Focus on Transplantation: Treatment Post-transplant for HBV and HCV

Focus on Transplantation: Treatment Post-transplant for HBV and HCV The Viral Hepatitis Congress, Frankfurt, 09. September 2012 Christoph Sarrazin J. W. Goethe-University Hospital Medizinische Klinik I Frankfurt am Main, Germany

Disclosures Speakers bureau, consulting and/or research grants by Abbott, Boehringer, BMS, Gilead, Janssen, MSD/Merck, Rottapharm, Roche, Vertex

Hepatitis B Post-Transplant

Natural course of hepatitis B after liver transplantation (OLT) Universal reinfection of the graft in pts. with chr. hepatitis B associated with ~50% graft / patient survival at 5 years FU n=6033 Survival after OLT between recipients with HBV and those with other diagnoses before introduction of reinfection prophylaxis (UNOS) n=675 Kim et al., Liver Transpl. 2004 HBV-related liver disease as a contraindication for OLT

Introduction of Hepatitis B Immune Globulin (HBIG) Binding to and neutralizing circulating virions by long-term, repeated administration of HBIG p<0.001 Survival after OLT comparing no prophylaxis, short-term ( 2 months) and long-term ( 6 months) HBIG prophylaxis in 359 patients from Europe Samuel et al., NEJM 1993

Introduction of a direct antiviral agent: nucleoside analogue lamivudine Antiviral activity against hepatitis B Safe in cirrhotics and transplant pts. and prevention of reinfection after OLT (9/10 pts. with >20 wks. survival after OLT) n=32 Dienstag et al., NEJM 1995 Grellier et al., Lancet 1996

Establishment of a new standard for hepatitis B and liver transplantation Combination therapy of long-term HBIG plus Lamivudine n=19007 n=1723 Kim et al., Liver Transpl. 2004 Mile stone for management of hepatitis B after OLT with <5% recurrence at 5y FU but: - HBIG is expensive - HBIG has to be administered i.v. every 4 weeks - Lamivudine has a low barrier to resistance with frequent viral break-through HBV-related liver disease as a preferred indication for OLT

Low-dose HBIG 400-800 IU versus 2000 IU per month HBIG + Lamivudine low dose HBIG + Lamivudine n=147, HBIG 400-800 IU i.m. per month plus Lam +/- Adefovir median follow-up 1860 days (~5 years) 1% and 4% risk of HBV recurrence at 1 and 5 years after OLT n=5 patients with recurrence (HBsAg and HBV DNA pos.) Alternatively 500 IU s.c. every (other) week Recurrence in all patients was associated with Lamivudine resistance Gane et al., Gastroenterology 2007

Nucleos(t)ide Mono- /Combo-Therapy Ensuring high barrier to resistance Nucleos(t)ide Analogue Mono / Combo n=80, monotherapy with Entecavir, no HBIG median follow-up 26 months n=10 patients with recurrence (HBsAg pos.) 18 patients with detectable HBsAg at their last visit (23%) 17/18 patients had undetectable HBV- DNA Importance of adherence Fung et al., Gastroenterology 2011

Switch to Nucleos(t)ide Mono- / Combo- Therapy HBIG + Nuc. Nucleos(t)ide Analogue Combo n=61, after 12 months HBIG+Nuc and stable conditions switch to Nuc combo (mainly LAM + Entecavir), mean follow-up 15 months 2 cases with reappearance (3.3%) Saab et al., Am J Transplant 2011

Active vaccination followed by discontinuation of prophylaxis HBIG + Lamivudine Active Vaccination n=17 in each study, all HBeAg- + HBV-DNA neg. before & after OLT; after 18 months HBIG +/- Lam 1-3 HBV vaccine cycles (à 3x40µg) 14/17 with antihbs >10 IU/l (82%) 3/17 with antihbs >10 IU/l (18%) Selection of pts., high doses, boosting required and LT follow-up? Sanchez-Fueyo et al., Hepatology 2000 Angelico et al., Hepatology 2002; Di Paolo et al., Dig Dis Sci 2006

Discontinuation of prophylaxis Measurement of cccdna / HBV DNA in the liver HBIG + Lamivudine Stop n=30, HBeAg- + HBV-DNA neg. before & after OLT; 64-195 m. post OLT 25/30 without HBV recurrence HBV DNA and cccdna undetectable in the liver Lenci et al., J Hepatol 2011

Hepatitis C Post-Transplant

Natural course of hepatitis C after liver transplantation (OLT) HCV Re-Infection after OLT is associated with reduced survival 76,6% 69,9% Gane EJ et al., NEJM 1996, Forman et al., Gastroenterology 2002

Natural course of hepatitis C after liver transplantation (OLT) fibrosing cholestatic hepatitis C 2-6% OLT > 99% HCV RNA+ 25-45% acute hepatitis 50-98% chron. hepatitis 8-44% cirrhosis 42-63% decomp. 1-3 years 0 72h 1-4 mo >4-6 mo 1-15 years accord. to Berenguer M. Clin Liver Dis 2007

Acute Hepatitis C re-infection Treatment of "acute hepatitis C" 2.000.000 HCV-RNA (copies/ml) 1.500.000 1.000.000 500.000 0 0 5 Days after liver transplantation 10 15 20 25 30 Fukumoto et al. Hepatology 1996 Berg et al. Transplantation 1998

Treatment of acute hepatitis C after OLT pre-emptive therapy Studies pre-emptive treatment High rates of complications High immuno suppression required Limited tolerability (discontinuation rates up to 60%) Frequent dose reductions (>70%) Limited SVR rates (8-39%) No general pre-emptive treatment Option for individual patients with severe reinfection and favorable virological profile Chalasani et al., Hepatology 2005, Sugawa et al., Transplantation 2004, Kuo et al., Liver Transpl 2008, Sheiner et al., Hepatology 1998, Singh et al., Transplantation 1998, Castells et al., J Hepatol 2005

Treatment of recurrent hepatitis C 4-6 months after OLT Therapy if histologically proven recurrent hepatitis C Limited tolerability: ~ 1/3 discontinuation (4-55%) ~ 60% dose reductions Sustained virologic response: ~ 30% Genotype 1 ~ 50% Genotype 2/3 Negative predictors: - cirrhosis of liver graft - virologic null-response - donor age No correlation: - CSA versus Tacrolimus - PEG2a vs PEG2b - Virolog. response previous therapy Morard und Negro, J Hepatol 2005, Berenguer et al., Liver Transpl 2009 Carrion et al., Gastroenterology 2007, Peveling et al., Med Microbiol Immunol 2009

Treatment of hepatitis C after OLT Improved survival (PEG)-IFN / Riba treatment after OLT, n=89, SVR 37% 93% 74% 62% p=0,04 69% p=0,032 7 years Treatment vs. Control SVR vs. Non-SVR Potentially also effective to prevent recurrence of HCC (n=46, retrospective) Berenguer et al., Am J Transplant 2008, Kohli et al., Transpl Int 2012

Treatment of hepatitis C after OLT Importance of IL28B polymorphism Importance of graft and donor IL28B genotype (rs12979860) with virologic response to IFN-based therapy after OLT (n=46) Association of IL28B T-allele with vir. resp. & fibrosis progression after OLT, (n=167) Lange et al., J Hepatol 2011; Eurich et al., Transplantation 2012

Future aims: Direct antiviral agents for treatment of hepatitis C after OLT HCV NS3 protease inhibitors (Telaprevir / Boceprevir) in combination with PEG-Interferon and Ribavirin (Triple-Therapy) 100 100 HCV RNA undetectable at week 16 [%] 80 60 40 20 0 71 PR-TVR HCV RNA undetectable at week 8 [%] 80 60 40 20 0 70 PR-TVR 56 PR-BOC Pts. with previous NR (n=7) or severe recurrent hepatitis C (n=28) Reduction of immunosuppr. doses, anemia most common AE Kwo et al., EASL 2012; Coilly et al., EASL 2012

Future aims: Prevention of re-infection Direct inhibition of HCV replication by i.v. silibinin 57 years, male HCV-3a, NR cirrhosis, HCC Child C, MELD 23 20mg/kg BW 61 years, male HCV-1a/4, NR cirrhosis, Child C, MELD 20 65 years, female HCV-2a, Relapse cirrhosis, HCC, Child C, MELD 20 Ferenci et al., Gastroenterology 2008; Neumann et al., J Hepatol 2010; Beinhardt et al., J Hepatol 2011; Aghemo et al., Hepat Mon 2012

Summary Hepatitis B after liver transplantation - Standard prophylaxis: HBIG plus Nucleos(t)ide - Reinfection is mainly associated with viral load pre OLT - Low dose HBIG in combination with Nuc - Switch or Nuc only leads to higher HBs-ag reappearance but suppressed HBV DNA (compliance!) - Discontinuation of prophylaxis needs further predictors Hepatitis C after liver transplantation - No general pre-emptive PEG-IFN/Riba therapy - Treatment of transplant hepatitis with PEG-IFN/Riba with poor tolerability and limited SVR rates - Triple-Therapy with Protease-Inh. Telaprevir / Boceprevir - Future aim: prevention of re-infection