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HCV targeting of patients with cirrhosis

  • Peter Ferenci
    Correspondence
    Corresponding author. Address: Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40 400 47350; fax: +43 1 40 400 47410.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Karin Kozbial
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Mattias Mandorfer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Harald Hofer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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      Summary

      Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN-containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona-vir/ombitasvir/±dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12 weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients.

      Keywords

      Compensated cirrhosis

      Most phase II and III studies excluded all [
      • Kowdley K.V.
      • Gordon S.C.
      • Reddy K.R.
      • et al.
      Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.
      ,
      • Ferenci P.
      • Bernstein D.
      • Lalezari J.
      • et al.
      ABT-450/r-ombitasvir-and dasabuvir with or without ribavirin for hepatitis C genotype 1.
      ,
      • Feld J.J.
      • et al.
      Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
      ,
      • Zeuzem S.
      • et al.
      Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
      ,
      • Andreone P.
      • Colombo M.G.
      • Enejosa J.V.
      • et al.
      ABT-450, ritonavir, ombitasvir, and dasabuvir achieve 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection.
      ,
      • 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.
      ] or just included only a small number of patients with cirrhosis [
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial.
      ,
      • Afdhal N.
      • Zeuzem S.
      • Kwo P.
      • et al.
      Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.
      ,
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      ,
      • 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.
      ,
      • Zeuzem S.
      • Dusheiko G.M.
      • Salupere R.
      • et al.
      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
      ,
      • Lawitz E.
      • Mangia A.
      • Wyles D.
      • et al.
      Sofosbuvir for previously untreated chronic hepatitis C infection.
      ]. Only one phase III trial was conducted in exclusively well compensated cirrhotic patients [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ].

      Genotype 1

      Patients with compensated cirrhosis were treated in phase III trials with either sofosbuvir/ledipasvir (SOF/LDV, Harvoni®) [
      • Reddy K.R.
      • Bourlière M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ] or paritaprevir/r/ombitasvir/dasabuvir (3D-regime [
      • Fried M.
      • DiBisceglie A.
      • Vierling J.M.
      • Gane E.J.
      • Nevens F.
      • Strasser S.I.
      • et al.
      TURQUOISE-II: regimens of ABT-450/r/ombitasvir and dasabuvir with ribavirin achieve high SVR12 rates in HCV genotype 1-infected patients with cirrhosis, regardless of baseline characteristics.
      ]; Viekira Pak® in the USA, Viekirax® + Exviera® in Europe). Sustained virologic response (SVR) rates >90% were achieved and treatment was well tolerated. Negative predictive factors for SVR to the 3D regimen were IL28B T/T, prior non-response and GT1a [
      • Fried M.W.
      • Forns X.
      • Reau N.
      • Wedemeyer H.
      • Shiffman M.L.
      • Castro A.
      • et al.
      TURQUOISE-II: regimens of ABT450/r/ombitasvir and dasabuvir with ribavirin achieve high SVR12 rates in HCV GT1 infected patients with cirrhosis, regardless of baseline characteristics.
      ]. Other regimes are the combinations of sofosbuvir with simeprevir (Optimist-2 study [
      • Lawitz E.
      • Matusow G.
      • De Jesus E.
      • Yoshida E.
      • Felizarta F.
      • Ghalib R.
      • et al.
      A phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naive or -experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTIMIST-2.
      ]) or Daclatasvir + RBV (Ally-I study [
      • Poordad F.
      • Schiff E.R.
      • Vierling J.M.
      • Landis C.
      • Fontana R.J.
      • Yang R.
      • et al.
      Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: phase 3 ALLY-1 study.
      ]). The SVR rate in the Optimist-2 trial [
      • Lawitz E.
      • Matusow G.
      • De Jesus E.
      • Yoshida E.
      • Felizarta F.
      • Ghalib R.
      • et al.
      A phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naive or -experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTIMIST-2.
      ] was 88% and 79% in treatment naïve or treatment-experienced cirrhotic patients, respectively. In the ALLY-1 study SVR was achieved in 82% patients. In both studies SVR rates were substantially lower in patients with advanced cirrhosis (Child-Pugh C). Similar results were obtained in the “real world” TARGET study with low SVR rates in cirrhotic patients with a MELD score ⩾10 [
      • Reddy R.
      • Lim J.K.
      • Kuo A.
      • Di Bisceglie A.M.
      • Vargas H.M.
      • Galati J.S.
      • et al.
      All oral HCV therapy is safe and effective in patients with decompensated cirrhosis: interim report from the HCV-TARGET real world experience.
      ]. The best results were achieved with 24 weeks of SOF + DCV + RBV in the French observational cohort [
      • Pol S.
      • Bourliere M.
      • Lucier S.
      • De Ledighen V.
      • Zoulim F.
      • Dorival-Mouly C.
      • et al.
      Safety and efficacy of the combination daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients from the French observational cohort ANRS CO22 HEPATHER.
      ].
      The major questions regarding patients with compensated cirrhosis with both regimens are; (1) if ribavirin (RBV) shows additional benefit; and (2) if treatment duration matters. Overall SVR rates in naïve patients (ION-1 study [
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection: a randomized trial.
      ]) were not different regarding HCV subtypes (1a vs. 1b); treatment with or without RBV, or length of treatment (12 vs. 24 weeks). Similar results were obtained in the few patients with cirrhosis (defined by a fibroscan >12 kPa). Longer treatment tended to increase SVR rates in small number of treatment-experienced cirrhotic patients (12 weeks ± RBV: 84.1%; 95%CI: 59.7–97.1; 24 weeks ± RBV: 100%; 84.6–100, n.s. [
      • Afdhal N.
      • Reddy K.R.
      • Nelson D.R.
      • et al.
      Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
      ]). LDV/SOF plus RBV was associated with a greater incidence of AEs as well as concomitant medication use than LDV/SOF alone [
      • Alqahtani S.A.
      • Afdhal N.
      • Zeuzem S.
      • Gordon S.C.
      • Mangia A.
      • et al.
      Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of phase III ION trials.
      ]. In an integrated analysis of patients with liver cirrhosis from the phase II and phase III clinical development program of SOF/LDV [
      • Reddy K.R.
      • Bourlière M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ] neither length of treatment (12 or 24 weeks) nor the addition of RBV had an impact on treatment outcome (see Table 1) [
      • Reddy K.R.
      • Bourlière M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ]. Only in treatment-experienced patients treated for 12 weeks, the addition of RBV increased SVR rates (SVR: 90% vs. 96%, n.s.). In a randomized controlled study in non-responders to triple therapy with the first generation of protease inhibitors with cirrhosis 24 weeks of SOF/LDV and 12 weeks of SOF/LDV plus RBV were equally effective [
      • Bourliere M.
      • Bronowicki J.
      • de Ledinghen V.
      • Hezode C.
      • Zoulim F.
      • Mathurin P.
      • et al.
      Sofosbuvir/Ledipasvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed to protease inhibitor based triple therapy.
      ]. Unfortunately, the study had no 12 weeks SOF/LDV arm. In the TURQUOISE-II study both study arms (12 or 24 weeks treatment) included RBV with SVR rates of 92% vs. 96% [
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ]. RBV dose reduction did not affect SVR rates. SVR rates were higher in genotype (GT)-1b patients and GT1a prior null-responders to P/R achieved higher SVR rates when treated for 24 weeks (24 vs. 12 weeks: 93 vs. 80%).
      Table 1Impact of treatment duration and addition of ribavirin on the response to IFN-free treatments in patients with cirrhosis due to HCV-GT1 infection.
      SOF, sofosbuvir; SMV, simeprevir; ASU, asunaprevir; DVC, daclatasvir; BCL, beclabuvir; LDV, ledipasvir; 3D, r/paritaprevir + dasabuvir + ombitasvir; GRZ, grazoprevir; ELB, elbasvir; n.s., not significant.
      *F3 + 4; §all study groups; $18 weeks treatment; *includes all fibrosis stages; $treatment naïve and experienced; §mostly GT1 patients (SVR in GT1: advanced cirrhosis: 85%, post OLT: 92%).

      Genotype 2

      No clinical trials were performed in cirrhotic patients infected with GT2 only, and just 75 patients with cirrhosis were treated with SOF/RBV in the four phase III trials (Fusion + Positron [
      • Jacobson I.M.
      • Gordon S.C.
      • Kowdley K.V.
      • et al.
      Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.
      ]: 19; VALENCE [
      • Zeuzem S.
      • Dusheiko G.M.
      • Salupere R.
      • et al.
      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
      ]:9; Fission [
      • Lawitz E.
      • Mangia A.
      • Wyles D.
      • et al.
      Sofosbuvir for previously untreated chronic hepatitis C infection.
      ]:30; Japan [
      • Omata M.
      • Nishiguchi S.
      • Ueno Y.
      • et al.
      Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial.
      ]:17) with SVR rates ranging between 60 and 93%. This limited number of cirrhotic patients does not allow us to draw any firm conclusions on how long to treat them. Real-life data [
      • Jensen D.M.
      • O’Leary J.G.
      • Pockros P.J.
      • Sherman K.E.
      • Kwo P.Y.
      • Maillard 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.
      • Flamm S.
      • Kowdley K.
      • 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.
      ] using SOF/RBV in patients with cirrhosis showed high SVR rates. In the absence of good data, making recommendations is difficult, nevertheless the EASL guidelines suggest considering a treatment extension in patients with cirrhosis of 16 or 20 weeks [
      • EASL
      Recommendations on treatment of hepatitis C.
      ].

      Genotype 3

      GT3 has emerged as a difficult to treat HCV genotype with IFN-free regimens. Not all of the newly available DAAs have activity against GT3 further limiting treatment choices in this patient group. Since GT3 is the second most prevalent genotype worldwide [
      • Gower E.
      • et al.
      Global epidemiology and genotype distribution of the hepatitis C virus infection.
      ], finding the most efficient treatment is an urgent medical need. While SVR rates of >90% were achieved with SOF/RBV in non-cirrhotic patients, they were substantially lower in naïve (86%) and treatment-experienced (60%) cirrhotic patients even treated for 24 weeks [
      • Zeuzem S.
      • Dusheiko G.M.
      • Salupere R.
      • et al.
      Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
      ,
      • Pawlotsky J.M.
      • Hepatitis C.
      Treatment: the data flood goes on-an update from the liver meeting 2014.
      ]. A recent randomized controlled study (BOSON-trial) indicated that in patients with cirrhosis due to GT2 or GT3 infection the combination of SOF/RBV with PegIFN given for 12 weeks was more effective that 24 weeks of SOF/RBV alone (86–91% vs.77–82% SVR) [
      • Foster G.R.
      • Pianko S.
      • Cooper C.
      • Brown A.
      • Forton D.
      • Nahass R.G.
      • et al.
      Sofosbuvir plus Peg-IFN/RBV for 12 weeks vs sofosbuvir/RBV for 16 or 24 weeks in genotype 3 HCV-infected patients and treatment-experienced cirrhotic patients with genotype 2 HCV: the BOSON study.
      ]. In the Ally-3 study [
      • Nelson D.
      • Cooper J.N.
      • Lalezari J.P.
      • et al.
      All-oral 12-week combination treatment with daclatasvir (DCV) and sofosbuvir (SOF) in patients infected with HCV genotype (GT) 3: ALLY-3 phase 3 study.
      ], the SVR rates of 12 weeks SOF plus daclatasvir (DCV) in non-cirrhotic patients was 91 to 95%, but only 73 and 63% in treatment-naïve and treatment-experienced cirrhotic patients, respectively [
      • Nelson D.
      • Cooper J.N.
      • Lalezari J.P.
      • et al.
      All-oral 12-week combination treatment with daclatasvir (DCV) and sofosbuvir (SOF) in patients infected with HCV genotype (GT) 3: ALLY-3 phase 3 study.
      ]. Similar data were obtained in cirrhotic patients treated with SOF/LDV + RBV [
      • Gane E.J.
      • Hyland R.H.
      • An D.
      • Svarovskaia E.S.
      • Pang P.S.
      • Symonds W.T.
      • et al.
      High efficacy of LDV/SOF regimens for 12 weeks for patients with HCV genotype 3 or 6 infection.
      ].

      Genotype 4–6

      Regardless of the stage of fibrosis [
      • Abdel-Razek W.
      Waked I optimal therapy in genotype 4 chronic hepatitis C: finally cured?.
      ] the limited available data for IFN-free treatments of HCV GT4–6 patients does not allow to comment on the need for RBV or treatment duration.

      Decompensated cirrhosis

      Patients with decompensated cirrhosis can be separated into two distinct populations: those who are OLT candidates and those who are not. In OLT candidates, potential benefits of antiviral therapy includes the improvement of hepatic function [
      • 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.
      ,
      • 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.
      ] sometimes to a point that a patient can be delisted [
      • Ruiz I.
      • Feray C.
      • Pawlotsky J.M.
      • Hézode C.
      • et al.
      Patient with decompensated hepatitis C virus-related cirrhosis delisted for liver transplantation after successful sofosbuvir-based treatment.
      ]. Moreover successful eradication of HCV before OLT prevents accelerated liver disease progression after OLT [
      • Gane E.J.
      The natural history of recurrent hepatitis C and what influences this.
      ].
      Two studies investigated IFN-free treatment of patients with decompensated cirrhosis. Afdhal et al. [
      • 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.
      ] randomized 50 patients with portal hypertension and compensated (Child Turcotte Pugh (CTP) class A or decompensated cirrhosis (CTP class B) to an immediate treatment with SOF/RBV for 48 weeks or a delayed treatment (after 24 weeks of observation) arm. Treatment response at week 8 was nearly universal. After 24 weeks, platelet count improved among treated CTP class A patients and albumin levels improved in both treated CTP class A and B patients when compared to the observational arm. However, treatment did affect the MELD score. In contrast to the observational arm, ascites and hepatic encephalopathy resolved in all treated patients.
      The SOLAR-1 study [
      • 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.
      ] investigated 108 treatment-naïve or treatment-experienced cirrhotic GT1 or GT4 patients with CTP class B or C treated with SOF/LDV plus RBV (starting at 600 mg/day, with the option for escalation) for either 12 or 24 weeks. All patients had a MELD score no greater than 21, and had a normal kidney function. SVR was achieved in 87% and 89% in the 12 and 24 week arms, respectively. SVR rates were comparable in patients with CTP class B and C cirrhosis. The rate of treatment discontinuations due to adverse events was low. Total bilirubin levels decreased, while albumin levels increased in both groups, suggesting improved hepatic function. CTP score improved in 70% of patients, remained unchanged in 20% and worsened in 10%. Similarly, MELD score improved in the majority of patients.
      There is an ongoing debate on a point of no return in the natural history of patients with decompensated cirrhosis. Given their poor prognosis it is unclear whether ‘palliative’ antiviral therapy is indicated in patients with advanced cirrhosis who are not candidates for OLT. Since viral eradication decrease portal hypertension in patients with advanced cirrhosis [
      • D’Amico G.
      • Garcia-Pagan J.C.
      • Luca A.
      • Bosch J.
      Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.
      ,
      • Iacobellis A.
      • Siciliano M.
      • Perri F.
      • Annicchiarico B.E.
      • Leandro G.
      • Caruso N.
      • et al.
      Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study.
      ] even patients with decompensated cirrhosis not listed for OLT may benefit from antiviral therapy with IFN-free regimens. HVPG decreased in 71 to 82% patients with virologic response to Peg/RBV [
      • Rincon D.
      • Ripoll C.
      • Lo Iacono O.
      • Salcedo M.
      • Catalina M.V.
      • Alvarez E.
      • et al.
      Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis.
      ,
      • Roberts S.
      • Gordon A.
      • McLean C.
      • Pedersen J.
      • Bowden S.
      • Thomson K.
      • et al.
      Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis.
      ].

      Treatment after liver transplantation

      Reinfection of the graft is unavoidable after successful OLT for hepatitis C. Antiviral therapies in the pre-DAA era were not very successful and poorly tolerated in patients infected with GT1 [
      • Chalasani N.
      • Manzarbeitia C.
      • Ferenci P.
      • Vogel W.
      • Fontana R.J.
      • Voigt M.
      • et al.
      Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials.
      ,
      • Berenguer M.
      Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin.
      ]. With triple therapy with telaprevir or boceprevir higher SVR rates could be achieved in GT1 patients after OLT, but significant side effects and drug-drug interactions were encountered [
      • Coilly A.
      • Roche B.
      • Dumortier J.
      • Leroy V.
      • Botta-Fridlund D.
      • Radenne S.
      • et al.
      Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.
      ,
      • Pungpapong S.
      • Aqel B.A.
      • Koning L.
      • Murphy J.L.
      • Henry T.M.
      • Ryland K.L.
      • et al.
      Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation.
      ,
      • Burton Jr, J.R.
      • O’Leary J.G.
      • Verna E.C.
      • Saxena V.
      • Dodge J.L.
      • Stravitz R.T.
      • et al.
      A US multicenter study of hepatitis c treatment of liver transplant recipients with protease-inhibitor triple therapy.
      ].
      There are five published studies on IFN-free treatment of patients with hepatitis C undergoing transplantation. The treatment regimens and patient selections varied considerably. In the CORAL-1 trial 33 of 34 (97%) patients with mild fibrosis (F0–2) receiving the 3D regimen for 24 weeks [
      • Kwo P.Y.
      • Mantry P.S.
      • Coakley E.
      • Te H.S.
      • Vargas H.E.
      • Brown Jr, R.
      • et al.
      An interferon-free antiviral regimen for HCV after liver transplantation.
      ] had an SVR at post-treatment weeks 12 and 24. Blood levels of calcineurin inhibitors were monitored, and dosages had to be modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. In an open-label study [
      • 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.
      ] 28 of 40 (70%) patients with recurrent HCV infection of any genotype achieved SVR after 24 weeks of SOF/RBV. Relapse accounted for all cases of virologic failure. No episodes of rejection nor interactions with concomitant immunosuppressive agents were reported.
      Forns et al. treated patients with early severe recurrent hepatitis C or cirrhosis (>12 months after OLT) with SOF and RBV ± PEG for 24 to 48 weeks [
      • 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.
      ]. Of the 92 patients assessed, 54 (59%) achieved SVR12; with a higher rate (73%) in patients with early severe recurrence. Twenty-six serious adverse events in 19 patients were associated with hepatic decompensation (18%). The Mayo study reported 128 patients treated post OLT with SOF/Simeprevir (SMV) ± RBV, 25 of them had F3–4 [
      • Pungpapong S.
      • Aqel B.
      • Leise M.
      • Werner K.T.
      • Murphy J.L.
      • Henry T.M.
      • et al.
      Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant.
      ]. The overall SVR rate was 91%, with lower rates in GT1a than in GT1b patients. RBV had no impact on the outcome. 1a; Advanced fibrosis (METAVIR F3–F4) was associated with diminished antiviral In the Miami cohort OLT recipients with GT1b had a 100% SVR12 rate (95% CI, 87%–100%), whereas SVR12 was 89% (95% CI, 74%–95%) for those with genotype efficacy in LT recipients with GT1a (SVR12, 67% (95% CI, 39%–86%)) [
      • Gutierrez J.A.
      • Carrion A.F.
      • Avalos D.
      • O’Brien C.
      • Martin P.
      • Bhamidimarri K.R.
      • et al.
      Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients.
      ]. Interim results of 627 patients who completed therapy in ongoing studies were reported at AASLD 2014. The overall SVR rate was 92% [
      • Beinhardt S.
      • Peck-Radosavjevic M.
      • Hofer H.
      • Ferenci P.
      Interferon-free antiviral treatment of liver transplant patients with chronic hepatitis C.
      ]. Again it should be emphasized, that most of the data were derived from non-cirrhotic patients, most treated with SOF plus RBV. There was no difference whether patients were treated for 12 or 24 weeks, but patients with F4 had lower response rates than F0-F3 patients. In the Solar 1 study in post OLT patients treatment with SOF/LDV achieved SVR rates of 88 to 98% [
      • Reddy K.R.
      • Flamm S.L.
      • Denning J.M.
      • Arterburn S.
      • Brandt-Sarif T.
      Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with post transplant recurrence: preliminary results of a prospective, multicenter study.
      ]. The Solar 2 trial investigated patients in the transplant setting. GT1 and GT4 patients were treated for 12 or 24 weeks with SOF/LDV + RBV. Since SOF/LDV does not interact with cyclosporin A or tacrolimus [
      • German P.
      • Pang P.S.
      • Fang L.
      • Chung D.
      • Mathias A.
      Drug-drug interaction profile of the fixed-dose combination tablet ledipasvir/sofosbuvir.
      ] no dose adjustments were needed. The SVR rates in post-transplant patients with F0–F4 (Child-Pugh [CP] A) were 95 and 98%, respectively [
      • Manns M.
      • Forns X.
      • Samuel D.
      • Denning J.
      • Arterburn S.
      • Brandt-Sarif T.
      • et al.
      Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver Transplantation patients with HCV infection: preliminary results of the prospective Solar 2 trial.
      ]. Liver function improved early after SVR but in CPC patients the benefits were less obvious. There is an ongoing debate whether CPC patients on the waiting list should be treated pre-OLT or after transplantation.

      Unresolved issues

      Optimal drug selection

      Drug-drug interactions are less important when regimens without protease inhibitors are used. Except for SOF, second generation protease inhibitors and to a lesser degree NS5A inhibitors are substrates and inhibitors of the CYP-3A4 and Pg-p metabolic pathways, which could interact with immune suppressive drugs, mainly calcineurin inhibitors. Using protease inhibitors with or without ritonavir boosting requires monitoring of calcineurin inhibitors, but dose adjustments can be easily performed [
      • Badri P.
      • Apurvasena P.
      • Cookley E.
      • Ding B.
      • Awni W.
      • Dutta S.
      • et al.
      Pharmacokinetics of cyclosporine and tacrolimus, following coadministration with the direct acting antiviral combination, ABT-450/r, ombitasvir and dasabuvir, in liver transplant patients with genotype-1 HCV infection.
      ].
      SMV, asunaprevir, and paritaprevir are metabolized by the liver and thus may accumulate in patients with advanced liver failure. In cirrhotic patients with moderate (CTP class B) or severe hepatic impairment (CTP class C) the mean steady-state AUC of SMV was 2.4-fold and 5.2-fold higher than in HCV-uninfected healthy subjects, respectively [
      • Ouwerkerk-Mahadevan M.
      • et al.
      Pharmacokinetics of simeprevir (TMC435) in volunteers with moderate or severe hepatic impairment.
      ]. Compared to subjects with normal hepatic function, paritaprevir, ritonavir and dasabuvir AUC values increased by 945%, 13%, and 325% respectively, and ombitasvir AUC values decreased by 54% in subjects with severe hepatic impairment [
      • Khatri A.
      • et al.
      Pharmacokinetics and safety of coadministered ABT-450 plus ritonavir(ABT-450/r), ABT-267 and ABT-333 as a single dose in subjects with normal hepatic function and in subjects with mild, moderate, and severe hepatic impairment.
      ]. Therefore in the absence of safety data SMV and the 3D-regimen are not recommended for use in patients with severe hepatic impairment (CPT class C). In contrast, dose adjustments for NS5A inhibitors are not needed. The use of new DAA’s has also to be adjusted to the degree of renal impairment. The AUC of SOF is 2.7-fold higher in patients with severe renal impairment, and the AUC0-inf of GS-331007, the renally excreted major SOF metabolite, is 5.5-fold higher [
      • Gane E.J.
      • Robson R.A.
      • Bonacicni M.
      • Maliakkal B.
      • Liu L.
      • Salwani K.
      • et al.
      Safety, anti-viral efficacy and pharmacokinetics (PK) of sofosbuvir (SOF) in patients with severe renal impairment.
      ]. According to the package insert patients with creatinine clearance ⩽30 ml/min or ⩽15 ml/min should not be treated with full dose SOF or SMV, respectively.

      Treatment duration

      The optimal length of treatment was not well studied. Preliminary data indicates that viral clearance on IFN- and RBV-free regimens is slower in patients with cirrhosis than in non-cirrhotic patients [
      • Kozbial K.
      • Freissmuth C.
      • Strassl R.
      • Al-Zoairy R.
      • Maieron A.
      • Stauber R.
      • et al.
      Viral kinetics during interferon-free sofosbuvir containing treatment regimens in a real-life cohort of chronic hepatitis C patients with advanced liver disease.
      ,
      • Welzel T.M.
      • Herrmann E.
      • Marcellin P.
      • Afdahl N.H.
      • Kowdley K.V.
      • Stamm L.M.
      • et al.
      On-treatment HCV RNA as a predictor of virologic response in the ledipasvir/sofosbuvir phase 3 program for HCV genotype 1 infection: analysis of the ION-1, ION-2, and ION-3 studies.
      ], although the degree of portal hypertension does not affect viral clearance [
      • Mandorfer M.
      • Kozbial K.
      • Stättermayer A.
      • Beinhardt S.
      • Schwabl P.
      • Schwarzer R.
      • et al.
      Impaired early viral kinetics in patients with cirrhosis treated with interferon-free regimens – The impact of portal pressure.
      ]. The differences of SVR rates in patients treated for 12 weeks or longer were minimal.
      The predictive value of HCV-RNA by One Signal Amplification (Versant HCV RNA 3.0, ART) at week 4 was low in non-cirrhotic patients [
      • Sidharthan S.
      • Kohli A.
      • Sims Z.
      • Nelson A.
      • Osinusi A.
      • Masur H.
      • et al.
      Utility of hepatitis C viral load monitoring on directly acting antiviral therapy.
      ]. By ART, undetectable HCV-RNA rates were lower than with the Cobas AmpliPrep/Cobas TaqMan [
      • Sidharthan S.
      • Kohli A.
      • Sims Z.
      • Nelson A.
      • Osinusi A.
      • Masur H.
      • et al.
      Utility of hepatitis C viral load monitoring on directly acting antiviral therapy.
      ,
      • Vermehren J.
      • Aghemo A.
      • Falconer K.
      • Susser S.
      • Lunghi G.
      • Zeuzem S.
      • et al.
      Clinical significance of residual viremia detected by two real-time PCR assays for response-guided therapy of HCV genotype 1 infection.
      ,
      • Sarrazin C.
      • Wedemeyer H.
      • Cloherty G.
      • Cohen D.E.
      • Chevaliez S.
      • Herman C.
      • et al.
      Importance of very early HCV RNA kinetics for prediction of treatment outcome of highly effective all oral direct acting antiviral combination therapy.
      ]. A suggestion to select treatment duration following the principles of response guided therapy is shown in Fig.1 which we are evaluating in a real world cohort of cirrhotic patients treated with IFN- and RBV-free combinations of SOF and DCV, SMV or LPV. At week 8 40% of patients had undetectable HCV-RNA (by ART) and 96% had an SVR after only 12 weeks of therapy. 30% had detectable <12 IU/ml HCV-RNA at week 8 and were treated for 16 to 24 weeks, all of them had an SVR (Kozbial et al., unpublished data). Thus, at least cirrhotic patients with undetectable HCV-RNA at week 8 need only 12 weeks of therapy. This algorithm has to be validated by prospective studies.
      Figure thumbnail gr1
      Fig. 1A tentative response guided algorithm to select the optimal treatment duration in patients with cirrhosis (based on data from Kozbial et al.
      [
      • Kozbial K.
      • Freissmuth C.
      • Strassl R.
      • Al-Zoairy R.
      • Maieron A.
      • Stauber R.
      • et al.
      Viral kinetics during interferon-free sofosbuvir containing treatment regimens in a real-life cohort of chronic hepatitis C patients with advanced liver disease.
      ]
      ). TND, target not detected by ART.

      Need for ribavirin

      Except for two studies the role of RBV was not explored in patients with cirrhosis prospectively. The impact of the addition of RBV is inconsistent among the various studies (see Table 1). With the 3D-regimen a trend toward lower SVR rates in patients infected with HCV-subtype 1a as compared to 1b was seen [
      • Ferenci P.
      • Bernstein D.
      • Lalezari J.
      • et al.
      ABT-450/r-ombitasvir-and dasabuvir with or without ribavirin for hepatitis C genotype 1.
      ,
      • Poordad F.
      • Hezode C.
      • Trinh R.
      • et al.
      ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
      ]. In treatment-naïve, non-cirrhotic patients in the Pearl IV study [
      • Ferenci P.
      • Bernstein D.
      • Lalezari J.
      • et al.
      ABT-450/r-ombitasvir-and dasabuvir with or without ribavirin for hepatitis C genotype 1.
      ] all HCV-subtype 1a patients from Europe were cured by the 3D-regimen irrespective whether they received placebo or RBV. All of the few non-responders were from the USA, pointing to geographic differences in pre-existing resistance mutations, like in studies using SMV [
      • Sarrazin C.
      • Lathouwers E.
      • Peeters M.
      • Daems B.
      • Buelens A.
      • Witek J.
      • et al.
      Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region.
      ]. Unfortunately, no efficacy data using the 3D-regime without RBV are available in cirrhotic patients. SVR rates in patients with HCV-1a and a prior null response to dual therapy differed significantly between the 24 and 12-week-arms (93% vs. 80%). The same observation was made in the Unity-1 trial, with a high proportion of patients from USA [
      • Poordad F.
      • Sievert W.
      • Mollison L.
      • Brau N.
      • Levin J.M.
      • Sepe T.E.
      • et al.
      All-oral, fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325 for non-cirrhotic patients with chronic HCV genotype 1 infection: UNITY-1 Phase 3 SVR12 results.
      ]. Nevertheless, addition of RBV to IFN-regimes became part of the label for certain groups of patients like GT1a patients treated with the 3D regime or treatment-experienced cirrhotic patients treated with SOF/LDV. Several “real world” series compared treatments with or without RBV. In the French observational cohort (ANRS CO22 HEPATHER) [
      • Pol S.
      • Bourliere M.
      • Lucier S.
      • De Ledighen V.
      • Zoulim F.
      • Dorival-Mouly C.
      • et al.
      Safety and efficacy of the combination daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients from the French observational cohort ANRS CO22 HEPATHER.
      ] and in the large cohort from the United Kingdom [
      • Foster G.R.
      • McLauchlan J.
      • Irving W.
      • Cheung M.
      • Hudson B.
      • Verma S.
      • et al.
      Treatment of decompensated HCV cirrhosis in patients with diverse genotypes: 12 weeks sofosbuvir and NS5A inhibitors with/without ribavirin is effective in HCV genotypes 1 and 3.
      ] addition of ribavirin or the extension of treatment duration to 24 weeks appeared to maximize SVR rates, but these reports may be affected by a selection bias. Other cohorts were successfully treated without RBV [
      • Kozbial K.
      • Freissmuth C.
      • Strassl R.
      • Al-Zoairy R.
      • Maieron A.
      • Stauber R.
      • et al.
      Viral kinetics during interferon-free sofosbuvir containing treatment regimens in a real-life cohort of chronic hepatitis C patients with advanced liver disease.
      ].
      Until now, the precise mode of action of RBV is unknown. Several mechanisms were suggested; including modulation of immune response, a depletion of GTP pool by inhibition of inosine monophosphate dehydrogenase, direct inhibition of HCV replication, and induction of mutagenesis, leading to production of defective viral particles [
      • Te H.S.
      • Randall G.
      • Jensen D.M.
      Mechanism of action of ribavirin in the treatment of chronic hepatitis C.
      ]. None of them can explain the role of RBV in IFN-free treatment. RBV is associated with substantial toxicities, thus a RBV-free regime would lessen the side effect profile of IFN-free regimes. For combination with PegIFN GT1 and GT4 patients required higher RBV-doses (∼1.5 mg/kg) than those with other genotypes [
      • Hadziyannis S.J.
      • Sette Jr., H.
      • Morgan T.R.
      • et al.
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
      ]. In a randomized controlled study in patients with GT2 and GT3 SVR rates were not different between 800 or 400 mg RBV/day [
      • Ferenci P.
      • Brunner H.
      • Laferl H.
      • Scherzer T.M.
      • Maieron A.
      • Strasser M.
      • et al.
      A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in HCV genotypes 2 and 3.
      ]. Decreasing the RBV dose in patients receiving triple therapy with boceprevir did not affect the outcome [
      • Poordad F.
      • Lawitz E.
      • Reddy K.R.
      • Afdhal N.H.
      • Hézode C.
      • Zeuzem S.
      • et al.
      Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection–a randomized trial.
      ]. In patients on IFN-free therapies in whom RBV is still needed the lowest dose of RBV required to prevent a relapse should be studied. Addition of RBV tended to increase SVR rates in studies which included a protease inhibitor in non-cirrhotic patients infected with GT1a [
      • Ferenci P.
      • Bernstein D.
      • Lalezari J.
      • et al.
      ABT-450/r-ombitasvir-and dasabuvir with or without ribavirin for hepatitis C genotype 1.
      ]. With SOF/LDV there was no additional benefit of RBV, except in nonresponders to dual therapy and cirrhosis [
      • Reddy K.R.
      • Bourlière M.
      • Sulkowski M.
      • Omata M.
      • Zeuzem S.
      • Feld J.J.
      • et al.
      An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin.
      ]. One other concern is the impact of impaired renal function on RBV in patients with decompensated cirrhosis.
      Thus, only a small proportion of GT1 patients really benefits from the addition of RBV. For the 2D combination, SVR rates without RBV were low in patients infected with GT2 and 3 [
      • Lawitz E.
      • Sullivan G.
      • Rodriguez-Torres M.
      • Bennett M.
      • Poordad F.
      • Kapoor M.
      • et al.
      Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection.
      ]. In view of the just minimal benefit of RBV, treating all patients with RBV would over treat about 90% of the patients for the gain of 5–7% SVR. In addition, avoiding side effects of RBV may improve treatment adherence.

      Emergence of resistance associated variants (RAV’s)

      Although most patients achieve viral eradication by IFN-free regimens, some experience a virologic relapse and typically harbor a population of RAVs. For example, all patients failing ombitasvir/paritaprevir/ritonavir plus dasabuvir have resistance to at least one drug class (NS3/4A, NS5A, and/or NS5B) [
      • Krishnan P.
      • Tripathi R.
      • Schnell G.
      • Reisch T.
      • Beyer J.
      • Dekhtyar T.
      • et al.
      Long-term follow-up of treatment-emergent resistance-associated variants iN NS3, NS5A and NS5B with paritaprevir/r-, ombitasvir- and dasabuvir-based regimens.
      ]. Similarly, most relapsers to SOF/LDV had NS5A and/or NS5B RAV’s, and a substantial proportion failed repeated treatment with 24 weeks of SOF/LDV [
      • Lawitz E.
      • Flamm S.
      • Yang J.C.
      • Pang P.S.
      • Zhu Y.
      • Svarovskaia E.
      • et al.
      Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks.
      ]. These RAV’s may persist for >2 years. Further sequential unsuccessful treatments with DAA therapies may generate complex resistant variants that limit future treatment options. Whether testing for NS5A RAV’s at baseline is useful is a matter of ongoing discussion.

      Conclusions

      The availability of IFN-free regimens has changed the approach to cure chronic hepatitis C. The new treatments also enable us to treat patients who could not be treated by IFN based regimes before. “Fine tuning” of treatments with respect to drug selection, treatment duration and the need for RBV is urgently needed. Further shortening of treatment may be possible [
      • Kohli A.
      • Osinusi A.
      • Sims Z.
      • Nelson A.
      • Meissner E.G.
      • Barrett L.
      • et al.
      Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study.
      ] but is far less important than efficacy and safety. It appears that shortening of treatment for shorter than 8 weeks carries the risk for post-treatment relapse [
      • Lawitz E.
      • Poordad F.
      • Gutierrez J.A.
      • Evans B.
      • Hwang P.
      • Robertson M.
      • et al.
      C-SWIFT: MK-5172 + MK-8742 + sofosbuvir in treatment-naive patients with hepatitis C virus genotype 1 infection, with and without cirrhosis, for durations of 4, 6, or 8 weeks.
      ,
      • Gane E.J.
      • Stedman C.A.
      • Hyland R.H.
      • Ding X.
      • Svarovskaia E.
      • Subramanian G.M.
      • et al.
      Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.
      ]. Which one of the two recently licensed regimens will be used depends more or less on the pricing policy. Under ideal circumstances a “head to head” comparison of both regimens should be performed, unfortunately this is unlikely to happen.
      In general, achieving SVR by any treatment effectively reduces hepatic decompensation and occurrence of hepatocellular carcinoma [
      • 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.
      ,
      • Rutter K.
      • Stättermayer A.F.
      • Beinhardt S.
      • Scherzer T.M.
      • Steindl-Munda P.
      • Trauner M.
      • et al.
      Successful antiviral treatment improves survival of patients with advanced liver disease due to chronic hepatitis C.
      ]. Until recently it was believed that cirrhosis was irreversible. There is now increasing evidence [
      • Marcellin P.
      • Gane E.
      • Buti M.
      • et al.
      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
      ] that cirrhosis can regress or even completely revert to the normal architecture if there is no more liver injury. In a study of paired pre- and post-treatment liver biopsies from 38 HCV patients, cirrhosis regression was found in 23 (61%) patients after a median period of 61 months (48–104 months) from an SVR to PEG/RBV therapy [
      • D’Ambrosio R.
      • Aghemo A.
      • Rumi M.G.
      • Ronchi G.
      • Donato M.F.
      • Paradis V.
      • et al.
      A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.
      ]. Fibrosis reversal will decrease portal hypertension and its associated risks. The risk for hepatocellular carcinoma remains, albeit at a much lower rate [
      • Scherzer T.M.
      • Reddy K.R.
      • Wrba F.
      • Hofer H.
      • Staufer K.
      • Steindl-Munda P.
      • et al.
      Hepatocellular carcinoma in long-term sustained virological responders following antiviral combination therapy for chronic hepatitis C.
      ]. Studies in patients with decompensated cirrhosis indicate that CTP and MELD score improve [
      • 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.
      ,
      • 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.
      ,
      • Ruiz I.
      • Feray C.
      • Pawlotsky J.M.
      • Hézode C.
      • et al.
      Patient with decompensated hepatitis C virus-related cirrhosis delisted for liver transplantation after successful sofosbuvir-based treatment.
      ]. HCV eradication before OLT improves graft, as well as overall survival rates in the long run. An important non-medical necessity is to make these drugs available to all patients in need for an effective treatment.

      Conflict of interest

      PF: Global Advisory board: Roche/Genentech, Merck.
      Advisor: AbbVie, Gilead, Janssen, Achilleon; Speaker’s bureau: Roche, MSD Austria, Janssen Austria, BMS Austria, Gilead, AbbVie, Böhringer-Ingelheim; Unrestricted research grant: Gilead Austria.
      KK: nothing to report.
      MM: Consulting: Janssen; Speaker’s bureau: Boehringer Ingelheim, Bristol-Myers Squibb, Janssen and Roche; Travel support from AbbVie, MSD and Roche.
      HH: Speaker fees from AbbVie, BMS, Gilead, Janssen, Advisor to BMS, Gilead, AbbVie, Janssen, Austria.

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