Management of Decompensated Chronic Hepatitis B Dr James YY Fung, - - PowerPoint PPT Presentation

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 25th Annual Scientific Meeting 18th November, 2012, Hong Kong

Natural History of HBV Cirrhosis

Acute flare Of CHB

Long term Benefits in Compensated Cirrhosis treated with Lamivudine

Patients, %

Placebo (n = 215) Lamivudine (n = 436) All P values ≤ .05 18% 9% 7% 8% 3% 4% 10 20 30 Overall Disease Progression CPT Increase HCC

651 patients – 41 sites (Asia-Pacific) – Randomized 2:1 LAM:Placebo

Liaw YF et al. N Engl J Med 2004;351:1521-31

Beneficial Effects of Antiviral Effects Diminished with Resistance

Wild type (n = 221) 5 10 15 20 25 6 12 18 24 30 36 Placebo (n = 215) 5% 21% M204I/V mutations (n = 209, 49%) 13% Time after randomisation (months) Patients with disease progression (%)

Liaw YF. Seminars in Liver Disease 2005; 25: 40-47.

Adefovir HBeAg+ Adefovir HBeAg- Telbivudine HBeAg+

% resistance

Fung J, et al. J Gastroenterol Hepatol 2008; 23:1182-92 5 Lamivudine Entecavir 20 40 60 80 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 4 4 5 4 1 2 Tenofovir 6 3 Telbivudine HBeAg-

Antiviral Resistance in Oral Therapies in Chronic Hepatitis B

Cirrhotic patients and patients with decompensated liver disease are unlikely to tolerate further flares if resistance occurs

2005-2008 1998

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

Garg H et al. Hepatology 2011;53:774-780

Tenofovir (n=14)vs plaecbo (n=13) INR>1.5; bilirubin >85mmol/L, ascites/encephalopathy

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

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

Pts with chronic hepatitis B and decompensated liver disease (N = 112) Tenofovir DF (n = 45) Emtricitabine + Tenofovir DF (n = 45) Entecavir (n = 22) Wk 168 Randomized 2:2:1 Interim analysis at Wk 48

Liaw YF et al. Hepatology 2011;53:62-72

Viral suppression and Mortality in Decompensated Cirrhosis treated with ETV

Shim JH et al. J Hepatol 2010;52:176-182

92.3%

6.9% 17%

70 patients with HBV decompensated cirrhosis treated with ETV 0.5mg

Changes in CTP and MELD Score at 12 Months with ETV

Change in CTP Score Through 12 Mos 8 6 4 2 8.1 ± 1.7 P < .001 10 12 6.6 ± 2.4 At 12 Months At Pretreatment Change in MELD Score Through 12 Mos 16 12 10 2 11.1 ± 3.8 P < .001 18 20 8.8 ± 2.3 At 12 Months At Pretreatment 14 8

Shim JH et al. J Hepatol 2010;52:176-182

ETV vs ADV in CHB Decompensation – Randomized Open Label Study

HBV-infected patients with decompensated liver disease* (N = 191) ETV 1.0 mg (n = 100) ADV 10 mg (n = 91) Wk 24 Yr 5

§ Primary efficacy endpoint: mean reduction in serum HBV DNA at Wk 24

Wk 48 Wk 96 Follow-up

Liaw YF et al. Hepatology 2011;54:91-100

ETV vs ADV in CHB Decompensation – Randomized Open Label Study

Liaw YF et al. Hepatology 2011;54:91-100

Mean HBV DNA (log10 copies/mL) B/L 9 8 7 6 5 4 3 2 1 4 8 12 16 20 24 28 32 36 40 44 48 Treatment (Wks) Limit of detection 300 copies/mL P < .0001

• 3.40
• 4.48

ETV 1.0 mg (n = 100) ADV 10 mg (n = 91) Patients With Measurements ETV ADV 100 91 98 88 92 80 87 80 76 73 71 66 69 61

ETV vs ADV in CHB Decompensation – Randomized Open Label Study

Liaw YF et al. Hepatology 2011;54:91-100

ADV (N=91) ETV (N=100) Δ MELD score (median)

• 1.7
• 2.6

¤ ¤CPT score ≥2 pts 27% 35%

1 ETV patient had lactic acidosis

ETV vs LAM in Decompensated CHB

ALT normalization & HBV DNA suppression

Hsu YC et al, 2012. Antiviral Ther; doi:10.3851/IMP2027 LAM LAM ETV ETV

Retrospective study on Decompensated HBV Hyperbilirubinemia >2x ULN Coagulopathy (Prolonged >3 secs) Antiviral therapy with LAM/ETV >1 week

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

Wong VWS et al. J Hepatol 2011(54):236-242

ALT >10x ULN, Br >3x ULN ETV (n=36) LAM (n=117)

ETV & LAM in Severe Acute Flares of CHB

Outcomes

Wong VWS et al. J Hepatol 2011(54):236-242

Overall Survival Liver-related Mortality

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

Wong VWS et al. J Hepatol 2011(54):236-242

Univariate Multivariate

Hazard ratio 95% CI P-value Hazard ratio 95% CI P-value

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

0.90 TDF 0.90 TDF/FTC 0.80 ETV

• No cases of lactic acidosis reported in any treatment arm

1.0 Median Creatinine (mg/dL) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 4 8 12 16 20 24 28 32 36 40 44 48 Wks on Study 45 45 22 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 TDF FTC/TDF ETV Pts at Risk, n

TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease

Liaw YF et al. Hepatology 2011;53:62-72

LDT & LAM in Decompensated CHB Clinical Response

Chan HLY et al , 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x

Multicenter Phase III Randomized Double Blind Trial Cirrhotics with CTP score ≥7, HBV DNA ≥5 log cpm

N=114 N=114

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

88%

Fontana RJ et al. Gastroenterology 2002;123:719-727 Overall Survival

154 HBV decompensated patients treated with LAM 6-month survival independent of early treatment efficacy

>6 months Survivors <6 months Survivors

Poor Survival éBr éCr éHBV DNA

Oral Therapy in Decompensated HBV Cirrhosis 1 year survival

70 75 80 85 90 95 100 LAM ADV TNV TVD ETV % 1 year survival

84%

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

86% 86% 93% 87%

*Non-head to head comparisons

LAM and ETV in Decompensated Cirrhosis

Undetectable HBV DNA (%) Months Months Virological breakthrough (%)

Hyun JJ et al, 2012. Liver Int;32(4):656-64

86 HBV decompensated patients (CTP ≥7) Treated with either LAM or ETV No difference in early mortality rates

Clinical Events for those with Cirrhosis and Without Virological Response

Zoutendijk R et al, 2012. Gut; doi:10.1136/gutjnl-2012-302024

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

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