1. Xavier Forns, MD Liver Unit, Hospital Clínic IDIBAPS and CIBREHD Barcelona, Octubre 2013 Tratamiento de poblaciones especiales Curso de Residentes AEEH

2. Patient survival in HCV-positive and HCV-negative individuals. ONT/ RETH (1991-2011) Hepatitis C recurrence after liver transplantation

3. 65-year old patient with HCV-related liver cirrhosis An US examination reveals 2 HCC (3,5+1 cm diameter) After extensive evaluation the patient is included in the waiting list for liver transplantation. Treatment of hepatitis C in the waiting list of liver transplantation Genotype 1b IL28 CT; Viral load 830.000 IU/mL Previous therapy with PegIFN and RBV in 2008: partial responder (> 2 log decrease in VL at week 12).

4. Should we treat this patient in the waiting list? Bilirubin 1 mg/dL, albumin 39 g/dL, platelets 119.000 No ascites, transient elastography 19 kPa. What treatment would you propose? a) PegIFN + RBV b) PegIFN+RBV+PI (telaprevir/boceprevir) Treatment of hepatitis C in the waiting list of liver transplantation

5. Triple therapy in patients with cirrhosis (CUPIC): efficacy Increased on treatment virological response with PR + BOC/TPV Hezode et al EASL 2013 0 20 40 60 80 % patientns with HCV-RNA < LOD 49% 51% 62% 81% 77% 58% BOC (n=190) TVR (n=295) 100 79% 16% Cirrhotic patients (CUPIC) relapsers/partial responders Week 4 Week 8 Week 12 Week 16

6. Probability of bacterial infections 060120180240300 0,0 0,2 0,4 0,6 0,8 1,0 P < 0.01 Child B–C(n = 57) Child A (n = 45) Time (days) Risk of life-threatening side effects: bacterial infections (SBP, SB) Carrion JA,et al. J Hepatol. 2009 Safety of antiviral therapy in patients awaiting liver transplantation

7. Patients, n (% patients with at least one event)Telaprevir n=295 Serious adverse events (SAEs)*160 (54.2%) Premature discontinuation Due to SAEs 139 (47.1%) 63 (21.3%) Death Septicemia, Septic shock, GI Bleeding, Encephalopathy, others 7 (2.1%) Infection (Grade 3/4)27 (9.1%) Hepatic decompensation (Grade 3/4)15 (5.1%) Boceprevir n=190 97 (51%) 80 (42.1%) 27 (14.2%) 3(1.6%) 8 (4.2%) 9 (4.7%) CUPIC French Cohort: safety analysis Hezode et al EASL 2013 FactorORIC 95%p Platelets < 100.000/mm33,111,3-7,70,009 Albumin < 3,5 g/dl6,332,6-15< 0,0001

8. Triple therapy in patients in the waiting list for liver transplantation Treatment: PegIFN alfa2a 180 + RBV 1.000 mg/d + Telaprevir 1125/12 h -24-20-16-12-8-404812162024 LT Viral load (IU/mL) Time (weeks) 10 1 10 2 10 3 10 4 10 5 10 6 Ramirez et al, Am J Transpl 2009 Risk of relapse post-LT Clinical and virological outcome 0481216 Viral load (IU/mL) - 10 1 10 2 10 3 10 4 10 5 10 6 Hemoglobin level (g/dL) - 20 8 10 12 14 16 RBV to 600 mg/d TVP PR LT

9. Treatment in patients awaiting LT: risk of resistance Years after end of therapy 00.51.01.5 2.0 91% 71% 62% 59% 100 80 60 40 20 0 V36M T54S R155K Any mutation Cumulative rate of reversion to wild-type (%) Weeks after end of therapy Vierling et al EASL 2010 Selection of PIs resistance strains may compromise treatment after LT in case of severe hepatitis C recurrence

10. Wk 0 +12 Sofosbuvir 400 mg QD + RBV SVR12 CONTAINMENT: Sofosbuvir + RBV Prior to Liver Transplant  40-60 HCV Patients on LT list due to HCC –Expected transplant within 3-12 months  Primary efficacy endpoint : SVR12 post-LT LT Treat up to time of LT or maximum of 24 weeks ClinicalTrials.gov. NCT01559844 DAA and prevention of hepatitis C recurrence

11. 66-year old patient with hepatitis C recurrence after LT Transient elastography (12 months after LT) 10 kPa. Liver biopsy: F3 Treatment of hepatitis C in the liver transplant setting Should we treat the patient? How? 1) PegIFN-RBV 2) PegIFN-RBV + PI

12. Carrion JA, et al. Gastroenterology 2007; Effect of SVR on disease progression 4 8 12 16 20 HVPG (mmHg) 0 12.0 6.7 5.0 3.5 p = 0.047 p = 0.004 p = 0.003 NO (n = 26) YES (n = 11) Sustained virological response Berenguer M, et al. Am J Transpl. 2008 Patient survival in SVR (n = 33) vs NR (n = 56) P= 0.032 Follow-up since LT (days) Outcomes and response to antiviral therapy after LT

13. Immunosuppression: tacrolimus 2 mg/d (levels 7 ng/mL) Treatment of hepatitis C in the liver transplant setting Bilirubin 1 mg/dL, AST 243 IU/L, GGT 323 IU/L, Br 1,6 mg/dL, Hb 12,6 g/L, platelets 121.000, neutrophils 2300 If we use a PI, use telaprevir or boceprevir?

14. Absorption Metabolism P-glycoprotein: absorption excretion of substrates CYP3A4: CsA and tacrolimus Protease inhibitors (PI): substrates and inhibitors CsA reduce to ~ 1/4 (200 mg/d to 50 mg/d) TAC reduce to ~ 1/30 (2 mg/d to 0.5 mg/week) Telaprevir: first day IS dosing CsA reduce to ~ 1/2 (200 mg/d to 100 mg/d) TAC reduce to ~ 1/8 (4 mg/d to 0.5 mg/d) Boceprevir: first day IS dosing Check every other day during first week of triple therapy (or until steady state) Back to baseline dose after IP interruption (check weekly for at least 1 month) Coilly et al, Liver Int 2013 Safety and efficacy of triple therapy in the LT setting

15. 08122448 Viral load (IU/mL) 10 1 10 2 10 3 10 4 10 5 10 6 Hemoglobin level (g/dL) 12 8 10 12 14 16 RBV 600 mg/d Transfusion and EPO 4 Fs 10 kPa Fs 6,3 kPa Treatment of hepatitis C in the liver transplant setting RBV 400 mg/d Tarcolimus 2 mg/d a 0,4 mg/dTarcolimus 0,4 mg/d a 2,5 mg/d PR PR+ BOC

16. Coilly et al EASL 2013; Verna et al EASL 2013 Safety and efficacy of triple therapy in the LT setting Baseline characteristicsFrench cohort n=98 Median age (years)50 F2-F4 (%) FCH (%) 69 10 Time to LT (months)37 Naïve /Non response/relapse (%)48/37/15 CsA vs TAC (%)41/53 Genotype 1a vs 1b30/70 Telaprevir vs Boceprevir58/42 USA cohort n=112 58 75 10 42 47/40/13 41/57 55/38 88/12

17. Coilly et al EASL 2013 French cohort Efficacy of triple therapy in the LT setting Week 12 EVR 0 20 40 60 80 % patientns with HCV-RNA < LOD 61% 82% BOC TVR 100 38% 88% Week 48 EOT n=41n=57 n=17n=16 USA cohort Week 4 RVR 0 20 40 60 80 % patientns with HCV-RNA < LOD 63% 100 67% Week 48 EOT n=43 Verna et al EASL 2013 65% Week 52 SVR4 n=43

18. Coilly et al EASL 2013; Verna et al EASL 2013 Safety and efficacy of triple therapy in the LT setting Frequency and type of side effectFrench cohort n=98 Serious adverse events leading discontunuation21% Anemia requiring EPO Anemia requiring Transfusion 95% 43% Rejection8% Renal failure16% Death6,3% USA cohort n=102 11% 79% 46% 4% 34% 6%

19. Patients awaiting LT (HCV) Child-Pugh < 8 (MELD < 18) Genotype 2,3 o 4 Peg-IFN + RBV a Genotype 1 Peg-IFN + RBV+/- TVP/BOC a,b Child-Pugh ≥ 8 (MELD ≥ 18) No treatment Consider clinical trial IFN-free (DAA) a Naive, relapsers and partials (in nulls lead-in phase) b Do not add PI if portal hypertension and albumin < 35g/L HCV recurrence Follow-up, individualize therapy (or wait for DAA) Mild progression of recurrence Liver Stiffness < 8.7 kPa F ≥ 2 and HVPG ≥ 6 mmHg Liver Stiffness > 8.7 kPa G2 or G3 Peg-RBV G1 Peg-RBV+/- IP Crespo et al Gastroenterology, 2012

20. HCV-infected patient with fibrosing cholestatic hepatitis 6 months post-LT Daclatasvir 60 mg/d + Sofosbuvir 400 mg/d (24 weeks) Fontana et al AASLD 2012 IFN-free regimen in HCV-infected LT recipients

21. Viral Hepatitis Unit Liver Transplantation Unit