Chronic hepatitis B and cirrhosis fibrosis Cirrhosis 5

Chronic hepatitis B and cirrhosis fibrosis Cirrhosis 5 year F 1 F 2 F 3 0% 6% 17% Decompensated cirrhosis - 5 year Ascites 49% 15 -20% Bleeding 9% Jaundice 12% Several 30%

Chronic hepatitis B and cirrhosis 161 untreated patients with compensated HBV-related cirrhosis 5 -year survival • Compensated cirrhosis : 86% • Decompensated cirrhosis : 14 -28% Risk factors for decompensation • HBe-Ag positivity • HBe-Ag negative/HBV-DNA positive Fattovich G. J Hepatol 2003; 39: S 50.

Antiviral agents • Interferon / Pegylated interferon Ø Lamivudine Ø Adefovir-dipivoxil Ø Entecavir Ø Tenofovir Ø Telbivudine Ø Clevudine Ø Emtricitabine…

Hepatitis B: future trends Incidence of cirrhosis Decompensated cirrhosis Need for transplantation HCC (? ) Decompensation / breakthrough Spontaneous exacerbation / cirrhosis

Management of decompensated HBVrelated cirrhosis • Objectives: Ø Symptomatic treatment of complications Ø Rapid assessment of HBV replication status Ø Antiviral treatment in those with significant HBV replication Ø Minimize the risk of resistance Ø Return to a state of compensated cirrhosis Ø Bridge those who do not return to compensated cirrhosis to transplantation

Management of decompensated HBVrelated cirrhosis • Decompensated cirrhosis Ø Ascites Ø Jaundice Ø variceal bleeding Ø Low coagulation factors • HBV-DNA > 104 - 105 copies/m. L • Whatever HBe Ag status • Indication for antiviral therapy

Interferon in decompensated HBV-related cirrhosis • Frequently contraindicated: Ø thrombocytopenia Ø leukopenia Ø initial flare Ø further deterioration of liver function Ø sepsis Ø other complications • Impossibility to reach optimal doses

Lamivudine in decompensated HBV cirrhosis Author Year Patients Agent HBV-DNA pos HBe-Ag pos Villeneuve JP 2000 35 Lam. 35/35 20/35 Yao FY 2001 23 Lam. 23/23 17/23 Perillo RP 2001 77 Lam. 48/77 (62%) 46/77

Lamivudine in decompensated HBV cirrhosis Author year Patients treated ≥ 6 months Villeneuve JP 2000 23/35 23/23 Yao FY 2001 16/23 16/16 Perillo RP 2001 22/77 17/22** * Branched immunoassay; ** at one year. HBV-DNA neg at 6 months*

Lamivudine in decompensated HBV cirrhosis 35 treated patients ü 5 death < 6 months ü 7 transplanted 26 treated ≥ 6 months 22 improved (63%) Villeneuve JP et al. Hepatology 2000; 31: 207. ü 19 alive without LT Follow up 19 ± 2 months

Lamivudine in decompensated HBV cirrhosis 23 treated patients ü 7 transplanted < 6 months 17 treated ≥ 6 months ü 2 transplanted ü 15 improved (65%)/alive Yao FY et al. Hepatology 2001; 34: 411.

Lamivudine in decompensated HBV cirrhosis Treated Control (n=23) Decrease in Child score ≥ 3 points Median change in Child score Return to Child score < 7 p 61% 0% <0. 0001 -3 +1 0. 01 7/23 0. 001 Yao FY et al. Hepatology 2001; 34: 411.

Steroids in patients with cirrhosis and severe alcoholic hepatitis steroids control p 1 month-survival 84% 65% 0. 001 Δ bilirubin day 14 (µmol/L) - 105 - 45 0. 002 -2 -1 0. 03 Δ prothrombin time day 28 (sec) Mathurin P et al. J Hepatol 2002; 36: 480.

Lamivudine in decompensated HBV cirrhosis Author Year Patients Resistance Follow-up Villeneuve JP 2000 35 25% 2 y Yao FY 2001 23 10% 1 y Perillo RP 2001 77 28% 54 -74 w

Resistance (%) Lamivudine resistance

Adefovir in candidates for LT with lamivudine resistant strains Adefovir 128 candidates for transplantation with lamivudine resistance Change in HBV-DNA - 4. 1 log 10 Normalization in ALT 76% Normalization in bilirubin 81% Normalization in prothrombin 50% Improvement in CPT score 90% Schiff ER et al. Hepatology 2003; 38: 1419.

New antiviral agents Lamivudine Tenofovir Adefovir Telbivudine Entecavir Clevudine

Antiviral agents in cirrhotic patients Tolerance Efficacy Rapidity Resistance Lamivudine +++ +++ Adefovir ++ ++ + ± +++ +++ - Tenofovir ++ +++ - Telbivudin * + +++ ++ Entecavir * * Except in patients with lamivudine resistance Combinations: not justified

Take home messages # 1 • Decompensated HBV-related cirrhosis with high viral load is an uncommon condition • Antiviral therapy should be started rapidly with the aims of: Ø returning to a state of compensated cirrhosis Ø bridging to transplantation those who do not rapidly improve (< 3 -6 months) Ø lowering the risk of post transplant recurrence • Acute-on-chronic liver failure in HBV carriers is an emerging issue Ø Urgent antiviral therapy is also justified • Entecavir and tenofovir currently represent the safest options

Case report # 1 • • • 48 year old man, past history of chronic hepatitis B Liver biopsy 1999 : A 2 -F 3, HBV-DNA > 106/L Lamivudine: HBV-DNA becomes negative 2004: the patient stops lamivudine Dec 2005 : acute exacerbation Ø Ø Bilirubin 550 µmol/L AST 50 times normal / ALT 60 times normal Prothrombin index: 19% HBV-DNA: 100 106/L • Initiation of Lamivudine + tenofovir • Occurrence of encephalopathy; transplantation ?

Case report # 1 Emergency liver transplantation

Case report # 1 • • • Emergency transplantation HBV-DNA 2 106/m. L Post operative course uneventful Lamivudine + tenofovir + anti-HBs Ig Explant : cirrhosis + massive necrosis One year post transplant: Normal serum transaminases Serum HBV-DNA undetectable Liver ccc. DNA undetectable

Take home message # 2 • Acute-on-chronic liver failure in chronic HBV carriers is an emerging condition Ø Breakthrough on antiviral therapy (resistance) Ø Immunosuppressive agents (cancer, autoimmune • New antiviral agents: highly effective at reducing viral load Ø Do not always result in recovery due to the underlying chronic disease • Positive serum HBV-DNA is no longer a contraindication for emergency transplantation Ø Provided antiviral agents and anti-HBs IGs are continued

Case report # 2 • 64 year old man • Diagnosis of chronic hepatitis B in 1988 Ø HBs Ag pos, HBe Ag neg, HBV-DNA pos • Cirrhosis with grade II varices • Lamivudine (100 mg/d) started in 2001 • Variceal bleeding in 2007, encephalopathy Ø ALT 2 times normal Ø INR 1. 1 Ø HBV-DNA 5. 06 log What to do with antiviral therapy ?

Case report # 2 • • • June 2007, started on lamivudine + adefovir Sept 2007, HBV-DNA 3. 14 log Apr 2008, HBV-DNA undetectable Refractory ascites Evaluation: Ø ALT 1. 2 N, bili. 11 µmol/L, creatinine 111 µmol/L, INR 1. 1, platelets 168 109/L Ø HBs Ag pos, HBe Ag neg, HBV-DNA neg

Case report # 2 • Options: Ø Medical management with a change in antiviral agents ? Ø TIPS ? Ø Liver transplantation ? Which treatment before transplantation ? Maintained on lamivudine + adefovir

Case report # 3 • • • 40 -year old man, originary from Africa Coinfection HBV-HDV Cirrhosis documented by biopsy Portal hypertension with variceal bleeding HBs Ag pos, HBe Ab neg, HBV-DNA undetectable, anti-HDV Ab pos • Prothombin index 50%, INR 1. 7, bili 61 µmol/L, AST 2 N, ALT 1. 5 N, creatinine 73 µmol/L, MELD 17, AFP normal

Case report # 3

Case report # 3 • Transplantation / cirrhosis ? • Transplantation / HCC ? • HCC outside the criteria / contra indication for transplantation ?

Case report # 3