Management of Decompensated Chronic Hepatitis B · 2012. 12. 9. · Decompensated HBV Patients 88% Fontana RJ et al. Gastroenterology 2002;123:719-727 Overall Survival 154 HBV decompensated

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

Patie

nts,

%

Placebo (n = 215)

Lamivudine (n = 436)

All P values ≤ .05

18%

9% 7% 8%

3% 4%

0

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)

0

5

10

15

20

25

0 6 12 18 24 30 36

Placebo (n = 215)

5%

21% M204I/V mutations (n = 209, 49%)

13%

Time after randomisation (months)

Patie

nts

with

dis

ease

pro

gres

sion

(%)

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

Adefovir HBeAg+

Adefovir HBeAg-

Telbivudine HBeAg+

% re

sist

ance

Fung J, et al. J Gastroenterol Hepatol 2008; 23:1182-92

5Lamivudine Entecavir

0

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

Cha

nge

in C

TP S

core

Thr

ough

12

Mos

8

6

4

2 8.1 ± 1.7

P < .001

10

12

6.6 ± 2.4 At 12

Months At

Pretreatment

Cha

nge

in M

ELD

Sco

re

Thro

ugh

12 M

os 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




Mea

n H

BV

DN

A

(log 1

0 cop

ies/

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



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


Overall Survival Liver-related Mortality

ETV & LAM in Severe Acute Flares of CHB Deaths Within 48 Weeks


ETV & LAM in Severe Acute Flares of CHB Factors Associated with Deaths Within 48 Weeks


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 M

edia

n C

reat

inin

e (m

g/dL

)

0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

0 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


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


LDT & LAM in Decompensated CHB Renal Function


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 éBr éCr

éHBV DNA

Oral Therapy in Decompensated HBV Cirrhosis 1 year survival

70

75

80

85

90

95

100

LAM ADV TNV TVD ETV

% 1

yea

r sur

viva

l

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

Und

etec

tabl

e H

BV

DN

A (%

)

Months Months

Viro

logi

cal b

reak

thro

ugh

(%)

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

Management of Decompensated Chronic Hepatitis B · 2012. 12. 9. · Decompensated HBV Patients 88% Fontana RJ et al. Gastroenterology 2002;123:719-727 Overall Survival 154 HBV decompensated

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