplant-eligible patients: cost-effectiveness analysis of new opportunities.
      • Patients with decompensated (Child-Pugh B or C) cirrhosis should be treated in experienced centres with easy access to liver transplantation and close monitoring during therapy is required, with the possibility of stopping therapy with evidence of worsening decompensation during treatment (A1).
      • Patients with decompensated (Child-Pugh B or C) cirrhosis, without HCC, awaiting liver transplantation with a MELD score <18–20 should be treated prior to liver transplantation. Treatment should be initiated as soon as possible in order to complete a full treatment course before transplantation and assess the effect of SVR on liver function, because significant improvement in liver function may lead to delisting in selected cases (A1).
      • Protease inhibitors-containing regimens are contraindicated in patients with decompensated (Child-Pugh B or C) cirrhosis (A1).
      • Patients with decompensated (Child-Pugh B or C) cirrhosis, without HCC, awaiting liver transplantation with a MELD score <18–20 can be treated with sofosbuvir and ledipasvir (genotypes 1, 4, 5 and 6), or with sofosbuvir and velpatasvir (all genotypes), with daily weight-based ribavirin (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively) for 12 weeks (A1).
      • In patients with decompensated (Child-Pugh B or C) cirrhosis without HCC awaiting liver transplantation with a MELD score <18–20 treated with sofosbuvir and ledipasvir with ribavirin, or with sofosbuvir and velpatasvir with ribavirin, ribavirin can be started at the dose of 600 mg daily and the dose subsequently adjusted depending on tolerance (B1).
      • Patients with decompensated (Child-Pugh B or C) cirrhosis with contraindications to the use of ribavirin or with poor tolerance to ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5 or 6), or the fixed-dose combination of sofosbuvir and velpatasvir (all genotypes), for 24 weeks without ribavirin (A1).
      • The higher risk of adverse events reported in patients with decompensated cirrhosis awaiting liver transplantation necessitates appropriately frequent clinical and laboratory assessments during and after HCV therapy (B1).
      • Patients with decompensated cirrhosis without HCC awaiting liver transplantation with a MELD score ≥18–20 should be transplanted first, without antiviral treatment. HCV infection should be treated after liver transplantation (B1).
      • Patients with decompensated cirrhosis without HCC awaiting liver transplantation with a MELD score ≥18–20 can be treated before transplantation if the waiting time on the transplant list exceeds 6 months, depending on the local situation (B2).

       Patients with HCC, without cirrhosis or with compensated cirrhosis, with an indication for liver transplantation

      In patients with HCC, without cirrhosis or with compensated cirrhosis, who have an indication for liver transplantation, the ideal timing for antiviral therapy (before or after liver transplantation) remains debated.
      • Beste L.A.
      • Green P.K.
      • Berry K.
      • Kogut M.J.
      • Allison S.K.
      • Ioannou G.N.
      Reply to: “Direct-acting antiviral therapy in patients with hepatocellular cancer: the timing of treatment is everything” and “More extended indication of DAA therapy in patients with HCC, affordability, and further statistical considerations”.
      • Mazzarelli C.
      • Cannon M.D.
      • Belli L.S.
      • Agarwal K.
      Direct-acting antiviral therapy in patients with hepatocellular cancer: the timing of treatment is everything.
      Lower SVR rates were reported in patients with HCC treated with regimens including sofosobuvir, sofosbuvir and ledipasvir, or ombitasvir and ritonavir-boosted paritaprevir plus dasabuvir, with or without ribavirin, than in patients without HCC or in patients with HCC treated after liver transplantation (74% vs. 91% and 94%, respectively).
      • Beste L.A.
      • Green P.K.
      • Berry K.
      • Kogut M.J.
      • Allison S.K.
      • Ioannou G.N.
      Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma.
      Post-liver transplantation treatment of HCV was reported to be cost-effective in patients with HCC.
      • Cortesi P.A.
      • Belli L.S.
      • Facchetti R.
      • Mazzarelli C.
      • Perricone G.
      • De Nicola S.
      • et al.
      The optimal timing of hepatitis C therapy in liver transplant-eligible patients: cost-effectiveness analysis of new opportunities.
      In patients with HCC, without cirrhosis or with compensated cirrhosis, who have an indication for liver transplantation, pre- or post-liver transplant antiviral treatment indications are similar to those in patients who do not have HCC, and depend on the HCV genotype, prior therapy and severity of liver disease (see general recommendations).
      • In patients with HCC awaiting liver transplantation with an HCV infection, liver transplantation must be considered as the main therapeutic goal and the antiviral treatment decision must be made on a case-by-case basis through a multidisciplinary discussion (A1).
      • Antiviral treatment can be initiated before liver transplantation to prevent recurrence of infection and post-transplant complications, provided that it does not interfere with the management of the patient on the waiting list (A2).
      • Antiviral treatment can be delayed until after transplantation, with a high likelihood of SVR (A2).
      • Patients with HCC without cirrhosis or with compensated (Child-Pugh A) cirrhosis awaiting liver transplantation should be treated, prior to or after liver transplantation, according to the general recommendations in patients without HCC (A1).

       Post-liver transplantation recurrence

      Recurrence of HCV infection is universal in patients with detectable HCV RNA at the time of liver transplantation.
      • Garcia-Retortillo M.
      • Forns X.
      • Feliu A.
      • Moitinho E.
      • Costa J.
      • Navasa M.
      • et al.
      Hepatitis C virus kinetics during and immediately after liver transplantation.
      The course of HCV-related liver disease is accelerated in liver transplant recipients and approximately one-third of them develop cirrhosis within 5 years following transplantation.
      • Forman L.M.
      • Lewis J.D.
      • Berlin J.A.
      • Feldman H.I.
      • Lucey M.R.
      The association between hepatitis C infection and survival after orthotopic liver transplantation.
      • Prieto M.
      • Berenguer M.
      • Rayon J.M.
      • Cordoba J.
      • Arguello L.
      • Carrasco D.
      • et al.
      High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes.
      • Berenguer M.
      • Ferrell L.
      • Watson J.
      • Prieto M.
      • Kim M.
      • Rayon M.
      • et al.
      HCV-related fibrosis progression following liver transplantation: increase in recent years.
      • Samuel D.
      • Forns X.
      • Berenguer M.
      • Trautwein C.
      • Burroughs A.
      • Rizzetto M.
      • et al.
      Report of the Monothematic EASL Conference on liver transplantation for viral hepatitis (Paris, France, January 12–14, 2006).
      Overall, graft survival is 30% lower in HCV-infected compared to non-HCV-infected liver transplant recipients, because of recurrent HCV disease, but also extra-hepatic manifestations of HCV infection, management issues and complications of immunosuppression. Cure of HCV infection following liver transplantation has been shown to significantly improve post-transplant survival.
      • Berenguer M.
      • Palau A.
      • Aguilera V.
      • Rayon J.M.
      • Juan F.S.
      • Prieto M.
      Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation.
      • Picciotto F.P.
      • Tritto G.
      • Lanza A.G.
      • Addario L.
      • De Luca M.
      • Di Costanzo G.G.
      • et al.
      Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation.
      Patients with fibrosing cholestatic hepatitis and patients with moderate to extensive fibrosis or portal hypertension one year after transplantation are at high risk of graft loss, and require urgent antiviral therapy.
      • Blasco A.
      • Forns X.
      • Carrion J.A.
      • Garcia-Pagan J.C.
      • Gilabert R.
      • Rimola A.
      • et al.
      Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation.
      • Neumann U.P.
      • Berg T.
      • Bahra M.
      • Seehofer D.
      • Langrehr J.M.
      • Neuhaus R.
      • et al.
      Fibrosis progression after liver transplantation in patients with recurrent hepatitis C.
      In the SOLAR-1 trial, transplant recipients with HCV genotype 1 or 4 recurrence were treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 or 24 weeks with ribavirin. In patients treated for 12 weeks with ribavirin, the SVR12 rates were 96% (53/55) in those without cirrhosis, 96% (25/26) in those with compensated (Child-Pugh A) cirrhosis, 85% (22/26) in those with decompensated Child-Pugh B cirrhosis, and 60% (3/5) in those with Child-Pugh C decompensated cirrhosis. The SVR12 rates were not higher in patients treated for 24 weeks with ribavirin: 98% (55/56), 96% (24/25), 88% (23/26), and 75% (3/4), respectively.
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr, R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease.
      Similar results were reported in the SOLAR-2 study in patients with genotype 1 receiving the same treatment regimens. In patients treated for 12 weeks with ribavirin, the SVR12 rates were 93% (42/45) in patients without cirrhosis, 100% (30/30) in those with compensated (Child-Pugh A) cirrhosis, 95% (19/20) in those with Child-Pugh B decompensated cirrhosis, and 50% (1/2) in those with Child-Pugh C decompensated cirrhosis. In patients treated for 24 weeks, the SVR12 rates were: 100% (44/44), 96% (27/28), 100% (20/20), and 80% (4/5), respectively. Twenty-five of the 27 patients infected with genotype 4 (93%) achieved SVR12.
      • Manns M.
      • Samuel D.
      • Gane E.J.
      • Mutimer D.
      • McCaughan G.
      • Buti M.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
      In another study, liver transplant recipients with HCV recurrence were treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin. The global SVR12 rate was 96% (76/79; 2 relapses). One genotype 1a patient out of 15 and one genotype 3 patient out of 35 relapsed.
      • Agarwal K.
      • Castells L.
      • Mullhaupt B.
      • Rosenberg W.M.
      • McNabb B.L.
      • Arterburn S.
      • et al.
      Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients.
      A number of real-world studies reported high SVR rates after treating liver transplant recipients with HCV recurrence with the combination of sofosbuvir and ledipasvir with or without ribavirin. Whether ribavirin is needed in all patients after liver transplantation in combination with sofosbuvir and ledipasvir, or with sofosbuvir and velpatasvir, remains to be determined.
      Because of frequent drug-drug interactions and the need for immunosuppressant drug dose adjustments, treatment regimens including a protease inhibitor are not optimal for HCV treatment post-liver transplantation. However, in liver transplant recipients with impaired kidney function, the combination of glecaprevir and pibrentasvir for 12 weeks is an alternative to sofosbuvir-based regimens. In the MAGELLAN-2 study, 80 liver and 20 kidney transplant recipients on a stable immunosuppressive regimen were included. Prednisone/prednisolone was permitted at ≤10 mg/day and cyclosporine A at ≤100 mg/day at the time of screening. All but one patients achieved SVR12.
      • Reau N.
      • Kwo P.Y.
      • Rhee S.
      • Brown R.S.
      • Agarwal K.
      • Angus P.
      • et al.
      MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection.
      • All patients with post-transplant recurrence of HCV infection should be considered for therapy (A1).
      • Treatment should be initiated early after liver transplantation, ideally as early as possible when the patient is stabilised (generally after the first 3 months post-transplant), because the SVR12 rates diminish in patients with advanced post-transplant liver disease (A1).
      • Fibrosing cholestatic hepatitis or the presence of moderate to extensive fibrosis or portal hypertension one year after transplantation indicate urgent antiviral treatment because they predict rapid disease progression and graft loss (A1).
      • Immunosuppressant drug levels during and after anti-HCV therapy must be monitored (A1).
      • Patients with post-transplant HCV recurrence without cirrhosis, with compensated (Child-Pugh A) cirrhosis or with decompensated (Child-Pugh B or C) cirrhosis can be treated with the fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5 or 6), or with the fixed-dose combination of sofosbuvir and velpatasvir (all genotypes) (A1).
      • Patients with post-transplant recurrence of HCV genotype 1, 4, 5 or 6 infection, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and ledipasvir or the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, without the need for pre-treatment immunosuppressant drug dose adjustments (A1).
      • Patients with post-transplant recurrence of HCV genotype 2 or 3, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, without the need for pre-treatment immunosuppressant drug dose adjustments (A1).
      • Patients with post-transplant recurrence of all HCV genotypes, without cirrhosis or with compensated (Child-Pugh A) cirrhosis, with an eGFR <30 ml/min/1.73 m2 can be treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks. Immunosuppressant drug levels need to be monitored and adjusted as needed during and after the end of treatment (B1).
      • Patients with post-transplant HCV recurrence with decompensated (Child-Pugh B or C) cirrhosis should be treated with the fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5 or 6), or with the fixed-dose combination of sofosbuvir and velpatasvir (all genotypes), for 12 weeks with daily weight-based ribavirin (1,000 or 1,200 mg in patients <75 kg or ≥75 kg, respectively). In these patients, ribavirin can be started at the dose of 600 mg daily and the dose subsequently adjusted depending on tolerance (B1).
      • Patients with decompensated (Child-Pugh B or C) cirrhosis and contraindications for ribavirin, or with poor tolerance to ribavirin on treatment, should be treated with the fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5 or 6) or the fixed-dose combination of sofosbuvir and velpatasvir (all genotypes) for 24 weeks without ribavirin (B1).

       Patients with decompensated cirrhosis without an indication for liver transplantation

      The main goal of anti-HCV therapy in patients with decompensated (Child-Pugh B or C) cirrhosis not on a transplant waiting list is to achieve improvement in liver function and survival. Several studies have demonstrated acceptably high SVR rates, equivalent in Child-Pugh B and C patients, in individuals with decompensated cirrhosis, together with an effect of therapeutic viral clearance on liver function, with significant improvements in bilirubin, albumin and international normalized ratio values and, as a result, in MELD and Child-Pugh scores in one-third to half of patients.
      • Charlton M.
      • Everson G.T.
      • Flamm S.L.
      • Kumar P.
      • Landis C.
      • Brown Jr, R.S.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease.
      • Manns M.
      • Samuel D.
      • Gane E.J.
      • Mutimer D.
      • McCaughan G.
      • Buti M.
      • et al.
      Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial.
      • Curry M.P.
      • O'Leary J.G.
      • Bzowej N.
      • Muir A.J.
      • Korenblat K.M.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
      • Flamm S.L.
      • Everson G.T.
      • Charlton M.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
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