Management of Decompensated Chronic Hepatitis B Dr James YY Fung, FRACP, MD Department of Medicine The University of Hong Kong Liver Transplant Center Queen Mary Hospital State Key Laboratory for Liver Research The University of Hong Kong International Symposium on Hepatology 2012 25 th Annual Scientific Meeting 18 th November, 2012, Hong Kong
Natural History of HBV Cirrhosis Acute flare Of CHB
Long term Benefits in Compensated Cirrhosis treated with Lamivudine 651 patients 41 sites (Asia-Pacific) Randomized 2:1 LAM:Placebo 30 All P values.05 Placebo (n = 215) Patients, % 20 10 18% 8% 9% 3% 7% Lamivudine (n = 436) 4% 0 Overall Disease Progression CPT Increase HCC Liaw YF et al. N Engl J Med 2004;351:1521-31
Beneficial Effects of Antiviral Effects Diminished with Resistance Patients with disease progression (%) 25 Placebo (n = 215) 20 M204I/V mutations (n = 209, 49%) 21% Wild type (n = 221) 15 13% 10 5 5% 0 0 6 12 18 24 30 36 Time after randomisation (months) Liaw YF. Seminars in Liver Disease 2005; 25: 40-47.
Antiviral Resistance in Oral Therapies in Chronic Hepatitis B 80 60 1998 Cirrhotic patients and patients with decompensated liver disease are unlikely to tolerate further flares if resistance occurs % resistance 40 20 2005-2008 0 1 2 3 4 5 1 2 3 1 2 3 4 1 2 1 2 1 2 3 4 5 6 1 2 3 Lamivudine Adefovir HBeAg+ Adefovir HBeAg- Telbivudine HBeAg+ Telbivudine HBeAg- Entecavir Tenofovir Fung J, et al. J Gastroenterol Hepatol 2008; 23:1182-92
Virological Response for ETV According to Severity of Liver Disease Zoutendijk R et al, 2012. Gut; doi:10.1136/gutjnl-2012-302024
Tenofovir vs Placebo in Acute on Chronic Liver Failure from HBV Tenofovir (n=14)vs plaecbo (n=13) INR>1.5; bilirubin >85mmol/L, ascites/encephalopathy Garg H et al. Hepatology 2011;53:774-780
Tenofovir vs Placebo in Acute on Chronic Liver Failure from HBV Garg H et al. Hepatology 2011;53:774-780
TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease Randomized 2:2:1 Interim analysis at Wk 48 Wk 168 Pts with chronic hepatitis B and decompensated liver disease (N = 112) Tenofovir DF (n = 45) Emtricitabine + Tenofovir DF (n = 45) Entecavir (n = 22) Outcome at 48 weeks TDF (n = 45) TDF/FTC (n = 45) ETV (n = 22) HBV DNA <400 cpm 71% 88% 73% Median log HBV DNA decline 3.11 3.92 3.40 Child Pugh score 2 decrease 26% 48% 42% Median MELD score change -2-2 -2 Liaw YF et al. Hepatology 2011;53:62-72
Viral suppression and Mortality in Decompensated Cirrhosis treated with ETV 70 patients with HBV decompensated cirrhosis treated with ETV 0.5mg 92.3% 6.9% 17% Shim JH et al. J Hepatol 2010;52:176-182
Changes in CTP and MELD Score at 12 Months with ETV Change in CTP Score Through 12 Mos 12 10 8 6 4 2 8.1 ± 1.7 P <.001 6.6 ± 2.4 Change in MELD Score Through 12 Mos 20 18 16 14 12 10 8 2 11.1 ± 3.8 P <.001 8.8 ± 2.3 At Pretreatment At 12 Months At Pretreatment At 12 Months Shim JH et al. J Hepatol 2010;52:176-182
ETV vs ADV in CHB Decompensation Randomized Open Label Study Primary efficacy endpoint: mean reduction in serum HBV DNA at Wk 24 Wk 24 Wk 48 Wk 96 Yr 5 HBV-infected patients with decompensated liver disease* (N = 191) ETV 1.0 mg (n = 100) ADV 10 mg (n = 91) Follow-up Liaw YF et al. Hepatology 2011;54:91-100
ETV vs ADV in CHB Decompensation Randomized Open Label Study Mean HBV DNA (log 10 copies/ml) 9 8 7 6 5 4 3 2 1 Limit of detection 300 copies/ml ETV 1.0 mg (n = 100) P <.0001-3.40-4.48 ADV 10 mg (n = 91) B/L 4 8 12 16 20 24 28 32 36 40 44 48 Treatment (Wks) Patients With Measurements ETV 100 98 92 87 76 71 69 ADV 91 88 80 80 73 66 61 Liaw YF et al. Hepatology 2011;54:91-100
ETV vs ADV in CHB Decompensation Randomized Open Label Study 1 ETV patient had lactic acidosis ADV (N=91) ETV (N=100) Δ MELD score (median) -1.7-2.6 CPT score 2 pts 27% 35% Liaw YF et al. Hepatology 2011;54:91-100
ETV vs LAM in Decompensated CHB ALT normalization & HBV DNA suppression Retrospective study on Decompensated HBV Hyperbilirubinemia >2x ULN Coagulopathy (Prolonged >3 secs) Antiviral therapy with LAM/ETV >1 week LAM ETV LAM ETV Hsu YC et al, 2012. Antiviral Ther; doi:10.3851/imp2027
ETV vs LAM in Decompensated CHB Overall Survival & Liver-Related Mortality Hsu YC et al, 2012. Antiviral Ther; doi:10.3851/imp2027
ETV & LAM in Severe Acute Flares of CHB ALT >10x ULN, Br >3x ULN ETV (n=36) LAM (n=117) Wong VWS et al. J Hepatol 2011(54):236-242
ETV & LAM in Severe Acute Flares of CHB Outcomes Overall Survival Liver-related Mortality Wong VWS et al. J Hepatol 2011(54):236-242
ETV & LAM in Severe Acute Flares of CHB Deaths Within 48 Weeks Wong VWS et al. J Hepatol 2011(54):236-242
ETV & LAM in Severe Acute Flares of CHB Factors Associated with Deaths Within 48 Weeks Univariate Hazard ratio 95% CI P-value Multivariate Hazard ratio 95% CI P-value Wong VWS et al. J Hepatol 2011(54):236-242
Could there be a possible cause for mortality associated with ETV use? 16 patients with HBV cirrhosis treated with ETV 5 developed lactic acidosis The MELD score (and not CPS) correlated with development of lactic acidosis All had MELD >18 All had impaired CrCl Important to dose-adjust for renal impairment Lange CM et al. Hepatology 2009;50:2001-2006
TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease No cases of lactic acidosis reported in any treatment arm Median Creatinine (mg/dl) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Pts at Risk, n TDF FTC/TDF ETV 0 45 45 22 0.90 TDF 0.90 TDF/FTC 0.80 ETV 4 8 12 16 20 24 28 32 36 40 44 48 Wks on Study 45 44 21 42 43 19 40 42 20 39 42 19 39 42 18 40 42 19 38 42 19 37 42 19 37 42 18 38 41 17 37 42 16 37 42 16 Liaw YF et al. Hepatology 2011;53:62-72
LDT & LAM in Decompensated CHB Clinical Response Multicenter Phase III Randomized Double Blind Trial Cirrhotics with CTP score 7, HBV DNA 5 log cpm N=114 N=114 Chan HLY et al, 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
LDT & LAM in Decompensated CHB Overall Survival Chan HLY et al, 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
LDT & LAM in Decompensated CHB Renal Function Chan HLY et al, 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
Biphasic Pattern of Survival in Decompensated HBV Patients 154 HBV decompensated patients treated with LAM 6-month survival independent of early treatment efficacy 88% >6 months Survivors Poor Survival é Br é Cr é HBV DNA Overall Survival <6 months Survivors Fontana RJ et al. Gastroenterology 2002;123:719-727
Oral Therapy in Decompensated HBV Cirrhosis 1 year survival 100 95 *Non-head to head comparisons 93% % 1 year survival 90 85 80 84% 86% 86% 87% 75 70 LAM ADV TNV TVD ETV Fontana RJ et al. Gastroenterology 2002;123:719-727 Schiff ER et al. Liver Transplant 2007;13:349-360 Schiff ER et al. Hepatology 2009;50:222 (Abstract) Shim et al. J Hepatol 2010;52:176-182
LAM and ETV in Decompensated Cirrhosis 86 HBV decompensated patients (CTP 7) Treated with either LAM or ETV No difference in early mortality rates Undetectable HBV DNA (%) Virological breakthrough (%) Months Months Hyun JJ et al, 2012. Liver Int;32(4):656-64
Clinical Events for those with Cirrhosis and Without Virological Response N=372 ETV treated patients Clinical events = HCC, decompensation, death Cirrhotic patients (<80 IU/mL) HBV DNA threshold of 2000 IU/mL was not associated with lower disease Progression in cirrhotic patients Zoutendijk R et al, 2012. Gut; doi:10.1136/gutjnl-2012-302024
HBV Cirrhosis Who Do We Treat? Asia Pacific Consensus on Chronic Hepatitis B 2012
Treatment of Decompensated CHB Summary I The short term outcome is not likely to be altered by antiviral therapy Determined by underlying liver reserve IFN-based therapy are contraindicated Oral NAs are comparable in Reducing viral load Improving MELD score and CTP score Short term survival
Treatment of Decompensated CHB Summary II All cirrhotics who are HBsAg+ should be considered for treatment Treatment should be lifelong Treat with a highly potent antiviral agent with high genetic barrier to resistance Patients unlikely to tolerate any further breakthrough flares Selection of mutant strains likely to limit choice of further treatment
Treatment of Decompensated CHB Summary III Early referral to a transplant unit is recommended for those with evidence of decompensation Br, Cr, INR, HBV DNA Hepatic encephalopathy Thank You