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EASL Recommendations on Treatment of Hepatitis C 2015

  • European Association for the Study of the Liver
Open AccessPublished:April 21, 2015DOI:https://doi.org/10.1016/j.jhep.2015.03.025

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      • Debilitating fatigue as a treatment indication in chronic hepatitis C
        Journal of HepatologyVol. 63Issue 6
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          According to the latest EASL recommendations on the treatment of hepatitis C (HCV) [1], patients with “debilitating fatigue” are to be prioritized regarding treatment candidature citing an A1 level recommendation, this corresponds to a strong recommendation upon high quality evidence, and as such “Further research is very unlikely to change our confidence in the estimate of effect”. We have several concerns regarding this position.
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      • Reply to “Debilitating fatigue as a treatment indication in chronic hepatitis C”
        Journal of HepatologyVol. 63Issue 6
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          We thank Hjerrild et al. for their comment about the recently released EASL Recommendations on Treatment of Hepatitis C 2015 [1]. The recommendations take into account that, in addition to the direct hepatic consequences of chronic hepatitis C virus (HCV) infection, there is a large published literature detailing the association of chronic hepatitis C with several extra-hepatic manifestations, including fatigue and depression, which impact upon patients living with hepatitis C. These data suggest that HCV-infected people experience a lower quality of life in comparison to the general population and healthy controls [2–4].
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      Introduction

      Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide [
      • Lavanchy D.
      Evolving epidemiology of hepatitis C virus.
      ]. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC). The number of chronically infected persons worldwide is estimated to be about 160 million, but most are unaware of their infection. The implementation of extended criteria for screening for HCV is a subject of major debate among different stakeholders. 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.
      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 in the European Union at the time of their publication.

      The standard of care up to 2014

      The primary goal of HCV therapy is to cure the infection. A sustained virological response (SVR) is defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion. The infection is cured in more than 99% of patients who achieve an SVR. The SVR is generally associated with resolution of liver disease in patients without cirrhosis. Patients with cirrhosis 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. Recent data suggest that the risk of HCC and all-cause mortality is significantly reduced, but not eliminated, in cirrhotic patients who clear HCV compared to untreated patients and non-sustained virological responders [
      • Arase Y.
      • Kobayashi M.
      • Suzuki F.
      • Suzuki Y.
      • Kawamura Y.
      • Akuta N.
      • et al.
      Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ]. HCV may also affect neurocognition and effective viral suppression is associated with reversal of cerebral magnetic resonance abnormalities [
      • Alsop D.
      • Younossi Z.
      • Stepanova M.
      • Afdhal N.H.
      Cerebral MR spectroscopy and patient-reported mental health outcomes in hepatitis C genotype 1 naive patients treated with ledipasvir and sofosbuvir.
      ].
      Until 2011, the combination of pegylated interferon (PegIFN)-α and ribavirin for 24 or 48 weeks was the approved treatment for chronic hepatitis C [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ]. With this regimen, patients infected with HCV genotype 1 had SVR rates of approximately 40% in North America and 50% in Western Europe. Higher SVR rates were achieved in patients infected with HCV genotypes 2, 3, 5, and 6 (up to about 80%, and higher for genotype 2 than for genotypes 3, 5, and 6) and intermediate SVR rates were achieved in those with HCV genotype 4 [
      • Antaki N.
      • Craxi A.
      • Kamal S.
      • Moucari R.
      • Van der Merwe S.
      • Haffar S.
      • et al.
      The neglected hepatitis C virus genotypes 4, 5, and 6: an international consensus report.
      ].
      In 2011, telaprevir and boceprevir were licensed for use in HCV genotype 1 infection. These two drugs are first-wave, first-generation direct-acting antivirals (DAAs). Both target the HCV NS3-4A serine protease and are thus referred to as protease inhibitors. Both telaprevir and boceprevir must be administered in combination with PegIFN-α and ribavirin. In the Phase III trials of boceprevir and telaprevir in HCV genotype 1 treatment-naïve patients, triple therapy regimens achieved higher SVR rates than PegIFN-α and ribavirin dual therapy, of the order of 65% to 75% [
      • Bacon B.R.
      • Gordon S.C.
      • Lawitz E.
      • Marcellin P.
      • Vierling J.M.
      • Zeuzem S.
      • et al.
      Boceprevir for previously treated chronic HCV genotype 1 infection.
      ,
      • Jacobson I.M.
      • McHutchison J.G.
      • Dusheiko G.
      • Di Bisceglie A.M.
      • Reddy K.R.
      • Bzowej N.H.
      • et al.
      Telaprevir for previously untreated chronic hepatitis C virus infection.
      ,
      • Poordad F.
      • McCone Jr., J.
      • Bacon B.R.
      • Bruno S.
      • Manns M.P.
      • Sulkowski M.S.
      • et al.
      Boceprevir for untreated chronic HCV genotype 1 infection.
      ,
      • Zeuzem S.
      • Andreone P.
      • Pol S.
      • Lawitz E.
      • Diago M.
      • Roberts S.
      • et al.
      Telaprevir for retreatment of HCV infection.
      ]. However, the side effect profiles of these triple combination therapies and the costs per SVR in patients with advanced hepatic fibrosis are such that they should ideally no longer be used in patients infected with HCV genotype 1, as soon as other, more efficacious and better tolerated options are available.
      Three new HCV DAAs have been licensed in the EU in 2014, for use as part of combination therapies for HCV infection. Sofosbuvir, a pangenotypic nucleotide analogue inhibitor of HCV RNA-dependent RNA polymerase, has been approved in January 2014. Simeprevir, a second-wave, first-generation NS3-4A protease inhibitor active against genotypes 1 and 4 has been approved in May 2014. Daclatasvir, a pangenotypic NS5A inhibitor, has been approved in August 2014.
      Each of these three DAAs can be used as a component of a triple combination regimen with PegIFN-α and ribavirin, yielding SVR rates of 60–100% according to the DAA used, the HCV genotype, the presence of detectable pre-existing amino acid substitutions conferring resistance to the DAA used and the severity of liver disease. Although these combinations are better tolerated than triple combination including telaprevir or boceprevir, their side effect profiles and management remain challenging because of the use of PegIFN-α and of ribavirin.
      With three new HCV DAAs approved, IFN-free combinations were broadly used across Europe in 2014, initially as part of early access programs, essentially in patients with advanced liver disease (fibrosis METAVIR score F3 or F4). The combination of sofosbuvir and ribavirin is indicated in patients infected with HCV genotypes 2 (12 weeks) or 3 (24 weeks), yielding SVR rates of the order of 80–95%. The IFN-free combination of sofosbuvir and simeprevir, with or without ribavirin, was used based on the results of the small-size Phase II COSMOS study in patients infected with genotype 1 who achieved SVR in 93–100% of cases [
      • Lawitz E.
      • Sulkowski M.S.
      • Ghalib R.
      • Rodriguez-Torres M.
      • Younossi Z.M.
      • Corregidor A.
      • et al.
      Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.
      ]. Recent preliminary real-life data from the US showed SVR rates slightly below those in the COSMOS trial in patients with genotype 1 infection: 82% SVR12 in the TRIO study, 89% SVR4 in the TARGET study [
      • Doab A.
      • Treloar C.
      • Dore G.J.
      Knowledge and attitudes about treatment for hepatitis C virus infection and barriers to treatment among current injection drug users in Australia.
      ,
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ]. The combination of sofosbuvir and daclatasvir, with or without ribavirin, has also been widely used in patients with advanced liver disease throughout Europe, based on the results of a Phase II study in patients infected with genotype 1 reporting SVR rates between 95% and 100% [
      • Sulkowski M.S.
      • Gardiner D.F.
      • Rodriguez-Torres M.
      • Reddy K.R.
      • Hassanein T.
      • Jacobson I.
      • et al.
      Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.
      ]. This combination was well tolerated over the course of therapy in the trial, and real-life data are awaited.
      The panel recognises the heterogeneity of per capita incomes and health insurance systems across Europe and in other regions, and therefore the possible necessity to continue to utilise regimens with PegIFN-α and ribavirin, with or without the first-wave, first-generation protease inhibitors telaprevir or boceprevir. However, the advent of new DAAs implies that these regimens are not recommended in 2015. It is hoped that the publication of up-to-date recommendations will guide reimbursement (and discounting of drug costs) in order to harmonize treatments across different countries and regions.

      Methodology

      These EASL recommendations have been prepared by a panel of experts chosen by the EASL Governing Board. The recommendations were approved by the EASL Governing Board. The recommendations have been based as far as possible on evidence from existing publications and presentations at international meetings, and, if evidence was unavailable, the experts’ provide personal experiences and opinion. Where 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. The strength of recommendations thus reflects the quality of underlying evidence. The principles of the GRADE system have been enunciated [
      • 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 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). The recommendations thus 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.
      Table 1Evidence grading used (adapted from the GRADE system).
      These recommendations are necessarily based on currently licensed drugs. They will be updated regularly, following approval of new drug regimens by the European Medicines Agency.

      Recommendations

      Diagnosis of acute and chronic hepatitis C

      The diagnosis of acute and chronic HCV infection is based on the detection of HCV RNA by a sensitive molecular method (lower limit of detection <15 international units [IU]/ml). Anti-HCV antibodies are detectable 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.
      ].
      The diagnosis of acute hepatitis C can be confidently made only if seroconversion to anti-HCV antibodies can be documented, since there is no serological marker which proves that HCV infection is in the de novo acquired acute phase. Not all patients with acute hepatitis C will be anti-HCV-positive at diagnosis. In these cases, acute hepatitis C can be suspected if the clinical signs and symptoms are compatible with acute hepatitis C (alanine aminotransferase [ALT] >10 times the upper limit of normal, 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 can be detected during the acute phase although brief interludes of undetectable HCV RNA may occur.
      The diagnosis of chronic hepatitis C is based on the detection of both anti-HCV antibodies and HCV RNA in the presence of biological or histological signs of chronic hepatitis. Since, in the case of a newly acquired HCV infection, spontaneous viral clearance is very rare beyond 4 to 6 months of infection, the diagnosis of chronic hepatitis C can be made after that time period.

      Screening for chronic hepatitis C

      Because of the approval of highly efficacious new HCV treatment regimens, access to therapy must be broadened. A substantial proportion of patients with chronic hepatitis C are unaware of their infection. 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, hepatitis C testing is required to identify infected persons and engage them in care and treatment, and targeted screening for markers of HCV infection must be implemented. Groups at higher risk of HCV infection can be identified, and should be tested. At-risk populations, that should be screened, depend on the local epidemiology of HCV infection. In addition to EIAs, rapid diagnostic tests (RDTs) can be used to screen for anti-HCV antibodies. RDTs use various matrices, including serum, plasma, but also fingerstick capillary whole blood or, for some of them, oral (crevicular) fluid, facilitating screening without the need for venous puncture, tube centrifugation, freezing and skilled labour. RDTs are simple to perform at room temperature without specific instrumentation or extensive training.

      Goals and endpoints of HCV therapy

      The goal of therapy is to cure HCV infection in order to 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.
      The endpoint of therapy is an SVR, defined by undetectable HCV RNA 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 the US and Europe, 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.
      ]. Long-term follow-up studies have shown that an SVR corresponds to a definitive cure of HCV infection in more than 99% 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.
      ].

      Pre-therapeutic assessment

      The causal relationship between HCV infection and liver disease should be established, 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, should be systematically investigated and all patients should be tested for other hepatotropic viruses, particularly hepatitis B virus (HBV), and for human immunodeficiency virus (HIV). Alcohol consumption should be assessed and quantified, and specific counselling to stop any use of alcohol should be given. Possible comorbidities, including alcoholism, autoimmunity, genetic or metabolic liver diseases (for instance genetic hemochromatosis, diabetes or obesity) and the possibility of drug-induced hepatotoxicity should be assessed.

      Assessment of liver disease severity

      Assessment of liver disease severity is recommended prior to therapy. Identifying patients with cirrhosis or advanced (bridging) fibrosis is of particular importance, as the post-treatment prognosis depends on the stage of fibrosis. The absence of significant fibrosis may also have important implications for stratification of disease and possibly the timing of therapy. Assessment of the stage of fibrosis is not required in patients with clinical evidence of cirrhosis. Patients with cirrhosis need surveillance for HCC. Since significant fibrosis may be present in patients with repeatedly normal ALT, evaluation of disease severity should be performed regardless of ALT levels.
      Liver biopsy has been for many years the reference method for grading the activity and histological progression (staging) of the disease. In chronic hepatitis C, considerable evidence suggest that non-invasive methods can now be used instead of liver biopsy to assess liver disease severity prior to therapy at a safe level of predictability. Liver stiffness measurement can be used to assess liver fibrosis in patients with chronic hepatitis C, provided that consideration is given to factors that may adversely affect its performance such as obesity. Well-established panels of biomarkers of fibrosis 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.
      The combination of blood biomarkers or the combination of liver stiffness measurement and a blood test improve accuracy and reduce the need for liver biopsy to resolve uncertainty [
      • 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.
      ]. These tests are of particular interest in patients with coagulation disorders, though transjugular liver biopsy may also be used safely in this situation with the bonus that portal pressure can also be assessed. In case of contradictory results with non-invasive markers, liver biopsy may be indicated. Also, histology may be required in cases of known or suspected mixed aetiologies (e.g. HCV infection with HBV infection, metabolic syndrome, alcoholism or autoimmunity).

      HCV RNA detection/quantification and genotype determination

      HCV RNA detection/quantification is indicated for the patient who may undergo antiviral treatment. HCV RNA quantification should be made by a reliable sensitive assay, and HCV RNA levels should be expressed in IU/ml.
      The HCV genotype, including genotype 1 subtype, should also be assessed prior to treatment initiation. Genotyping/subtyping should be performed with an assay that accurately discriminates subtype 1a from 1b [
      • 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.
      ].
      HCV resistance testing prior to first-line therapy is not required. Indeed, the presence of pre-existing resistance-associated variants as detected by population sequencing does not have a major impact on the results of therapy and will not influence the treatment decision (with the exception of the effect of the Q80K substitution in patients with subtype 1a infection treated with the combination of PegIFN-α, ribavirin, and simeprevir, see below).

      Determination of host genetics

      IL28B genotyping has lost predictive value with the new highly efficacious IFN-free treatment regimens. Thus, IL28B genotyping is useful only in settings where only PegIFN-α and ribavirin are available or to select cost-effective treatment options in settings with economical restrictions.

      Contra-indications to therapy

      IFN-α and ribavirin

      Treatment of chronic hepatitis C with PegIFN-α and ribavirin-containing regimens is absolutely contra-indicated in the following patient groups: uncontrolled depression, psychosis or epilepsy; pregnant women or couples unwilling to comply with adequate contraception; severe concurrent medical diseases and comorbidities including retinal disease, autoimmune thyroid disease; decompensated liver disease.
      The use of PegIFN-α is not recommended in patients with absolute neutrophil counts <1500/mm3 and/or platelet counts ⩽90,000/mm3. Treatment of patients with advanced liver disease whose parameters fall outside of label recommendations may be feasible in experienced centres under careful monitoring and informed consent.

      Approved DAAs

      Based on existing knowledge, no absolute contra-indications to the DAAs approved in the EU region in 2015 exist. Caution is required with the use of sofosbuvir in patients with severe renal impairment, as the effect of impaired renal function on clearance of sofosbuvir-derived metabolites is still being ascertained. The combination of ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir is undergoing evaluation in patients with Child-Pugh B decompensated cirrhosis and is contra-indicated in patients with Child-Pugh C decompensated cirrhosis. Studies are on-going to assess the pharmacokinetics and safety of simeprevir in decompensated cirrhosis.

      Indications for treatment: who should be treated?

      All treatment-naïve and –experienced patients with compensated or decompensated chronic liver disease related to HCV, who are willing to be treated and who have no contra-indications to treatment, should be considered for therapy. Because not every HCV-infected patient can be treated within the next year or so, prioritization is necessary (Table 2). The panel acknowledges that priorities may be modulated according to local and/or societal considerations.
      Table 2Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when?
      Treatment priority should be based on fibrosis stage, risk of progression towards more advanced disease, presence of extra-hepatic manifestations of HCV infection and risk of HCV transmission. Treatment should be prioritized in patients with advanced fibrosis (METAVIR score F3 to F4), including patients with decompensated cirrhosis who have a contra-indication to the use of IFN-α but can be safely treated with IFN-free regimens. Indeed, data from clinical trials and real-life cohorts indicate that these patients could benefit more from a cure of HCV infection in the short-term, because substantial decreases in Child-Pugh and MELD scores and reductions in the incidence of clinical events have been observed. However, evidence for an improved outlook is still limited in patients with Child-Pugh scores above 12 and MELD scores higher than 20. IFN-free treatment in patients with decompensated disease should only be attempted in experienced centres until further safety and efficacy data have accumulated.
      High priority groups also include patients with HIV or HBV coinfection, patients in the pre- or post-liver transplant setting, 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), and patients with debilitating fatigue, regardless of their liver fibrosis stage.
      Treatment should also be prioritized regardless of the fibrosis stage or extra-hepatic manifestations in individuals at risk of transmitting HCV, including active injection drug users, men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, haemodialysis patients, and incarcerated individuals. Injection drug users and men who have sex with men with high-risk sexual practices should be made aware of the risk of reinfection and should apply preventative measures after successful treatment.
      Treatment is justified in patients with moderate fibrosis (METAVIR score F2). The timing and nature of therapy for patients with minimal or no fibrosis (METAVIR score F0–F1) and no severe extra-hepatic manifestations is debatable, and informed deferral can be considered. The decision to defer treatment for a specific patient should consider the patient’s preference and priorities, the natural history and risk of progression, the presence of comorbidities, and the patient’s age. Patients who have treatment deferred should be assessed on a regular basis for evidence of progression, to reconsider the indication for treatment, and to discuss new therapies as they emerge or become available and affordable.
      Treatment is not recommended in patients with limited life expectancy due to non–liver-related comorbidities.

      Available drugs in the European Union in 2015

      The HCV drugs available in the European Union are listed in this paragraph and in Table 3. Their known drug-drug interactions are also listed. For a more comprehensive listing of drug-drug interactions, see Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4FA–F and www.hep-druginteractions.org.
      Table 3Approved HCV drugs in the European Union in 2015.
      Table 4ADrug-drug interactions between HCV DAAs and HIV antiretrovirals.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Known or anticipated increase in tenofovir concentrations with boosted regimens and with efavirenz and rilpivirine when given sofosbuvir plus ledipasvir: caution and frequent renal monitoring needed.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be co-administered.
      • 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 4BDrug-drug interactions between HCV DAAs and illicit recreational drugs.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.
      • 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) 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.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be co-administered.
      • 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.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be co-administered.
      • 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.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be co-administered.
      • 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.
      SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir.
      Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. Red: These drugs should not be co-administered.
      • 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.
      PegIFN-α. PegIFN-α2a should be used at the dose of 180 μg/week, whereas PegIFN-α2b should be used at the weight-based dose of 1.5 μg/kg/week.
      Ribavirin. The ribavirin dose should be 1000 or 1200 mg/day, based on body weight (<75 kg or ⩾75 kg, respectively).
      Sofosbuvir should be administered at the dose of 400 mg (one tablet) once per day. 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. This indicates that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted. Currently, no sofosbuvir dose recommendation can be given for patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2) or with end-stage renal disease due to higher exposures (up to 20-fold) of GS-331007. 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. The most common adverse events (⩾20%) observed in combination with PegIFN-α and ribavirin were fatigue, headache, nausea, insomnia and anaemia. 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-glycoprotein (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 other known inducers of P-gp, such as rifampin, carbamazepine, phenytoin or St. John’s wort. Other potential interactions may occur with rifabutin, rifpentine, and modafinil. No other significant drug-drug interactions have been reported, in particular with all of the antiretroviral agents tested, including emtricitabine, tenofovir, rilpivirine, efavirenz, darunavir/ritonavir, and raltegravir, and there are no potential drug-drug interactions with the remaining antiretrovirals. Co-administration of amiodarone (and possibly dronedarone) with sofosbuvir in combination with daclatasvir, simeprevir or ledipasvir is contra-indicated due to a serious risk of symptomatic bradycardia (one lethal case reported). The mechanism of interaction as well as the role of other co-medications is unknown and requires investigation. Bradycardia has been observed within hours to days of starting the DAAs, but cases have been observed up to 2 weeks after initiating HCV treatment.
      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 (approximately 1%), whereas sofosbuvir is principally renally excreted, as noted above. The median terminal half-lives of sofosbuvir and its predominant metabolite GS-331007 following administration of sofosbuvir/ledipasvir 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 (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. 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.
      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 P-gp and breast cancer resistant protein (BCRP), any co-administered drugs that are potent P-gp inducers will decrease not only 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. One area of focus for ledipasvir interactions is the inhibition of P-gp and/or BCRP whereby ledipasvir may increase 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. aliskrein, amlodipine, buprenorphine, carvedilol, cyclosporine). Co-administration of amiodarone (and possibly dronedarone) with sofosbuvir/ledipasvir is contra-indicated due to a serious risk of symptomatic bradycardia (see above, mechanism of interaction is unknown). The use of rosuvastatin is also not recommended (thought to be due to inhibition of OATP by ledipasvir) and interactions with other statins cannot be excluded. It is important to monitor carefully for statin 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 famotidine 40 mg and proton pump inhibitors simultaneously at a dose comparable to omeprazole 20 mg.
      Ledipasvir/sofosbuvir may be given with all antiretrovirals. However, due to an increase in tenofovir 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, darunavir/cobicistat, all in combination with tenofovir/emtricitabine) should be used with caution, with frequent renal monitoring if other alternatives are not available. There are currently no safety and efficacy data of the combination of sofosbuvir and ledipasvir administered with boosted HIV protease-containing regimens and the interaction is not mitigated by staggering administration by 12 h. Tenofovir is also increased in efavirenz-containing regimens and caution is required.
      Simeprevir should be administered at the dose of 150 mg (one capsule) once per day. Simeprevir is extensively bound to plasma proteins (>99.9%), primarily to albumin. Simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Elimination occurs via biliary excretion, whereas renal excretion is negligible.
      The mean steady-state AUC of simeprevir is 2.4-fold higher in HCV-uninfected subjects with moderate hepatic impairment (Child-Pugh B). It is 5.2-fold higher in HCV-uninfected subjects with severe hepatic impairment (Child-Pugh C). Simeprevir has not been extensively studied in such patients, but has been used in real-life settings. However, substantially higher simeprevir exposures occur in this group and simeprevir is not recommended for these patients.
      No dose adjustment of simeprevir is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of simeprevir have not been studied in patients with a creatinine clearance below 30 ml/min or end-stage renal disease, including patients on dialysis. However, because simeprevir is highly protein-bound, dialysis is unlikely to result in significant removal of simeprevir.
      Adverse reactions with at least 3% higher frequency in patients receiving simeprevir in combination with PegIFN-α and ribavirin were rash (including photosensitivity), pruritus and nausea. Because simeprevir is an inhibitor of the hepatic transporters OATP1B1 and MRP2 [
      • Huisman M.T.
      • Snoeys J.
      • Monbaliu J.
      • Martens M.A.
      • Sekar V.J.
      • Raoof A.
      In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters.
      ], mild, transient hyperbilirubinaemia not accompanied by changes in other liver parameters was observed in approximately 10% of cases.
      Because the primary enzyme involved in the metabolism of simeprevir is CYP3A4, co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of CYP3A4 is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively. A number of compounds are contra-indicated in patients receiving simeprevir, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antibiotics (erythromycin, clarithromycin, telithromycin), antimycobacterials (rifampin, rifabutin, rifapentine), systemically administered antifungals (itraconazole, ketoconazole, posaconazole, fluconazole, voriconazole), systemically administered dexamethasone, cisapride, herbal products (milk thistle, St John’s wort) and a number of antiretroviral drugs, including cobicistat-based regimens, efavirenz, etravirine, nevirapine, ritonavir, and any HIV protease inhibitor, boosted or not by ritonavir. Raltegravir, maraviroc, rilpivirine, tenofovir, emtricitabine, lamivudine and abacavir have no interactions with simeprevir and can thus be safely used in patients receiving this drug. Dose adjustments are needed with some antiarrhythmics, warfarin, calcium channel blockers, HMG Co-A reductase inhibitors and sedative/anxiolytics.
      No dose changes are required when used in combination with the immunosuppressants tacrolimus and sirolimus, although routine monitoring of blood concentrations of the immunosuppressant is recommended. In contrast, the use of simeprevir with cyclosporine resulted in significantly increased plasma concentrations of simeprevir (due to hepatic uptake transporter inhibition), such that it is not recommended to co-administer the drugs.
      Daclatasvir should be administered at the dose of 60 mg (one tablet), or 30 mg (one tablet) when a reduced dose is needed, once per day. Approximately 90% of daclatasvir is eliminated in faeces (half as unchanged drug) and less than 10% is excreted in the urine (primarily as unchanged drug).
      The pharmacokinetics of daclatasvir in non-HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment indicate that the exposure of total daclatasvir (free and protein-bound drug) is lower in subjects with hepatic impairment. However, hepatic impairment does not have a clinically significant effect on the free drug concentrations of daclatasvir. Thus, no dose adjustment of daclatasvir is required for patients with mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
      The pharmacokinetics of daclatasvir following a single 60 mg oral dose have been studied in non-HCV-infected subjects with renal impairment. Daclatasvir unbound AUC was estimated to be 18%, 39%, and 51% higher for subjects with creatinine clearance values of 60, 30, and 15 ml/min, respectively, relative to subjects with normal renal function. Subjects requiring haemodialysis had a 27% increase in daclatasvir AUC and a 20% increase in unbound AUC compared to subjects with normal renal function. Thus, no dose adjustment of daclatasvir is required for patients with any degree of renal impairment.
      The most frequently reported side effects with daclatasvir were fatigue, headache and nausea.
      Daclatasvir is a substrate of CYP34A, and a substrate and inhibitor of P-gp. In addition, it is an inhibitor of OATP1B1 and BCRP. Co-administration of daclatasvir with drugs that strongly induce CYP3A4 and P-gp and thus reduce daclatasvir exposure is contra-indicated. This includes anticonvulsants (carbamazepine, phenytoin, oxcarbazepine, phenobarbital), antimycobacterials (rifampicin, rifabutin, rifapentine), systemic dexamethasone and St John’s wort. Strong inhibitors of CYP3A4 increase the plasma levels of daclatasvir; therefore, dose adjustments of daclatasvir are recommended. The dose of daclatasvir should be reduced to 30 mg once daily with atazanavir/ritonavir and cobicistat containing antiretroviral regimens. In contrast, recent data suggest that no dose adjustment is necessary with either darunavir/ritonavir or lopinavir/ritonavir. In the ALLY-2 study in HIV-coinfected patients receiving sofosbuvir and daclatasvir, patients on a darunavir-based regimen who had daclatasvir dose reduced to 30 mg (based on the original atazanavir/ritonavir study data) had a reduced rate of SVR12, particularly in the 8-week treatment arm, pointing to the need for the standard dose of daclatasvir in patients on this boosted protease inhibitor. With efavirenz (an enzyme inducer), the dose of daclatasvir is recommended to be increased to 90 mg. Due to a lack of data, the same is not recommended with etravirine and nevirapine, both enzyme inducers. There are no drug interactions with tenofovir, emtricitabine, abacavir, lamivudine, zidovudine, stavudine, rilpivirine, raltegravir, dolutegravir or maraviroc.
      The dose of daclatasvir should also be reduced to 30 mg with the antibacterials clarithromycin, telithromycin, erythromycin and the antifungals ketoconazole, itraconazole, posaconazole and voriconazole. Studies have been performed with acid-reducing agents (famotidine, omeprazole), escitalopram and an oral contraceptive with no dose adjustment of daclatasvir or the co-medication. However, due to daclatasvir inhibiting some transport proteins, monitoring is required with dabigatran and digoxin and other P-gp substrates.
      Ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. Paritaprevir is an NS3-4A 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 in 250 mg tablets administered 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. As a result, no dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A) and no dose adjustment is expected to be required for patients with moderate hepatic impairment (Child-Pugh B). In contrast, this combination is contra-indicated in patients 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. Whether paritaprevir, ombitasvir and/or dasabuvir are partly removed by dialysis is unknown.
      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 contra-indicated 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 contra-indicated 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 contra-indications, there are other drugs where caution needs to be exercised and there may be 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 contra-indicated. Efavirenz, etravirine and nevirapine are contra-indicated, 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. Elvitegravir/cobicistat should not be used because of the additional boosting effect.

      Treatment of chronic hepatitis C, including patients without cirrhosis and patients with compensated (Child-Pugh A) cirrhosis

      In 2015 and onwards, treatment-naïve and treatment-experienced patients with compensated and decompensated liver disease will benefit from a broad choice of drug combinations. Indications will depend on the HCV genotype/subtype, the severity of liver disease, and/or the results of prior therapy. Notwithstanding the respective costs of these options, IFN-free regimens are the best options when available, because of their virological efficacy, ease of use and tolerability. The indications are the same in HCV-monoinfected and HIV-coinfected patients. However, treatment alterations or dose adjustments may be needed in the latter due to drug-drug interactions (see above, drug-drug interactions).

      Recommendations

      Figure thumbnail fx14
      Table 5Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C without cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on PegIFN-α and ribavirin (RBV).
      Table 6Treatment recommendations for HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on PegIFN-α and ribavirin (RBV).

      Treatment of HCV genotype 1 infection

      Six treatment options are available in 2015 for patients infected with HCV genotype 1, including two IFN-containing regimens and four IFN-free regimens. The combination of sofosbuvir and ribavirin should not be used in patients infected with HCV genotype 1. In settings where none of the proposed options is available, the double combination of PegIFN-α and ribavirin, or the triple combination of PegIFN-α, ribavirin and either telaprevir or boceprevir, remain acceptable for selected patients likely to respond to these regimens until new DAAs become available and affordable; see prior EASL Clinical Practice Guidelines [
      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.
      ].

      IFN-containing options

      Figure thumbnail fx36

      Genotype 1, IFN-containing Option 1

      Comments: This combination has been evaluated in the NEUTRINO Phase III trial in treatment-naïve patients [
      • Lawitz E.
      • Mangia A.
      • Wyles D.
      • Rodriguez-Torres M.
      • Hassanein T.
      • Gordon S.C.
      • et al.
      Sofosbuvir for previously untreated chronic hepatitis C infection.
      ]. The overall SVR rate was 89% (259/291), 92% (207/225) for subtype 1a and 82% (54/66) for subtype 1b. Patients with cirrhosis had a lower SVR rate than non-cirrhotic patients (80% vs. 92%, respectively). Patients who failed on this regimen did not select HCV variants resistant to sofosbuvir.
      No Phase II data with this regimen has been presented in patients who failed prior PegIFN-α and ribavirin treatment. However, based on SVR rates in historical studies and the NEUTRINO trial, the US Food and Drug Administration predicted that 78% of patients who failed prior PegIFN-α and ribavirin treatment would achieve an SVR with the triple combination of PegIFN-α, ribavirin and sofosbuvir (although different models yielded slightly different predictions) [
      • Mishra P.
      • Florian J.
      • Qi K.
      • Zeng W.
      • Naeger L.K.
      • Donaldson E.
      • et al.
      FDA perspective on sofosbuvir therapy for patients with chronic hepatitis C virus genotype 1 infection who did not respond to treatment with pegylated interferon and ribavirin.
      ]. Similarly, there is no data with this regimen in patients who failed prior PegIFN-α, ribavirin and either telaprevir or boceprevir treatment. The SVR12 rate with the triple combination of PegIFN-α, ribavirin and sofosbuvir was 74% in patients who failed to achieve an SVR after receiving PegIFN-α, ribavirin and an investigational protease inhibitor alone or in combination with a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase or ledipasvir [
      • Pol S.
      • Sulkowski M.
      • Hassanein T.
      • Gane E.
      • Liyun N.
      • Ho H.
      • et al.
      Successful retreatment with sofosbuvir of HCV genotype 1-infected patients who failed prior therapy with peginterferon plus ribavirin plus one or two additional direct-acting antiviral agents.
      ]. There is no data with this combination in HIV-coinfected patients, and relatively small numbers of patients with cirrhosis were included. Whether longer treatment duration would be needed in the most difficult-to-cure population is unknown.
      Preliminary results from two large-scale US real-life studies have been presented. In HCV TARGET 2.0 [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ], the overall SVR4 rate with the triple combination of PegIFN-α, ribavirin and sofosbuvir was 85% (140/164; 55% were treatment-naïve and 45% treatment-experienced patients). SVR4 was achieved in 90% (114/127) of non-cirrhotic patients but 70% (26/37) of cirrhotic patients. In the TRIO real-life study, which included 58% of treatment-naïve and 42% of treatment-experienced patients, SVR12 was achieved in 81% (112/138) of treatment-naïve non-cirrhotic patients and 81% (25/31) of treatment-naïve cirrhotic patients, and in 77% (30/39) of treatment-experienced patients without cirrhosis and 62% (53/85) of treatment-experienced patients with cirrhosis (intent-to-treat) receiving PegIFN-α, ribavirin and sofosbuvir [
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ].

      Genotype 1, IFN-containing Option 2

      Figure thumbnail fx37
      In monoinfected patients who previously relapsed to IFN-α/ribavirin-based therapy, SVR24 was achieved in 86% (128/149) of subtype 1b patients and in 70% (78/111) of subtype 1a patients. Among patients infected with genotype 1a, SVR24 was achieved in 78% of those without and 47% of those with a detectable Q80K substitution at baseline [
      • Forns X.
      • Lawitz E.
      • Zeuzem S.
      • Gane E.
      • Bronowicki J.P.
      • Andreone P.
      • et al.
      Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.
      ]. The SVR rate in HIV-coinfected relapsers was 87% (13/15) in another study [
      • Dieterich D.
      • Rockstroh J.K.
      • Orkin C.
      • Gutierrez F.
      • Klein M.B.
      • Reynes J.
      • et al.
      Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study.
      ].
      In the ATTAIN Phase III study, SVR12 was achieved in 70% (101/145) of prior partial responders and 44% (102/234) of null responders to IFN-α/ribavirin-based therapy treated with the triple combination of PegIFN-α, ribavirin and simeprevir, vs. 68% (100/146) and 46% (110/238) of the same groups who received telaprevir, respectively [
      • Reddy K.R.
      • Zeuzem S.
      • Zoulim F.
      • Weiland O.
      • Horban A.
      • Stanciu C.
      • et al.
      Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial.
      ]. In HIV-coinfected patients, 70% (7/10) of partial responders and 54% (15/28) of null responders achieved an SVR24 in another study [
      • Dieterich D.
      • Rockstroh J.K.
      • Orkin C.
      • Gutierrez F.
      • Klein M.B.
      • Reynes J.
      • et al.
      Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study.
      ].

      IFN-free options

      Figure thumbnail fx38

      Genotype 1, IFN-free Option 1

      Comments: This recommendation is based on the results of the three Phase III trials ION-1, ION-2 and ION-3 [
      • 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.
      ]. In ION-1, treatment-naïve patients, including 16% with compensated cirrhosis, achieved SVR12 in 99% (211/214) and 97% (211/217) of cases after 12 weeks of the fixed-dose combination of sofosbuvir and ledipasvir without or with ribavirin, respectively. The SVR12 rates were 98% (212/217) and 99% (215/217) after 24 weeks of the same combination without or with ribavirin, respectively [
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • Chojkier M.
      • Gitlin N.
      • Puoti M.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      ]. In ION-3 in treatment-naïve patients without cirrhosis (F3 in only 13% of patients who underwent liver biopsy), the SVR12 rates were 94% (202/215) without ribavirin for 8 weeks, 93% (201/216) with ribavirin for 8 weeks and 95% (205/216) without ribavirin for 12 weeks. The absolute number of post-treatment relapses was, however, higher in the 8-weeks arms: 11/215, 9/216 and 3/216, respectively. Post hoc analysis indicated that only patients with an HCV RNA level <6 million (6.8 Log) IU/ml at baseline could be treated for 8 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.
      ]. However, HCV RNA level determination can be inaccurate within this range of values with currently available HCV RNA assays and real-life confirmation is needed to determine that 8 weeks of treatment with this combination is sufficient. Interestingly, the relapse rates were 1% (1/84) and 1% (1/96) in female patients treated for 8 weeks with sofosbuvir and ledipasvir without and with ribavirin, respectively, and 8% (10/129) and 7% (8/114) in males, respectively, in the ION-3 study [
      • 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.
      ]. In another Phase II study, the combination of sofosbuvir and ledipasvir was given for 12 weeks without ribavirin to patients with HCV genotype 1 infection coinfected with HIV, including 13 not treated for their HIV infection and 37 receiving antiretroviral therapy. All but one patient (98%) achieved an SVR12 [
      • Townsend K.S.
      • Osinusi A.
      • Nelson A.K.
      • Kohli A.
      • Gross C.
      • Polis M.A.
      • et al.
      High efficacy of sofosbuvir/ledipasvir for the treatment of HCV genotype 1 in patients coinfected with HIV on and off antiretroviral therapy: results from the NIAID ERADICATE trial.
      ].
      In ION-2, in treatment-experienced patients (prior PegIFN-α and ribavirin or PegIFN-α, ribavirin and either telaprevir or boceprevir), including 20% with cirrhosis, the SVR12 rates were 94% (102/109) and 96% (107/111) without or with ribavirin, respectively. After 24 weeks of therapy, SVR rates were 99% (108/109) and 99% (110/111), respectively [
      • Townsend K.S.
      • Osinusi A.
      • Nelson A.K.
      • Kohli A.
      • Gross C.
      • Polis M.A.
      • et al.
      High efficacy of sofosbuvir/ledipasvir for the treatment of HCV genotype 1 in patients coinfected with HIV on and off antiretroviral therapy: results from the NIAID ERADICATE trial.
      ].
      An integrated analysis of 513 genotype 1 patients with compensated cirrhosis treated with the fixed-dose combination of sofosbuvir and ledipasvir, with or without ribavirin, in different Phase II and III studies showed overall SVR12 rates of 95% (305/322) after 12 weeks and 98% (188/191) after 24 weeks of therapy [
      • Bourlière M.
      • Sulkowski M.S.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • Lawitz E.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ]. Neither treatment duration nor ribavirin had an impact on SVR12 in treatment-naïve patients (SVR12 rates between 96% and 100%). In contrast, in treatment-experienced patients, the SVR12 rates were 90% after 12 weeks without ribavirin, 96% after 12 weeks with ribavirin, 98% after 24 weeks without ribavirin, and 100% after 24 weeks with ribavirin. A platelet count <75 × 103/μl was associated with a lower rate of SVR among treatment-experienced patients (based on 28 patients) [
      • Bourlière M.
      • Sulkowski M.S.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • Lawitz E.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ].
      In the SIRIUS study, 12 weeks of the fixed-dose combination of sofosbuvir and ledipasvir with ribavirin or 24 weeks of the same combination without ribavirin in patients with compensated cirrhosis who failed to achieve an SVR after treatment with PegIFN-α, ribavirin and either telaprevir or boceprevir yielded SVR12 rates of 96% (74/77) and 97% (75/77), respectively [
      • Bourlière M.
      • Bronowicki J.P.
      • de Ledinghen V.
      • Hézode C.
      • Zoulim F.
      • Mathurin P.
      • et al.
      Ledipasvir/sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor based triple therapy.
      ].

      Genotype 1, IFN-free Option 2

      Figure thumbnail fx39
      In non-cirrhotic treatment-experienced patients (PegIFN-α and ribavirin failures) treated with this combination with ribavirin for 12 weeks in SAPPHIRE-II, the SVR12 rates were 96% (166/173) in subtype 1a and 97% (119/123) in subtype 1b patients. Overall, the SVR12 rates were 95% (82/86) in prior relapsers, 100% (65/65) in prior partial responders and 95% (139/146) in prior null responders [
      • Zeuzem S.
      • Jacobson I.M.
      • Baykal T.
      • Marinho R.T.
      • Poordad F.
      • Bourliere M.
      • et al.
      Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
      ]. SVR12 was achieved in 100% (91/91) of cases without ribavirin and 97% (85/88) with ribavirin in patients infected with subtype 1b receiving this combination in the PEARL-II trial [
      • 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 treatment-naïve and treatment-experienced patients with compensated cirrhosis, the rates of SVR were 92% (191/208) after 12 weeks and 96% (165/172) after 24 weeks of the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir plus ribavirin in the TURQUOISE-II trial. SVR12 was achieved in 92% (239/261) of genotype 1a and 99% (118/119) of genotype 1b patients [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • Kowdley K.V.
      • Zeuzem S.
      • Agarwal K.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ]. In patients with α-fetoprotein level <20 ng/ml, platelet count ⩾90 × 109/L and albumin level ⩾35 g/L prior to treatment, the relapse rates were 1% (1/87) and 0% (0/68) after 12 or 24 weeks of treatment, respectively; in patients with α-fetoprotein level ⩾20 ng/ml and/or platelet count <90 × 109/L and/or albumin level <35 g/L prior to treatment, they were 21% (10/48) and 2% (1/45) after 12 or 24 weeks of treatment, respectively [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • Kowdley K.V.
      • Zeuzem S.
      • Agarwal K.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ].

      Genotype 1, IFN-free Option 3

      Figure thumbnail fx40
      Preliminary results from two large-scale US real-life studies with sofosbuvir and simeprevir indicate that this combination is well tolerated and yields high SVR rates, which are however lower than those reported in the COSMOS trial, in particular in patients with advanced stages of liver disease [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ,
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ]. These studies are not conclusive as to the value of adding ribavirin to the sofosbuvir-simeprevir combination (ribavirin addition was at the prescriber’s discretion and may have been influenced by various pretreatment parameters). In HCV TARGET 2.0 [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ], the overall SVR4 rate was 89% (269/303). SVR4 was achieved in 92% (113/123) of non-cirrhotic patients, 87% (156/180) of cirrhotic patients, and 75% (61/81) of cirrhotic patients with prior decompensation. SVR4 was more frequent in subtype 1b than 1a patients: 95% (88/93) and 89% (47/53), respectively. SVR4 was achieved in 81% (44/54) of patients who failed on a prior treatment with PegIFN-α, ribavirin and either telaprevir or boceprevir, including in 85% (17/20) of non-cirrhotic patients and 79% (27/34) of cirrhotic patients. Preliminary data from the TRIO real-life study showed SVR12 in 88% (68/88) of treatment-naïve non-cirrhotic and 75% (41/55) of treatment-naïve cirrhotic patients; SVR rates were 87% (64/74) and 76% (53/70) in treatment-experienced non-cirrhotic and cirrhotic patients, respectively (intent-to-treat) [
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ].

      Treatment of HCV genotype 2 infection

      The best first-line treatment option for patients infected with HCV genotype 2 is the IFN-free combination of sofosbuvir and ribavirin. Other options may be useful in the small number of patients who fail on this regimen. In settings where these options are not available, the combination of PegIFN-α and ribavirin remains acceptable, according to previously published EASL Clinical Practice Guidelines [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ].

      Treatment of HCV genotype 3 infection

      Three treatment options are available for patients infected with HCV genotype 3. The combination of sofosbuvir and ribavirin is suboptimal, in particular in patients with cirrhosis who have previously failed IFN and ribavirin. Based on data with other genotypes and results in a small group of genotype 3-infected patients, the triple combination of PegIFN-α, ribavirin and sofosbuvir appears to be valuable. The IFN-free combination of sofosbuvir and daclatasvir, with or without ribavirin, is another attractive option for patients infected with HCV genotype 3.
      Ledipasvir is considerably less potent against genotype 3 than daclatasvir in vitro; in clinical trials with ledipasvir, the respective roles of ledipasvir and ribavirin in combination with sofosbuvir cannot be determined in the absence of control arms with sofosbuvir and ribavirin alone. Thus, although this combination has been used, pending further studies in larger populations including appropriate control arms, the combination of sofosbuvir plus ledipasvir is not recommended in patients infected with HCV genotype 3.
      In settings where none of these options is available, the combination of PegIFN-α and ribavirin remains acceptable, according to previous EASL Clinical Practice Guidelines [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ].

      Genotype 3, Option 2

      Figure thumbnail fx46
      The combination of sofosbuvir and ribavirin was well tolerated and very few patients stopped therapy. No virological breakthroughs were observed in treatment-adherent patients, and relapses were not associated with the selection of resistant HCV variants.

      Treatment of HCV genotype 4 infection

      Six treatment options are available in 2015 for patients infected with HCV genotype 4, including two IFN-containing regimens and four IFN-free regimens. In settings where none of these options is available, the combination of PegIFN-α and ribavirin remains acceptable; see prior EASL Clinical Practice Guidelines [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ].

      IFN-containing options

      Figure thumbnail fx48

      Genotype 4, IFN-containing Option 1

      Comments: This combination has been evaluated in the NEUTRINO Phase III trial in treatment-naïve patients [
      • Lawitz E.
      • Mangia A.
      • Wyles D.
      • Rodriguez-Torres M.
      • Hassanein T.
      • Gordon S.C.
      • et al.
      Sofosbuvir for previously untreated chronic hepatitis C infection.
      ]. The SVR rate in genotype 4 patients was 96% (27/28). The patient who failed on this regimen did not select HCV variants resistant to sofosbuvir. No data with this regimen is available in treatment-experienced patients or in HIV-coinfected patients. Whether longer treatment duration would be needed in the most difficult-to-treat population is unknown.

      IFN-free options

      Figure thumbnail fx50

      Genotype 4, IFN-free Option 1

      Comments: The SYNERGY trial assessed the efficacy and safety of the combination of sofosbuvir and ledipasvir without ribavirin in patients with genotype 4 infection. After 12 weeks of therapy, 95% (20/21) of them achieved an SVR (the remaining patient withdrew consent at week 4) [
      • Kapoor R.
      • Kohli A.
      • Sidharthan S.
      • Sims Z.
      • Petersen T.L.
      • Osinusi A.
      • et al.
      All-oral treatment for genotype 4 chronic hepatitis C infection with sofosbuvir and ledipasvir: interim results from the NIAID SYNERGY trial.
      ]. It is unclear whether treatment duration can be shortened to 8 weeks (as in certain patients infected with genotype 1 based on the ION-3 study results) because of the lack of data with genotype 4.

      Treatment of HCV genotype 5 or 6 infection

      The three treatment options for patients infected with HCV genotypes 5 or 6 are the triple combination of PegIFN-α, ribavirin and sofosbuvir, the IFN-free combination of sofosbuvir and ledipasvir, and the IFN-free combination of sofosbuvir and daclatasvir. In settings where none of these options is available, the combination of PegIFN-α and ribavirin remains acceptable [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ].

      Treatment monitoring

      Treatment monitoring includes monitoring of treatment efficacy and of safety and side effects.

      Monitoring of treatment efficacy

      Monitoring of treatment efficacy is based on repeated measurements of HCV RNA levels. A sensitive, accurate assay with a broad dynamic range of quantification should be used. The same assay, ideally from the same laboratory, should be used in each patient to measure HCV RNA at different time points, in order to assure consistency of results [
      • Chevaliez S.
      • Bouvier-Alias M.
      • Brillet R.
      • Pawlotsky J.M.
      Overestimation and underestimation of hepatitis C virus RNA levels in a widely used real-time polymerase chain reaction-based method.
      ,
      • Sarrazin C.
      • Shiffman M.L.
      • Hadziyannis S.J.
      • Lin A.
      • Colucci G.
      • Ishida H.
      • et al.
      Definition of rapid virologic response with a highly sensitive real-time PCR-based HCV RNA assay in peginterferon alfa-2a plus ribavirin response-guided therapy.
      ,
      • Vermehren J.
      • Kau A.
      • Gartner B.C.
      • Gobel R.
      • Zeuzem S.
      • Sarrazin C.
      Differences between two real-time PCR-based hepatitis C virus (HCV) assays (RealTime HCV and Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for RNA detection and quantification.
      ].
      In order to monitor treatment efficacy, HCV RNA level measurements should be performed at specific time points. Measurements should be made to assess patient adherence to therapy. For some treatment regimens, the HCV RNA level results obtained can determine whether treatment should be abandoned (the futility rule) or abbreviated (response-guided therapy). In all cases, HCV RNA level monitoring indicates whether treatment has been successful (end of treatment and post-treatment SVR assessment). Little is known about the impact of the analytical sensitivity and lower limits of detection or quantification of different HCV RNA assays for assessment of futility rules and determination of treatment duration.

      Stopping (futility) rules

      Futility rules have been defined only with the triple combination of PegIFN-α, ribavirin and simeprevir.

      Monitoring treatment safety

      PegIFN-α-containing regimens

      Flu-like symptoms are often present after PegIFN-α injections. They are easily controlled by paracetamol and tend to attenuate after 4–6 weeks of therapy. At each visit, the patients should be assessed for clinical side effects, such as severe fatigue, depression, irritability, sleeping disorders, skin reactions and dyspnoea. Thyroxin and thyroid stimulating hormone (TSH) levels should be measured every 12 weeks while on therapy [
      • Fried M.W.
      Side effects of therapy of hepatitis C and their management.
      ].
      Haematological side effects of PegIFN-α and ribavirin include neutropenia, anaemia, thrombocytopenia and lymphopenia. These parameters should be assessed at weeks 1, 2, and 4 of therapy and at 4 to 8 week intervals thereafter.

      Ribavirin-containing regimens

      Mild anaemia can occur in IFN-free regimens containing ribavirin; indeed, haemoglobin decreases have been greater and more common when DAAs were combined with ribavirin than in regimens without ribavirin.
      Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential and/or their male partners must use an effective form of contraception during treatment and for a period of 6 months after the treatment has concluded.

      DAA-containing regimens

      New DAA regimens are generally well tolerated. Frequencies of high grade or serious adverse events leading to discontinuation of IFN-free regimens are low. However, data in patients with decompensated cirrhosis or in liver transplant recipients are scarce. The efficacy and toxicity of concurrent drugs given for comorbidities and potential drug-drug interactions should be monitored during treatment.
      Simeprevir. Patients receiving simeprevir may experience mild to moderate rashes and photosensitivity; sun protection measures and limiting sun exposure is necessary. Indirect hyperbilirubinaemia may occur, but the increment in bilirubin concentrations is less in patients not receiving ribavirin. Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity.
      In the COSMOS trial [
      • Lawitz E.
      • Sulkowski M.S.
      • Ghalib R.
      • Rodriguez-Torres M.
      • Younossi Z.M.
      • Corregidor A.
      • et al.
      Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.
      ], the most common (>10%) adverse reactions reported during 12 weeks treatment with simeprevir in combination with sofosbuvir without ribavirin were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with simeprevir in combination with sofosbuvir, dizziness (16%) and diarrhoea (16%) were also commonly reported.
      The safety and efficacy of simeprevir has not been studied in HCV-infected patients with severe renal impairment or end-stage renal disease (creatinine clearance below 30 ml/min) or end-stage renal disease, including patients requiring dialysis.
      Daclatasvir. The overall safety profile of daclatasvir, either in combination with sofosbuvir with or without ribavirin or in combination with PegIFN-α and ribavirin, suggests that the most common adverse reactions related to this drug are fatigue, headache and nausea.
      Sofosbuvir and ledipasvir. The proportion of patients who permanently discontinued treatment due to adverse events during treatment was 0%, <1%, and 1% for patients receiving sofosbuvir and ledipasvir for 8, 12, and 24 weeks, respectively; and <1%, 0%, and 2% for patients receiving sofosbuvir and ledipasvir plus ribavirin combination therapy for 8, 12, and 24 weeks, respectively.
      In clinical studies, fatigue and headache were more common in patients treated with sofosbuvir and ledipasvir compared to placebo. When sofosbuvir and ledipasvir were administered with ribavirin, the most frequent adverse drug reactions were consistent with the known safety profile of ribavirin. Renal function should be checked regularly in patients receiving sofosbuvir.
      Ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir. Based on an integrated safety analysis, pruritus, fatigue, nausea, asthenia and insomnia were the most common adverse events encountered in clinical trials with this combination. The more frequent side effects were considered related to ribavirin, but pruritus was considered related to the 3 DAAs regimen. Severe adverse events occurred in <2.5% of cases. Treatment discontinuation due to adverse events occurred in 1–2% per study. Haemoglobin reductions were consistent with ribavirin-induced haemolysis, and largely resolved by post-treatment week 4. Haemoglobin reductions may require ribavirin dose reductions.
      Asymptomatic serum ALT elevations generally occurred within the first 4 weeks of treatment, but all resolved without intervention and with continued DAA treatment, none of them being synchronous with bilirubin elevations. Transient increases in indirect serum bilirubin were observed in patients receiving ribavirin, related to the inhibition of bilirubin transporters OATP1B1 and OATP1B3 by paritaprevir and associated haemolysis. A greater frequency of total bilirubin increases was observed in patients with cirrhosis. Oestrogen containing medication use was associated with a greater risk of ALT elevations.

      Monitoring drug-drug interactions

      It is important to review all the drugs taken by the patient, including over the counter preparations and recreational drugs. Also, the following series of questions should be asked: (i) are all the co-administered drugs necessary during the period of HCV treatment (it may be possible to stop a drug, such as a statin, for a period of 8–12 weeks)? (ii) If not, is there an alternative in the same therapeutic class without a drug interaction? Finally, (iii) can a drug interaction be managed either by a change of dose or a clear monitoring plan? For specific drug-drug interactions and dose adjustments, see above.

      Treatment dose reductions

      The PegIFN-α dose should be reduced in case of severe side effects, such as clinical symptoms of severe depression, and if the absolute neutrophil count falls below 750/mm3, or the platelet count falls below 50,000/mm3. When using PegIFN-α2a, the dose can be reduced from 180 μg/week to 135 μg/week, and then to 90 μg/week. When using PegIFN-α2b, the dose can be reduced from 1.5 μg/kg/week to 1.0 μg/kg/week and then to 0.5 μg/kg/week. PegIFN-α should be stopped in case of marked depression, if the neutrophil count falls below 500/mm3 or the platelet count falls below 25,000/mm3. If and when neutrophil or platelet counts rise from those nadir values, treatment can be restarted, but at a reduced dose. IFN treatment interruptions should be as brief as possible. Switch to IFN-free options should be considered in patients who need to stop IFN administration.
      If significant anaemia occurs (haemoglobin <10 g/dl), the dose of ribavirin should be adjusted downward by 200 mg at decrements. A more rapid reduction of dose may be required for patients with rapidly declining haemoglobin, particularly if the baseline haemoglobin was low. Ribavirin administration should be stopped if the haemoglobin level falls below 8.5 g/dl [
      • Fried M.W.
      Side effects of therapy of hepatitis C and their management.
      ,
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • Smith C.
      • Marinos G.
      • Goncales Jr., F.L.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ,
      • Hadziyannis S.J.
      • Sette Jr., H.
      • Morgan T.R.
      • Balan V.
      • Diago M.
      • Marcellin P.
      • et al.
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
      ,
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • Rustgi V.K.
      • Shiffman M.
      • Reindollar R.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
      ,
      • Shiffman M.L.
      • Salvatore J.
      • Hubbard S.
      • Price A.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha.
      ,
      • Soza A.
      • Everhart J.E.
      • Ghany M.G.
      • Doo E.
      • Heller T.
      • Promrat K.
      • et al.
      Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C.
      ,
      • Afdhal N.H.
      • Dieterich D.T.
      • Pockros P.J.
      • Schiff E.R.
      • Shiffman M.L.
      • Sulkowski M.S.
      • et al.
      Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study.
      ,
      • Pockros P.J.
      • Shiffman M.L.
      • Schiff E.R.
      • Sulkowski M.S.
      • Younossi Z.
      • Dieterich D.T.
      • et al.
      Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy.
      ,
      • Sulkowski M.S.
      • Poordad F.
      • Manns M.P.
      • Bronowicki J.P.
      • Reddy R.K.
      • Harrison S.A.
      • et al.
      Anemia during treatment with peginterferon alfa-2b/ribavirin and boceprevir: analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial.
      ].
      Treatment should be promptly stopped in case of a hepatitis flare (ALT levels above 10 times normal, if not already present at the time of starting treatment) or if a severe bacterial infection occurs at any site, regardless of neutrophil count. Any visual symptoms should be assessed and fundoscopic examination performed during treatment.
      No dose adjustments are recommended for sofosbuvir, simeprevir, daclatasvir, sofosbuvir-ledipasvir or ritonavir-boosted paritaprevir/ombitasvir/dasabuvir. Treatment must be stopped in case of severe adverse events, such as sepsis in patients with decompensated cirrhosis. The effects on efficacy and the number of allowable days for pausing treatment, and duration of retreatment in patients who restart after interruption of IFN-free therapy are unknown.

      Measures to improve treatment adherence

      Full adherence to all drugs is associated with high SVR rates. In contrast, suboptimal exposure to therapy is associated with virological breakthrough or post-treatment relapse and the emergence of resistance-associated variants, especially during the early phase of treatment. Simple measures to enhance adherence to treatment should thus be implemented.
      Before starting antiviral therapy, patients must be instructed about the daily schedule and the likely side effects (of both IFN- and ribavirin-containing and IFN-free regimens) to be expected during treatment. Patients should also be instructed about the preventive and therapeutic measures to ameliorate these side effects, for example by using antipyretics, analgesics, or antidepressants if they receive IFN. Regular follow-up visits must be scheduled so that treatment progress and management of side effects can be discussed. Patient recall procedures in cases of missed appointments should be instituted.
      The key element of effective HCV clinical management is access to a multidisciplinary team, generally including clinician and nursing clinical assessment and monitoring, virology, drug and alcohol services, HIV infection services, psychiatric support for selected cases, pharmacy, and social work and other social support services (including peer support, if available). Measures to increase adherence are interdisciplinary. They include HCV education and monitoring services and, particularly, the help of a dedicated nurse [
      • Alavian S.M.
      • Aalaei-Andabili S.H.
      Education by a nurse increases the adherence to therapy in chronic hepatitis C patients.
      ,
      • Rodis J.L.
      • Kibbe P.
      Evaluation of medication adherence and quality of life in patients with hepatitis C virus receiving combination therapy.
      ]. For foreign patients, the language and comprehension difficulties should be addressed before starting treatment.
      To maximize the likelihood of benefit for patients who begin new HCV treatment regimens, resources should be devoted to patient pretreatment assessment and preparation, as well as to on treatment adherence monitoring and support, which is becoming easier with the new therapeutic regimens.
      Alcohol consumption has an impact on treatment adherence [
      • Anand B.S.
      • Currie S.
      • Dieperink E.
      • Bini E.J.
      • Shen H.
      • Ho S.B.
      • et al.
      Alcohol use and treatment of hepatitis C virus: results of a national multicenter study.
      ]. Patients should therefore be advised to stop or to reduce alcohol consumption before start of treatment. Treatment for patients not able to abstain from alcohol should be fitted to the individual, focussing on their ability to adhere to medication and appointments. Hepatitis C patients with on-going alcohol consumption during treatment profit from additional support during antiviral therapy [
      • Anand B.S.
      • Currie S.
      • Dieperink E.
      • Bini E.J.
      • Shen H.
      • Ho S.B.
      • et al.
      Alcohol use and treatment of hepatitis C virus: results of a national multicenter study.
      ,
      • Bruggmann P.
      • Dampz M.
      • Gerlach T.
      • Kravecz L.
      • Falcato L.
      Treatment outcome in relation to alcohol consumption during hepatitis C therapy: an analysis of the Swiss Hepatitis C Cohort Study.
      ,
      • Le Lan C.
      • Guillygomarc’h A.
      • Danielou H.
      • Le Dreau G.
      • Laine F.
      • Vedeilhie C.
      • et al.
      A multi-disciplinary approach to treating hepatitis C with interferon and ribavirin in alcohol-dependent patients with ongoing abuse.
      ,
      • Siu L.
      • Foont J.
      • Wands J.R.
      Hepatitis C virus and alcohol.
      ]. Pharmacists should advise on potential drug-drug interactions.

      Post-treatment follow-up of patients who achieve an SVR

      Non-cirrhotic patients who achieve an SVR should be retested for HCV RNA at 48 weeks post-treatment. If HCV RNA is still not detected, the infection can be considered as definitely cured and HCV RNA need not be retested. As hypothyroidism may occur after stopping IFN therapy, thyroxin and TSH levels should also be assessed 1 and 2 years after treatment if the patient has received IFN. Patients with pre-existing cofactors for liver disease (notably, history of alcohol drinking and/or type 2 diabetes) should be carefully and periodically subjected to a thorough clinical assessment, as needed.
      Cirrhotic patients who achieve an SVR should remain under surveillance for HCC every 6 months by ultrasound, and for oesophageal varices by endoscopy if varices were present at pretreatment endoscopy (though first variceal bleed is seldom observed after SVR). The presence of cofactors for liver disease, such as history of alcohol drinking and/or type 2 diabetes, may determine that additional assessments are necessary. The exact duration of HCC surveillance in patients with advanced fibrosis or cirrhosis who achieve an SVR is unknown in the current state of knowledge, but is probably indefinite. Indeed, long-term post-SVR follow-up studies showed that, although it is significantly reduced compared to untreated patients or patients who did not achieve an SVR, the risk of developing HCC remains in patients with cirrhosis who eliminate HCV [
      • Arase Y.
      • Kobayashi M.
      • Suzuki F.
      • Suzuki Y.
      • Kawamura Y.
      • Akuta N.
      • et al.
      Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C.
      ,
      • van der Meer A.J.
      • Veldt B.J.
      • Feld J.J.
      • Wedemeyer H.
      • Dufour J.F.
      • Lammert F.
      • et al.
      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
      ]. The level of risk will be determined in prospective studies.
      There remains some concern that reinfection due to recurrent or persistent risk behaviour may negate the potential benefit of treatment. Reported rates of reinfection following successful HCV treatment among patients at high risk, such as people who inject drugs or men who have sex with men, are low, with estimates of 1–5% risk per year [
      • Backmund M.
      • Meyer K.
      • Edlin B.R.
      Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users.
      ,
      • Currie S.L.
      • Ryan J.C.
      • Tracy D.
      • Wright T.L.
      • George S.
      • McQuaid R.
      • et al.
      A prospective study to examine persistent HCV reinfection in injection drug users who have previously cleared the virus.
      ,
      • Dalgard O.
      Follow-up studies of treatment for hepatitis C virus infection among injection drug users.
      ,
      • Grebely J.
      • Knight E.
      • Ngai T.
      • Genoway K.A.
      • Raffa J.D.
      • Storms M.
      • et al.
      Reinfection with hepatitis C virus following sustained virological response in injection drug users.
      ,
      • Grebely J.
      • Pham S.T.
      • Matthews G.V.
      • Petoumenos K.
      • Bull R.A.
      • Yeung B.
      • et al.
      Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection.
      ]. However the ease of IFN-free therapy may increase the likelihood of reinfection. In order to maximize the benefit of therapy, the risks of reinfection should be emphasized to patients at risk, and behavioural modifications should be positively reinforced.

      Retreatment of non-sustained virological responders

      Retreatment of patients who failed after a double combination of PegIFN-α and ribavirin

      Several studies indicate that patients who failed to achieve an SVR after treatment with PegIFN-α and ribavirin alone do not respond differently to IFN-free regimens from treatment-naïve patients. Thus, these patients should be retreated with an IFN-free regimen according to the above recommendations (Table 5, Table 6).

      Retreatment of genotype 1 patients who failed after a triple combination of PegIFN-α, ribavirin, and either telaprevir or boceprevir (Table 7)

      IFN-free treatment regimens have been tested in patients infected with HCV genotype 1 who did not achieve an SVR after treatment with the triple combination of PegIFN-α, ribavirin, and either telaprevir or boceprevir. Experience of retreatment of such patients with the combination of sofosbuvir and simeprevir, with or without ribavirin, for 12 weeks is limited to on-going observational real-life cohorts. In the TARGET 2.0 cohort study, previous failure of triple combination therapy was a significant negative predictor of SVR4 [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ]. The role of the presence, at retreatment start, of protease inhibitor resistance-associated variants is unknown. In the TRIO Network real-life study [
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ], the SVR12 rate with sofosbuvir and simeprevir was 82% (27/33) in patients who failed on triple combination therapy, not different from patients who failed on PegIFN-α and ribavirin alone (80% [60/80]). Retreatment with the combination of PegIFN-α, ribavirin and sofosbuvir of such patients yielded SVR rates of 73% (29/40) and 67% (24/36), respectively [
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ].
      Table 7Treatment recommendations for retreatment of HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C who failed to achieve an SVR on prior antiviral therapy containing one or several DAA(s) RBV: ribavirin.
      Currently, there is limited data to firmly support these retreatment recommendations, which are based on indirect evidence and consideration of HCV genotype, known resistance profiles of the previously administered drugs, number of drugs used, use of ribavirin, treatment duration. Thus, these recommendations are subject to change when more data become available.
      In non-cirrhotic patients who failed on triple combination therapy, 24 weeks of the combination of sofosbuvir and daclatasvir yielded SVR rates of 95% (19/21) and 100% (21/21) without and with ribavirin, respectively [
      • Sulkowski M.S.
      • Gardiner D.F.
      • Rodriguez-Torres M.
      • Reddy K.R.
      • Hassanein T.
      • Jacobson I.
      • et al.
      Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.
      ]. In the ION-2 trial, the SVR rates in patients without cirrhosis retreated with sofosbuvir and ledipasvir for 12 weeks, without or with ribavirin, were 96% (50/52) and 100% (50/51), respectively; they were 97% (35/36) and 100% (38/38) after 24 weeks of therapy without and with ribavirin, respectively [
      • 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.
      ]. It is noteworthy that in the ION-2 trial, the SVR rates in cirrhotic patients retreated with sofosbuvir and ledipasvir for 12 weeks, without or with ribavirin, were 86% (12/14) and 85% (11/13), respectively; SVR rates increased to 100% (14/14) and 100% (13/13) after 24 weeks of therapy without and with ribavirin, respectively [
      • 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 the SIRIUS study, the SVR rates with sofosbuvir plus ledipasvir, for either 12 weeks with ribavirin or 24 weeks without ribavirin, were 96% (74/77) and 97% (75/77), respectively [
      • Bourlière M.
      • Bronowicki J.P.
      • de Ledinghen V.
      • Hézode C.
      • Zoulim F.
      • Mathurin P.
      • et al.
      Ledipasvir/sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor based triple therapy.
      ].

      Retreatment of patients who failed after a regimen containing one or more second-wave DAAs (Table 7)

      Sofosbuvir has a high barrier to resistance. Clinically meaningful resistant HCV variants have been exceptionally reported with sofosbuvir, and they rapidly disappeared after treatment cessation. Thus, retreatment strategies should include sofosbuvir. In contrast, patients exposed to a protease inhibitor (simeprevir, paritaprevir), an NS5A inhibitor (daclatasvir, ledipasvir, ombitasvir) or a non-nucleoside inhibitor of HCV polymerase (dasabuvir) who fail to achieve SVR select viruses with amino acid substitutions in the NS3 protease, NS5A and polymerase regions, respectively, that confer drug resistance. Viruses resistant to protease inhibitors and, probably also but more slowly, viruses resistant to non-nucleoside polymerase inhibitors progressively decrease in proportion to become undetectable by means of population sequencing (direct sequence analysis) within a few months to 2 years after treatment cessation. In contrast, viruses resistant to NS5A inhibitors are fit and remain dominant for many years, perhaps forever, after they have been selected by a regimen including an NS5A inhibitor [
      • Barnard R.J.
      • Howe J.A.
      • Ogert R.A.
      • Zeuzem S.
      • Poordad F.
      • Gordon S.C.
      • et al.
      Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies.
      ,
      • McPhee F.
      • Hernandez D.
      • Yu F.
      • Ueland J.
      • Monikowski A.
      • Carifa A.
      • et al.
      Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir.
      ,
      • Sullivan J.C.
      • De Meyer S.
      • Bartels D.J.
      • Dierynck I.
      • Zhang E.Z.
      • Spanks J.
      • et al.
      Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials.
      ,
      • Wang C.
      • Sun J.H.
      • O’Boyle 2nd, D.R.
      • Nower P.
      • Valera L.
      • Roberts S.
      • et al.
      Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir.
      ,
      • Lenz O.
      • Verbinnen T.
      • Fevery B.
      • Tambuyzer L.
      • Vijgen L.
      • Peeters M.
      • et al.
      Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies.
      ,
      • Krishnan P.
      • Tripathi R.
      • Schnell G.
      • Reisch T.
      • Beyer J.
      • Irvin M.
      • et al.
      Pooled analysis of resistance in patients treated with ombitasvir/ABT-450/r and dasabuvir with or without ribavirin in Phase 2 and Phase 3 clinical trials.
      ,
      • Sarrazin C.
      • Dvory-Sobol H.
      • Svarovskaia E.S.
      • Doehle B.
      • McCarville J.F.
      • Pang P.S.
      • et al.
      Baseline and post-baseline resistance analyses of Phase 2/3 studies of ledipasvir/sofosbuvir ± RBV.
      ].
      Currently, there is no data to firmly support retreatment recommendations, which must be based on indirect evidence (HCV genotype, known resistance profiles of the administered drugs, number of drugs used, use of ribavirin, treatment duration). Whether assessing the sequence of the target HCV genes (HCV resistance testing) prior to retreatment is helpful to make a decision remains unknown, as well as which therapeutic decision should be made based on this result.
      Intuitively, patients who failed on a DAA-containing regimen should be retreated with an IFN-free combination including a drug with a high barrier to resistance (currently, sofosbuvir), plus one or two other drugs, ideally with no cross-resistance with the drugs already administered. Based on results in difficult-to-cure patient populations, retreatment should be for 12 weeks with ribavirin, or extended to 24 weeks with or without ribavirin (no data available comparing these approaches).
      Patients who failed on sofosbuvir alone or sofosbuvir plus ribavirin or sofosbuvir plus PegIFN-α and ribavirin can be retreated with a combination of sofosbuvir plus simeprevir (genotype 1 or 4), sofosbuvir plus daclatasvir (all genotypes) or sofosbuvir plus ledipasvir (genotypes 1, 4, 5 or 6), with ritonavir-boosted paritaprevir, ombitasvir and dasabuvir (genotype 1), or with ritonavir-boosted paritaprevir and ombitasvir (genotype 4). In a study, retreatment with 12 weeks of sofosbuvir plus ledipasvir with ribavirin yielded SVR in 98% (50/51) of genotype 1 patients who failed prior treatment with sofosbuvir plus placebo, or sofosbuvir plus ribavirin, or sofosbuvir plus PegIFN-α and ribavirin [
      • Wyles D.L.
      • Pockros P.J.
      • Yang J.C.
      • Zhu Y.
      • Pang P.S.
      • McHutchison J.G.
      • et al.
      Retreatment of patients who failed prior sofosbuvir-based regimens with all-oral fixed-dose combination ledipasvir/sofosbuvir plus ribavirin for 12 weeks.
      ].
      Genotype 1 and 4 patients who failed on a regimen combining PegIFN-α, ribavirin and simeprevir should be retreated with a combination of sofosbuvir with daclatasvir or ledipasvir. Patients who failed on a regimen combining PegIFN-α, ribavirin and daclatasvir should be retreated with a combination of sofosbuvir and simeprevir (genotype 1 and 4).
      Patients infected with genotype 1 or 4 who failed on a regimen containing sofosbuvir and simeprevir should be retreated with a combination of sofosbuvir with daclatasvir or ledipasvir, whereas patients who failed on a regimen containing sofosbuvir and daclatasvir or ledipasvir should be retreated with a combination of sofosbuvir and simeprevir (genotype 1 and 4). The retreatment strategy is unclear for patients infected with genotypes 2, 3, 5 or 6 who failed on a regimen containing sofosbuvir and daclatasvir or ledipasvir; retreatment with the same option may be proposed, provided that ribavirin is added and/or treatment duration is extended to 24 weeks.
      Patients who failed on the triple combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir should be retreated with a sofosbuvir-based regimen. The value and safety of retreatment strategies combining three drugs, including sofosbuvir, a protease inhibitor and an NS5A inhibitor, is unknown.
      Patients without an urgent need for treatment can wait until more data and/or alternative therapeutic options become available.

      Treatment of patients with severe liver disease

      Patients with decompensated cirrhosis without an indication for liver transplantation

      The main goal of anti-HCV therapy in patients with decompensated cirrhosis not on a transplant waiting list is to achieve improvement in liver function and survival. A 48-week regimen of sofosbuvir and ribavirin is being assessed in patients with cirrhosis and portal hypertension [
      • Afdhal N.
      • Everson G.
      • Calleja J.L.
      • McCaughan G.
      • Symonds W.T.
      • Denning J.
      • et al.
      Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety.
      ]. Preliminary results demonstrated excellent on treatment responses and slight improvements in liver function tests. The long-term clinical benefits and the effect of this treatment on portal pressure have not been reported.
      A study assessed the safety and efficacy of the fixed-dose combination of sofosbuvir and ledipasvir with ribavirin for 12 or 24 weeks in patients with decompensated cirrhosis (Child-Pugh score up to 12) infected with HCV genotype 1 or 4 [
      • Flamm S.L.
      • Everson G.T.
      • Charlton M.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study.
      ]. The SVR rates were 87% (45/52) and 89% (42/47) after 12 and 24 weeks of treatment, respectively; treatment was equally effective in patients with Child-Pugh B and Child-Pugh C cirrhosis. There was a clear effect of viral clearance on liver function, with significant improvements in bilirubin, albumin and INR values and, as a result, in MELD and Child-Pugh scores. Improvement of liver function was reported 4 weeks after treatment interruption. It will thus be important to assess the benefit of HCV elimination on liver function and subsequent survival at later time points. These preliminary results suggest that patients with decompensated cirrhosis benefit from this treatment regimen. The treatment indication should take into account the presence of comorbidities that may impact survival. Data in patients with more advanced liver disease (Child-Pugh >12) are limited.

      Patients with HCC without an indication for liver transplantation

      HCV is a leading cause of HCC worldwide and the morbidity and mortality from HCV-associated HCC is increasing, especially in high-income areas. HCC occurs at an annual rate of 1–7% in patients with cirrhosis. The risk is related to the severity of fibrosis among other factors. An SVR has been shown to be associated with a reduction in all-cause mortality, liver mortality and a reduction in the risk of HCC. Several metanalysis have examined the relationship between achievement of SVR and reduction in the risk of HCC, which suggest that SVR is associated with a reduction in HCC [
      • Moon C.
      • Jung K.S.
      • Kim D.Y.
      • Baatarkhuu O.
      • Park J.Y.
      • Kim B.K.
      • et al.
      Lower incidence of hepatocellular carcinoma and cirrhosis in hepatitis C patients with sustained virological response by pegylated interferon and ribavirin.
      ,
      • Morgan R.L.
      • Baack B.
      • Smith B.D.
      • Yartel A.
      • Pitasi M.
      • Falck-Ytter Y.
      Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.
      ]. However, most of these studies are observational and retrospective and were based on SVR achieved with IFN-based treatments.
      As IFN has been shown to improve outcomes following ablation or resection of HCV, it is possible that the high rates of SVR achieved with new IFN-free regimens could reduce the risk of recurrence following resection or ablation of HCC [
      • Singal A.K.
      • Freeman Jr., D.H.
      • Anand B.S.
      Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma.
      ]. If the incidence of recurrent HCC can be reduced via this strategy, higher rates of resection or ablation plus an SVR with antiviral treatment could possibly reduce the subsequent need for transplantation for HCV-associated HCC. Further data is required to evaluate the impact of highly effective IFN-free regimens on the risk of recurrent HCC following resection or ablation.

      Patients with an indication for liver transplantation

      Liver transplantation is the treatment of choice for patients with end-stage liver disease. However, hepatitis C recurrence due to 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 is reduced in patients with recurrent hepatitis C.
      Treatment of HCV infection in patients awaiting a liver transplantation has two complementary goals: preventing liver graft infection after transplantation (in all cases) and improving liver function before transplantation (in patients with decompensated liver disease). It might be argued that as treatment of HCV infection can be achieved in the vast majority of patients after transplantation, there is no need to treat HCV infection prior to transplantation, especially because the duration of antiviral therapy cannot be predicted in a patient on the waiting list. Nevertheless, prevention of liver graft infection substantially facilitates post-transplant management. In addition, improvement of liver function implies delisting of some patients [
      • Gane E.
      • Pilmore H.
      Management of chronic viral hepatitis before and after renal transplantation.
      ], an appropriate strategy in the current context of organ shortage [
      • Flamm S.L.
      • Everson G.T.
      • Charlton M.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study.
      ]. Also, the risk of HCC recurrence could theoretically be reduced by antiviral therapy after resection; thus, more patients could possibly be offered resection.
      In a recently published study [
      • Curry M.P.
      • Forns X.
      • Chung R.T.
      • Terrault N.A.
      • Brown Jr., R.
      • Fenkel J.M.
      • et al.
      Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study.
      ], 61 patients infected with genotypes 1 or 4 with Child-Pugh A cirrhosis were treated with sofosbuvir and ribavirin up to 48 weeks prior to transplantation; 46 of them were transplanted. The per-protocol efficacy population consisted of 43 patients with an HCV RNA level <25 IU/ml at the time of transplantation. Among them, 30 (70%) had post-transplantation SVR12, meaning no recurrence of infection. The duration of undetectable HCV RNA pre-transplant was the best predictor of response (undetectable HCV RNA for more than 30 continuous days). This proof of concept study demonstrated that an IFN-free regimen administered for a few weeks before transplantation prevented HCV graft infection in a majority of treated patients. In patients infected with genotype 2, the combination of sofosbuvir and ribavirin is the treatment of choice, with very high SVR rates. For other genotypes, this combination should be administered until liver transplantation only if no other treatment choice is available. Treatment with PegIFN-α, ribavirin and sofosbuvir for 12 weeks is acceptable in patients with compensated (Child-Pugh A) cirrhosis awaiting liver transplantation if IFN-free combinations are not available, based on a study in 164 genotype 1-infected patients, half treatment-experienced and one-third with cirrhosis, who achieved SVR4 in 85% of cases [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ].
      The combination of sofosbuvir and ledipasvir with ribavirin for 12 or 24 weeks was assessed in genotype 1 and 4 patients with compensated (Child-Pugh A) or decompensated (Child-Pugh B and C, up to 12 points) cirrhosis [
      • Flamm S.L.
      • Everson G.T.
      • Charlton M.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study.
      ]. In Child-Pugh A patients, data from this and other studies showed SVR12 rates above 95%, both in treatment-naïve and treatment-experienced individuals, independent of treatment duration. In patients with decompensated cirrhosis, preliminary analysis showed SVR12 rates of 88% (50/57) and 88% (37/42) in Child-Pugh B and C patients, respectively, independent of treatment duration [
      • Flamm S.L.
      • Everson G.T.
      • Charlton M.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated cirrhosis: preliminary results of a prospective, multicenter study.
      ]. At week 4 post-treatment, the MELD scores had improved by 1 to 8 points in 64% (34/53) of Child-Pugh B patients and in 70% (28/40) of Child-Pugh C patients. Child-Pugh scores improved by 1 to 3 points in approximately two-thirds of patients. The safety profile of this combination was good and most serious adverse events, including death, were unrelated to the study drugs. Although the study was not specifically designed to assess the impact of antiviral therapy in patients awaiting liver transplantation, the data support the use of this combination in patients with compensated and decompensated cirrhosis on the waiting list.
      Data on the efficacy and safety of the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir with ribavirin in compensated cirrhotic patients infected with genotype 1 have been published [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • Kowdley K.V.
      • Zeuzem S.
      • Agarwal K.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ]. Patients with compensated cirrhosis awaiting liver transplantation typically have more advanced liver disease and portal hypertension than those included in this study; however, patients with low albumin levels (<35 g/dl, 43 patients) and low platelet counts (<100,000 cells/ml, 78 patients) were included. In patients with a platelet count <100,000 cells/ml, the SVR12 rates were 89% and 97% in the 12- and 24-week treatment duration arms, respectively. The SVR rates in patients with an albumin level <35 g/dl were 84% and 89%, respectively. Thus, this combination can be considered in individuals with compensated cirrhosis and HCC who are on the waiting list.
      The combination of sofosbuvir and simeprevir, with or without ribavirin, has been assessed in large real-life cohorts including a significant number of patients with cirrhosis [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ]. In patients with HCV genotype 1 infection and compensated cirrhosis, the SVR4 rates were in the order of 90%. Preliminary data in 81 genotype 1-infected patients with decompensated cirrhosis showed an SVR4 rate of 75%, with a good safety profile. However, simeprevir is not indicated in patients with decompensated cirrhosis, due to the higher drug concentrations observed.

      Post-liver transplantation recurrence

      HCV infection recurrence 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.
      ]. Patients with acute cholestatic hepatitis and patients with moderate to extensive fibrosis or portal hypertension one year after transplantation are at high risk of graft loss, and must urgently receive 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.
      ].
      Treatment with PegIFN-α and ribavirin yields low SVR rates and is poorly tolerated in liver transplant recipients. The addition of telaprevir or boceprevir increases the SVR rates to 60–70% in patients infected with genotype 1, but at the cost of frequent severe adverse events. Moreover, adjustments in the doses of calcineurin inhibitors are necessary to avoid toxicity due to drug-drug interactions. Nevertheless, HCV clearance has been shown to have a positive impact on both graft and patient 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.
      ,
      • Gambato M.
      • Lens S.
      • Navasa M.
      • Forns X.
      Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation.
      ].
      The first study assessing the safety and efficacy of an IFN-free regimen in HCV-infected liver transplant recipients used a combination of sofosbuvir and ribavirin for 24 weeks [
      • Charlton M.
      • Gane E.
      • Manns M.P.
      • Brown Jr., R.S.
      • Curry M.P.
      • Kwo P.Y.
      • et al.
      Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation.
      ]. The cohort included 40 patients, of whom 40% had cirrhosis and 88% were non-responders to an IFN-based treatment. This regimen yielded an SVR12 rate of 70%, with an excellent safety profile (severe adverse events in 15% of patients, anaemia in 20% and treatment discontinuations in 5%). Calcineurin inhibitor dose adjustments were not required due to the lack of significant interactions of sofosbuvir with tacrolimus or cyclosporine. The beneficial impact of HCV clearance on liver function and patient survival post-liver transplantation is supported by data from the sofosbuvir compassionate use program, which included patients with severe hepatitis C recurrence and a life expectancy without antiviral therapy of less than 12 months [
      • Forns X.
      • Charlton M.
      • Denning J.
      • McHutchison J.G.
      • Symonds W.T.
      • Brainard D.
      • et al.
      Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C following liver transplantation.
      ]. Patients received up to 48 weeks of sofosbuvir and ribavirin, with or without PegIFN-α. The SVR12 rate was 59%. Fifty-seven percent of patients had a significant clinical improvement at the last study visit, whereas 22% were unchanged, 3% had worsened their clinical status and 13% died. These results suggest that HCV clearance impacts survival in these very sick patients, particularly those with severe early recurrence. In real-life patients infected with genotype 2, the combination of sofosbuvir and ribavirin post-liver transplant yielded a very high SVR rate in the TARGET study [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Mailliard M.E.
      • et al.
      Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real-world experience in a diverse, longitudinal observational cohort.
      ].
      Preliminary data from an on-going clinical trial assessing the efficacy and safety of the fixed-dose combination of sofosbuvir and ledipasvir with ribavirin for 12 or 24 weeks were presented [
      • Reddy R.K.
      • Everson G.T.
      • Flamm S.L.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post-transplant recurrence: preliminary results of a prospective, multicenter study.
      ]. The patients included treatment-naïve and mostly treatment-experienced patients with genotype 1 or 4 infection, with all fibrosis stages (F0 to F4) including patients with Child-Pugh B and C decompensated cirrhosis. The SVR rates were 97% (108/111) in F0-F3 patients, 96% (49/51) in Child-Pugh A patients, and 84% (37/44) in Child-Pugh B patients. Data were available in only 8 Child-Pugh C patients, 5 of whom (62%) achieved an SVR. There were no differences in efficacy between 12 and 24 weeks of therapy and the combination had an excellent safety profile. As in immunocompetent patients, MELD scores at week 4 post-treatment improved in the majority of Child-Pugh A and B patients who achieved viral clearance [
      • Reddy R.K.
      • Everson G.T.
      • Flamm S.L.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post-transplant recurrence: preliminary results of a prospective, multicenter study.
      ].
      The antiviral efficacy and safety of the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir with ribavirin for 24 weeks was tested in 34 HCV genotype 1 liver transplant recipients [
      • Mantry P.S.
      • Kwo P.Y.
      • Coakley E.
      • Te H.S.
      • Vargas H.E.
      • Brown R.S.
      • et al.
      High sustained virologic response rates in liver transplant recipients with recurrent HCV genotype 1 infection receiving ABT-450/r/ombitasvir plus dasabuvir plus ribavirin.
      ]. All of them were treatment-naïve post-transplantation and had F0 to F2 fibrosis. All but one achieved SVR12, while only 6% of patients reported severe adverse events, 17% anaemia, and 1 patient had to discontinue therapy. Due to drug-drug interactions with ritonavir and paritaprevir, tacrolimus or cyclosporine dose adjustments were required during the treatment period. In patients with more advanced liver disease, data must be extrapolated from patients not in the post-transplant recurrence setting.
      Data from real-life cohorts with a combination of sofosbuvir and simeprevir with or without ribavirin for 12 weeks were reported. SVR12 was achieved in 91% (60/66) of patients infected with genotype 1, most of whom were treatment-experienced with one-third having advanced fibrosis or compensated cirrhosis. The SVR rate was slightly lower in genotype 1a patients with advanced fibrosis [
      • Dieterich D.
      • Bacon B.R.
      • Flamm S.L.
      • Kowdley K.V.
      • Milligan S.
      • Tsai N.
      • et al.
      Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population.
      ]. In the TARGET real-life cohort study, in which most patients were treatment-experienced and more than half had cirrhosis, the combination of sofosbuvir and simeprevir yielded a 90% (61/68) SVR4 rate [
      • Brown R.S.
      • Reddy K.R.J.
      • O’Leary J.G.
      • Kuo A.
      • Morelli G.
      • Stravitz R.T.
      • et al.
      Safety and efficacy of new DAA-based therapy for hepatitis C post-transplant: interval results from the HCV-TARGET longitudinal, observational study.
      ].
      Little data is available with the combination of sofosbuvir and daclatasvir in the post-transplant setting, mostly from small real-life cohorts. Overall, SVR is achieved in more than 90% of cases, including in patients with fibrosing cholestatic hepatitis [
      • Leroy V.
      • Dumortier J.
      • Coilly A.
      • Sebagh M.
      • Fougerou-Leurent C.
      • Radenne S.
      • et al.
      High rates of virological response and major clinical improvement during sofosbuvir and daclatasvir-based regimens for the treatment of fibrosing cholestatic HCV recurrence after liver transplantation: the ANRS CO23 CUPILT study.
      ], with this well tolerated regimen.

      Treatment of special groups

      HBV coinfection

      In patients with HCV-HBV coinfection, the HBV DNA level is often low or undetectable, although it may fluctuate widely, and HCV is usually the main driver of chronic hepatitis activity. Patients should be carefully characterized for the replicative status of both HBV and HCV, and hepatitis delta virus infection should be sought. When HCV is replicating and causes liver disease, it should be treated following the same rules as applied to HCV monoinfected patients. There is a potential risk of HBV reactivation during or after HCV clearance [
      • Potthoff A.
      • Berg T.
      • Wedemeyer H.
      Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin.
      ]. In that case, or if HBV replication is detectable at a significant level, concurrent HBV nucleoside/nucleotide analogue therapy is indicated. Simeprevir increases exposure to tenofovir. Thus, in patients receiving tenofovir as anti-HBV treatment, the eGFR and tubular function should be monitored frequently during treatment and tenofovir doses should be consequently adjusted.

      Immune complex-mediated manifestations of chronic hepatitis C

      Several severe systemic immune complex-mediated manifestations of chronic HCV infection have been described. Mixed cryoglobulinemia underlain by B lymphocyte expansion may cause a systemic vasculitis in which multiple organs are involved as a result of vascular deposition of immune complexes. The treatment of mixed cryoglobulinemia relies on causal (antiviral) therapy and/or immunosuppressive therapy. Rituximab, an anti-CD20 monoclonal antibody, has been used for both skin and organ involvement.
      There is a significant association between hepatitis C and B cell non-Hodgkin lymphoma. Diffuse large B cell lymphoma is the most common. The disease is treated with standard of care R-CHOP regimens; the outcome with rituximab appears to be enhanced albeit that rituximab may enhance viral replication. Rituximab has been associated with the possibility of hepatic toxicity and transaminase elevations although the risk is low.
      The association of chronic HCV infection and chronic renal disease is well-established. A spectrum of histopathological lesions has been reported but the most frequent is type I membrano-proliferative glomerulonephritis, usually in the context of type II mixed cryoglobulinemia. Focal segmental glomerulosclerosis, vasculitic involvement and interstitial nephritis may also occur. Approaches to therapy of HCV-associated renal disease include antiviral therapy, corticosteroids and cyclophosphamide, B cell depletion therapy to prevent the formation of immune complexes, or plasma exchange. It is possible but unproven that the more effective and rapid antiviral response observed with new IFN-free antiviral regimens will improve outcome. Some evidence for rituximab in the management of HCV-induced renal disease exists. However, there are questions regarding its safe and optimal use together with rapidly acting DAAs that need to be addressed. An interdisciplinary approach is recommended.

      Patients with comorbidities

      Haemodialysis patients

      HCV infection is prevalent in the haemodialysis population and is associated with an increased risk for all-cause and liver-related mortality. Cardiovascular disease remains, however, the main cause of death in dialysis patients irrespective of HCV status. As in all settings, the candidacy of a dialysis patient for antiviral therapy requires special consideration of co-morbid conditions, since the liver disease may have little impact on predicted morbidity and mortality of that patient. HCV-associated liver damage may be accelerated by immunosuppression. For this reason, antiviral therapy should be considered for all haemodialysis patients who will be candidates for renal transplantation.
      The use of ribavirin is problematic in this setting. Individualized ribavirin dosing of 200 mg/day or 200 mg/every other day or 200 mg thrice weekly after haemodialysis is recommended, and substantial hematopoietic support is essential. There are no published data to describe the pharmacokinetics, dosing safety and efficacy of current IFN-free anti-HCV regimens in haemodialysis patients. This is an urgent unmet need.

      Non-hepatic solid organ transplant recipients

      HCV infection in kidney transplant recipients may be associated with an increased rate of liver fibrosis progression. Most studies of kidney transplant cohorts show that HCV positivity is associated with impaired renal graft and patient survival. Impaired graft survival partly reflects increased patient mortality. In addition, specific HCV-related causes such as glomerulonephritis and increased risk of diabetes will affect graft outcome. HCV positivity is associated with increased all-cause and liver-related mortality, though cardiovascular disease remains the main cause of patient death [
      • Scott D.R.
      • Wong J.K.
      • Spicer T.S.
      • Dent H.
      • Mensah F.K.
      • McDonald S.
      • et al.
      Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand.
      ]. As cirrhosis is an important predictor of poor post-transplant survival after kidney transplantation, it is advisable to assess the stage of liver fibrosis in all HCV-positive kidney transplant candidates [
      • Gane E.
      • Pilmore H.
      Management of chronic viral hepatitis before and after renal transplantation.
      ]. For patients with established cirrhosis and portal hypertension who fail (or are unsuitable for) HCV antiviral treatment, isolated renal transplantation may be contra-indicated and consideration should be given to combined liver and kidney transplantation [
      • Van Wagner L.B.
      • Baker T.
      • Ahya S.N.
      • Norvell J.P.
      • Wang E.
      • Levitsky J.
      Outcomes of patients with hepatitis C undergoing simultaneous liver-kidney transplantation.
      ]. As IFN-based treatment may lead to graft rejection, there is an urgent need to offer these patients IFN-free regimens. It remains to be determined whether patients with chronic hepatitis C without cirrhosis should optimally proceed to renal transplantation, with the expectation that their hepatitis C can be cured post-transplant to improve the outcome.
      Data on HCV infection after heart transplantation are scarce and controversial, with studies showing unaltered or decreased survival rates in patients infected with HCV. No studies on the risks and benefits of antiviral therapy are available in these patients and the risk of graft rejection on IFN-α treatment remains unclear. In this context, treatment of chronic HCV infection in heart transplant recipients must be based on IFN-free regimens and the indication should be assessed on a case-by-case basis, if HCV infection is life-threatening.
      International guidelines list chronic HCV infection as a contra-indication to lung transplantation [
      • Orens J.B.
      • Estenne M.
      • Arcasoy S.
      • Conte J.V.
      • Corris P.
      • Egan J.J.
      • et al.
      International guidelines for the selection of lung transplant candidates: 2006 update-a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.
      ]. Treatment of lung transplant candidates before transplantation has been recommended by some authors, but there is limited experience with this approach. No data are available on the impact of HCV infection and its treatment after pancreas or small bowel transplantation.

      Active drug addicts and patients on stable maintenance substitution

      Ageing cohorts of people who inject drugs (PWID) with chronic HCV and low treatment uptake are making a significant contribution to the population with advanced liver disease and to liver-related mortality [
      • Darke S.
      • Kaye S.
      • Duflou J.
      Comparative cardiac pathology among deaths due to cocaine toxicity, opioid toxicity and non-drug-related causes.
      ,
      • Grebely J.
      • Raffa J.D.
      • Lai C.
      • Kerr T.
      • Fischer B.
      • Krajden M.
      • et al.
      Impact of hepatitis C virus infection on all-cause and liver-related mortality in a large community-based cohort of inner city residents.
      ]. The prevalence of HCV among PWIDs is approximately 65% [
      • Hagan H.
      • Pouget E.R.
      • Des Jarlais D.C.
      • Lelutiu-Weinberger C.
      Meta-regression of hepatitis C virus infection in relation to time since onset of illicit drug injection: the influence of time and place.
      ,
      • Nelson P.K.
      • Mathers B.M.
      • Cowie B.
      • Hagan H.
      • Des Jarlais D.
      • Horyniak D.
      • et al.
      Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews.
      ,
      • Shepard C.W.
      • Finelli L.
      • Alter M.J.
      Global epidemiology of hepatitis C virus infection.
      ] and >80% among long-term PWIDs [
      • Hagan H.
      • Pouget E.R.
      • Des Jarlais D.C.
      • Lelutiu-Weinberger C.
      Meta-regression of hepatitis C virus infection in relation to time since onset of illicit drug injection: the influence of time and place.
      ].
      HCV treatment must be considered for PWIDs, provided they wish to receive treatment and are able and willing to maintain regular appointments. Guidelines for pre-therapeutic assessment for HCV-infected individuals are available [
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      ,
      • Grebely J.
      • Dore G.J.
      What is killing people with hepatitis C virus infection?.
      ]. Modelling studies suggest that implementation of HCV treatment for PWIDs could reduce transmission [
      • Martin N.K.
      • Vickerman P.
      • Foster G.R.
      • Hutchinson S.J.
      • Goldberg D.J.
      • Hickman M.
      Can antiviral therapy for hepatitis C reduce the prevalence of HCV among injecting drug user populations? A modeling analysis of its prevention utility.
      ,
      • Martin N.K.
      • Vickerman P.
      • Miners A.
      • Foster G.R.
      • Hutchinson S.J.
      • Goldberg D.J.
      • et al.
      Cost-effectiveness of hepatitis C virus antiviral treatment for injection drug user populations.
      ]. Decisions to treat must be made on a case-by-case basis. PWIDs with on-going social issues and/or with a history of psychiatric disease or with more frequent drug use during therapy are at risk of lower adherence and reduced likelihood of achieving SVR and need to be monitored closely during therapy, and also need more supporting measures.
      HCV treatment has been delivered successfully to drug users through various clinical models, including within general hospital liver disease and viral hepatitis clinics, drug detoxification clinics, opioid substitution therapy clinics, prisons and community-based clinics. Strategies to enhance treatment adherence were discussed above.
      DAA clinical development programs have excluded individuals with active drug use, but many trials have included those on opioid substitution therapy. DAA-based safety and treatment outcome data has not been presented on clinical trial sub-populations of individuals on opioid substitution therapy. Drug-drug interaction studies have been undertaken with sofosbuvir and simeprevir on the one hand, methadone [
      • van Heeswijk R.
      • Vandevoorde A.
      • Verboven P.
      • Boogaerts G.
      • De Paepe E.
      • van Solingen-Ristea R.
      • et al.
      The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir.
      ] and buprenorphine [
      • Luo X.
      • Trevejo J.
      • Van Heeswijk R.
      • Garg V.
      No significant effect of the HCV protease inhibitor telaprevir on pharmacokinetics and pharmacodynamics of buprenorphine in HCV-negative volunteers.
      ] on the other hand, with no clinically important interactions observed. Interaction studies with daclatasvir and methadone/buprenorphine are underway.
      In addition to opioid substitution therapy, antidepressants, antipsychotics and sedatives are frequently used in patients or used by patients with addiction problems. No significant drug-drug interaction has been reported with sofosbuvir. Simeprevir increases blood concentrations of orally administered midazolam and potentially triazolam. Caution is thus warranted when these drugs with a narrow therapeutic index are co-administered via the oral route. Little data is available with daclatasvir. Pharmacokinetic studies on recreational and illicit drug use have not been performed.

      Haemoglobinopathies

      The most frequent haemoglobinopathy associated with chronic hepatitis C is thalassemia major, which requires frequent blood transfusions and is prevalent in countries where blood supply screening may be, or has been, suboptimal. Chronic HCV infection is also frequent in individuals with sickle cell anaemia. Treatment has often been withheld in these patients because both PegIFN-α and ribavirin can cause anaemia. No trials with antiviral therapy have been published in this population, but trials are in progress. In the absence of published studies to examine the safety of IFN-free treatment regimens in patients with haemoglobinopathies, there is no reason to consider that these drugs are specifically contra-indicated. Thus, IFN-free, ribavirin-free drug regimens should be used in these patients because they have the great advantage of not aggravating the anaemia.

      Bleeding disorders

      Haemophilia is an inherited bleeding disorder caused by a deficiency of either factor VIII or IX in haemophilia A and B, respectively. Patients suffer spontaneous and traumatic bleeds. Treatment is based on intravenous replacement of these factors which, until recently, were prepared from plasma donations. Clotting factor concentrates are prepared from pools of plasma containing up to 30,000 donations and prior to 1985 were infused into recipients without any viral inactivation. Haemophiliacs exposed to non-virally inactivated concentrates prior to 1985 had an almost 100% chance of being infected with HCV with their first exposure to concentrate. There are a number of other inherited bleeding disorders treated with concentrates, including von Willebrand disease, and deficiencies of fibrinogen and factors II, VII, X, XI, and XIII.
      Progression to end-stage liver disease in patients with haemophilia is similar to HCV-positive individuals in the general population. The investigation of chronic liver disease in haemophilia is the same as in non-haemophilic individuals. Transjugular liver biopsies have enhanced the safety of the procedure. Non-invasive methods can be utilised to monitor disease progression. Death from liver failure in HCV-positive individuals is among the commonest causes of death in patients with inherited bleeding disorders. With the exception of unavailability of liver histology, the management of chronic hepatitis C in haemophilia is similar to the non-haemophilic population. New HCV DAAs are applicable to patients with haemophilia.
      Over 100 liver transplants have been carried out in haemophilic patients worldwide. Factor VIII/IX concentrate is administered immediately before the surgery, either by bolus injection or continuous infusion, and for the immediate post-operative period for 12–48 h, after which no further concentrate is required. Coinfection with HIV/HCV is not a contra-indication to liver transplantation in haemophilia. The indications for liver transplantation in humans with haemophilia are the same as non-haemophilic individuals, but the procedure has the major advantage of producing a phenotypic cure of the haemophilia as a result of factor VIII production by the transplanted liver.

      Follow-up of untreated patients and of patients with treatment failure

      Untreated patients with chronic hepatitis C and those who failed to respond to previous treatment should be regularly followed. The reason(s) for non-treatment and treatment failure should be clearly documented. Untreated patients should be assessed every 1 to 2 years with a non-invasive method. Patients with cirrhosis should undergo specific surveillance for HCC every 6 months.

      Treatment of acute hepatitis C

      Most patients with acute hepatitis C are asymptomatic, but a high rate of chronicity is expected without treatment (50–90%). Symptomatic disease with jaundice, female gender, a young age, and genetic polymorphisms in the region upstream of the IL28B gene have been associated with spontaneous viral clearance, but none of these parameters accurately predicts spontaneous resolution at the individual level.
      Patients with acute hepatitis C should be considered for antiviral therapy in order to prevent progression to chronic hepatitis C. High SVR rates (>90%) have been reported with PegIFN-α monotherapy, regardless of the HCV genotype. Lower SVR rates have been reported with this regimen in patients with HIV coinfection. Combination therapy with ribavirin does not increase the SVR rate in HCV-monoinfected patients, but used to be considered during treatment in patients with slow response, HIV coinfection and other negative predictors of treatment response [
      • Deterding K.
      • Gruner N.
      • Buggisch P.
      • Wiegand J.
      • Galle P.R.
      • Spengler U.
      • et al.
      Delayed versus immediate treatment for patients with acute hepatitis C: a randomised controlled non-inferiority trial.
      ,
      • Kamal S.M.
      Acute hepatitis C: a systematic review.
      ,
      • Mondelli M.U.
      • Cerino A.
      • Cividini A.
      Acute hepatitis C: diagnosis and management.
      ,
      • Santantonio T.
      • Wiegand J.
      • Gerlach J.T.
      Acute hepatitis C: current status and remaining challenges.
      ,
      • Strader D.B.
      • Wright T.
      • Thomas D.L.
      • Seeff L.B.
      Diagnosis, management, and treatment of hepatitis C.
      ,
      • Wiegand J.
      • Jackel E.
      • Cornberg M.
      • Hinrichsen H.
      • Dietrich M.
      • Kroeger J.
      • et al.
      Long-term follow-up after successful interferon therapy of acute hepatitis C.
      ,
      European ATNAHCICP. Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference.
      ,
      • Santantonio T.
      • Fasano M.
      • Sagnelli E.
      • Tundo P.
      • Babudieri S.
      • Fabris P.
      • et al.
      Acute hepatitis C: a 24-week course of pegylated interferon alpha-2b versus a 12-week course of pegylated interferon alpha-2b alone or with ribavirin.
      ,
      • Mangia A.
      • Santoro R.
      • Copetti M.
      • Massari M.
      • Piazzolla V.
      • Spada E.
      • et al.
      Treatment optimization and prediction of HCV clearance in patients with acute HCV infection.
      ]. A study reported higher SVR rates after the addition of telaprevir to PegIFN-α and ribavirin in HIV-coinfected patients infected with genotype 1 [
      • Fierer D.S.
      • Dieterich D.T.
      • Mullen M.P.
      • Branch A.D.
      • Uriel A.J.
      • Carriero D.C.
      • et al.
      Telaprevir in the treatment of acute hepatitis C virus infection in HIV-infected men.
      ]. No data are available on the use of new IFN-free treatment regimens in patients with acute hepatitis C.
      The ideal time point for starting therapy has not been firmly established. Some investigators estimate that the onset of ALT elevation, with or without clinical symptoms, may be the ideal time point for treatment [
      • Camma C.
      • Almasio P.
      • Craxi A.
      Interferon as treatment for acute hepatitis C. A meta-analysis.
      ,
      • Gerlach J.T.
      • Diepolder H.M.
      • Zachoval R.
      • Gruener N.H.
      • Jung M.C.
      • Ulsenheimer A.
      • et al.
      Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.
      ,
      • Micallef J.M.
      • Kaldor J.M.
      • Dore G.J.
      Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.
      ,
      • Poynard T.
      • Regimbeau C.
      • Myers R.P.
      • Thevenot T.
      • Leroy V.
      • Mathurin P.
      • et al.
      Interferon for acute hepatitis C.
      ]. It has also been suggested that patients should be followed with 4-weekly HCV RNA quantification and that only those who remain HCV RNA positive at 12 weeks from onset should be treated [
      • Hofer H.
      • Watkins-Riedel T.
      • Janata O.
      • Penner E.
      • Holzmann H.
      • Steindl-Munda P.
      • et al.
      Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.
      ].
      Recommendations for treatment of patients with acute hepatitis C can only be inferred from results obtained in a priori more difficult-to-cure chronically infected patients. There is currently no indication for antiviral therapy as post-exposure prophylaxis in the absence of documented HCV transmission.

      Perspective of new treatments

      Other treatment regimens are at the clinical developmental stage and could reach the market within the next few years. They include nucleotide analogue-based regimens; nucleotide-free triple combinations of three drugs, each with a low barrier to resistance, which collectively achieve a high barrier to resistance; and nucleotide-free double combinations of two drugs that include at least one “second-generation” drug with a higher barrier to resistance [
      • Pawlotsky J.M.
      New hepatitis C therapies: the toolbox, strategies, and challenges.
      ,
      • Pawlotsky J.M.
      Hepatitis C treatment: the data flood goes on: an update from the Liver Meeting 2014.
      ]. New pangenotypic agents with greater potency and a higher barrier to resistance will be required to offset drug resistance associated with treatment failures as treatment is expanded. Thus, these recommendations will be updated regularly, following approval of new drug regimens by the European Medicines Agency.

      Conflict of interest

      • Jean-Michel Pawlotsky: Grant and research support: Gilead. Advisory Boards: Abbvie, Achillion, Bristol-Myers Squibb, Gilead, Janssen, Merck. Speaking and teaching: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche.
      • Alessio Aghemo: Advisory Boards: Abbvie, Gilead, Janssen, and Merck. Speaking and teaching: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Roche.
      • David Back: Grant and research support: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Viiv. Advisory Boards: Abbvie, Gilead, Janssen, and Merck. Speaking and teaching: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck.
      • Geoffrey Dusheiko: Grant and research support: Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, and Merck. Advisory Boards: Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, and Merck. Speaking and teaching: Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, and Merck.
      • Xavier Forns: Grant and research support: Janssen. Advisory Boards: Abbvie, Gilead, and Janssen. Speaking and teaching: Gilead, and Janssen.
      • Massimo Puoti: Grant and research support: Gilead. Advisory Boards: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck. Speaking and teaching: Bristol-Myers Squibb, Gilead, Janssen, and Merck.
      • Christoph Sarrazin: Grant and research support: Abbott Molecular, Abbvie, Gilead, Janssen, Qiagen, Roche, and Siemens. Advisory Boards: Abbott Molecular, Abbvie, Achillion, Bristol-Myers Squibb, Gilead, Janssen, and Merck. Speaking and teaching: Abbott Molecular, Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Qiagen, and Siemens.

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