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Xavier Forns, MD Liver Unit , Hospital Clínic IDIBAPS and CIBREHD Barcelona, Octubre 2013

Xavier Forns, MD Liver Unit , Hospital Clínic IDIBAPS and CIBREHD Barcelona, Octubre 2013. Curso de Residentes AEEH. Tratamiento de poblaciones especiales. Hepatitis C recurrence after liver transplantation.

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Xavier Forns, MD Liver Unit , Hospital Clínic IDIBAPS and CIBREHD Barcelona, Octubre 2013

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

  2. Hepatitis C recurrence after liver transplantation Patientsurvival in HCV-positive and HCV-negativeindividuals. ONT/ RETH (1991-2011)

  3. Treatment of hepatitis C in the waiting list of liver transplantation • 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. • 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. 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 • Bilirubin 1 mg/dL, albumin 39 g/dL, platelets 119.000 • No ascites, transient elastography 19 kPa. • Should we treat this patient in the waiting list?

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

  6. 1,0 P < 0.01 0,8 0,6 Peg-IFN + RBV (n = 51) Probability of bacterial infections 0,4 Control (n = 51) 0,2 0,0 0 60 120 180 240 300 Time (days) 1,0 P < 0.01 0,8 Child B–C(n = 57) 0,6 Probability of bacterial infections 0,4 Child A (n = 45) 0,2 0,0 0 60 120 180 240 300 Time (days) Safety of antiviral therapy in patients awaiting liver transplantation Risk of life-threatening side effects: bacterial infections (SBP, SB) Carrion JA ,et al. J Hepatol. 2009

  7. CUPIC French Cohort: safety analysis Hezode et al EASL 2013

  8. Risk of relapse post-LT LT LT 16 106 106 RBV to 600 mg/d 14 105 105 12 104 104 Hemoglobin level (g/dL) - Viral load (IU/mL) - Viral load (IU/mL) 10 103 103 8 102 102 101 101 0 4 8 12 16 20 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 Time (weeks) Ramirez et al, Am J Transpl 2009 Triple therapy in patients in the waiting list for liver transplantation Treatment: PegIFN alfa2a 180 + RBV 1.000 mg/d + Telaprevir 1125/12 h Clinical and virological outcome TVP PR

  9. Weeks after end of therapy 100 91% 80 71% 62% 60 Cumulative rate of reversion to wild-type (%) 59% 40 V36MT54S R155KAny mutation 20 0 2.0 0 0.5 1.0 1.5 Years after end of therapy Treatment in patients awaiting LT: risk of resistance Selection of PIs resistance strains may compromise treatment after LT in case of severe hepatitis C recurrence Vierling et al EASL 2010

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

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

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

  13. 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 • Immunosuppression: tacrolimus 2 mg/d (levels 7 ng/mL) • If we use a PI, use telaprevir or boceprevir?

  14. P-glycoprotein: absorption excretion of substrates Absorption Protease inhibitors (PI): substrates and inhibitors Metabolism CYP3A4: CsA and tacrolimus Telaprevir: first day IS dosing Boceprevir: first day IS dosing 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) 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) Safety and efficacy of triple therapy in the LT setting • 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

  15. Tarcolimus 2 mg/d a 0,4 mg/d Tarcolimus 0,4 mg/d a 2,5 mg/d PR+ BOC RBV 600 mg/d RBV 400 mg/d Treatment of hepatitis C in the liver transplant setting PR Fs 6,3 kPa Fs 10 kPa 16 106 14 105 12 104 Hemoglobin level (g/dL) Viral load (IU/mL) Transfusion and EPO 10 103 8 102 101 0 4 8 12 24 48 12

  16. Safety and efficacy of triple therapy in the LT setting Coilly et al EASL 2013; Verna et al EASL 2013

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

  18. Safety and efficacy of triple therapy in the LT setting Coilly et al EASL 2013; Verna et al EASL 2013

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

  20. IFN-free regimen in HCV-infected LT recipients 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

  21. Viral Hepatitis Unit Liver Transplantation Unit

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