Actue Decompensation Management of Hepatitis B patients

(1)

中國附醫消化內科

賴學洲醫師

(2)

ld

l



43 years old male



Present illness: progressive jaundice for 2-3 days.



Present illness: progressive jaundice for 2 3 days.



Past history: hepatitis B for 10 years



Family history: father and brother had DM, and

hypertension

yp

(3)



Lab data:(2007-9-28) ALT:2802, AST:1507,

Bili-T:14.80, bili-D:8.35, PT:21.26 (control 10.44

,

(

sec), INR:1.81, HBsAg(+), HCVAb (-), HBeAg

(+) Anti-HBeAb (-) Anti-HBc IgM (+) HBV

(+), Anti HBeAb ( ), Anti HBc IgM (+), HBV

DNA:1.60 x 10

6 copies/mL, genotype B.

(4)

(5)



60 years old female



Chief complaint: fatigue and poor appetite for



Chief complaint: fatigue and poor appetite for

one week

P h

h

B f 20



Past history: hepatitis B for 20 years



Family history: mother, five sisters and four

y

,

brothers were hepatitis B carrier

Al h l i

( ) ki

( ) T

i



Alcohol consumption (-), smoking (-), Tattooing

(6)



Lab data: (2010-1-39)ALT:932, AST:1076, Bili-T:

1.40, bili-D:0.4, PT:15.00 (control 11.34 sec),

,

INR 1.34, HBsAg(+), HCVAb (-), HBeAg (-),

Anti-HBeAb (+) HBV DNA>6 4 x 10

8 Anti-HBeAb (+), HBV DNA>6.4 x 10

copies/mL.

h

l

h

l d

6

(7)

(8)

Current Understanding of HBV Infection

Anti-HBe

Current Understanding of HBV Infection

HBeAg

HBV DNA ALT activity Phase Immune Tolerant Immune Clearance Inactive Carrier State Reactivation Minimal Ch i ti Mild hepatitis A ti Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation

O

l

Optimal treatment times

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

(9)

Three phases + one variant phase of CHB

Immune tolerant phase Immune clearance phase Inactive residual phase Reactivation HBeAg reversion HBeAg-negative IU/ml 2x109

HBV DNA

_{Acute Hepatic}

hepatitis 2x104

HCC HBeAg-positive Anti-HBe-positive

Wild type Mutant > Wild

Pre C/BCP Wild > Mutant Mutant

p

Decompensation

(<5%)

Cirrhosis HCC HBsAg loss Cirrhosis HCC ALT Active hepatitis Minimal Minimal/inactive Nucleus Nucleus/cytoplasm Absent

Active hepatitis Nucleus/cytoplasm Histology Liver HBcAg 60 35 20 Age ₃₅ year

Liaw & Chu Lancet 2009

(10)

Three phases + one variant phase of CHB

Immune tolerant phase Immune clearance phase Inactive residual phase Reactivation HBeAg reversion HBeAg-negative IU/ml 2x109 HBV DNA hepatitis 2x104 HCC HBeAg-positive Anti-HBe-positive Wild > Mutant

Wild type Mutant > Wild

Pre C/BCP Mutant Cirrhosis HCC HBsAg loss Cirrhosis HCC

Chronic Hepatic

Decompensation

(~4%)

ALT

( 4%)

Active hepatitis Minimal Minimal/inactive

Nucleus Nucleus/cytoplasm Absent

Active hepatitis Nucleus/cytoplasm Histology Liver HBcAg 60 35 20 Age ₃₅ year

Liaw & Chu Lancet 2009

(11)

Spontaneous HBeAg seroconversion

A critical

biologic “lock”,

leaks sometimes

HBeAg loss and

seroconversion

HBeAg+

hepatitis

~15*

_94-100%

~5%

0-6%

~5%

HBeAg+ hepatitis

HBV-DNA >10

5

_cp/ml

Sustained remission

HBV DNA <10

4

_cp/ml

~3.5*

HBV-DNA >10 cp/ml

_{HBV-DNA <10}

4

_cp/ml

1.5*

HBeAg

 hepatitis

HBV-DNA >10

4-5

_cp/ml

<5%

Liver cirrhosis

2.9*

Inactive carrier

~4*

_2-6*

1.5*

5%

* %/year

Decompensation

HCC

HBsAg loss

1.5 * %/year

(12)

5-yr Survival in Patients with

5 yr Survival in Patients with

Chronic Hepatitis B

N=121 (97%) N=12 8 (86%) (86%) N=130

P<0.001

N=379

_(55%)

(13)

Survival of 98 patients with HBV related cirrhosis

p

92%

79%

(14)

Survival and Compensation

84% vs 14%

(15)

Peginterferon alfa-2a

Lamivudine

Entecavir

Tenofovir

I

f

lf 2b

Ad f

T lb

d

1990

1998

2002

2005

2006

2008

(16)

N=18; Child’s B/C:78/22; Median Rx:18Ms

(17)

35 patients

Chils’s B/C: 28/72

Rx with lamivudine

5 deaths < 6Ms

23 treated > 6Ms

(mean, 19M)

7 OLT <6Ms

1 no improvement

OLT t 16 M

22 improved

OLT at 16 M

2 d

th

20 alive

2 deaths

SBP at 17M; HCC at

31M

57%

Villeneuve et al. Hepatology 2000

57%

(18)

77 patients enrolled

47 t

l

t d

30 not transplanted

(R

26 M)

39%

47 transplanted

30 not transplanted

5 t

t d < 12

k

3 withdrawn at week 1

(Rx 38M)

(Rx: 26 M)

5 treated < 12 weeks

3 withdrawn at week 1

42 > 12 weeks

27 treated > 1 week

3 deaths; 2 withdrawals

37 treated >52 weeks

22 treated > 52 weeks

(19)

(20)

(21)

84%

70%

14%

Adapted from De Jongh et al.Gastroenterology

1992 and Perrillo et al. Hepatology 2001

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162 LAM (+)

162 LAM ( )

147 LAM (-)

91 LT

_{84 LT}

71 non-LT

18 Deaths

83 non-LT

10 Deaths

18 Deaths

10 Deaths

12 Delisted

7 Delisted

(8.4%)

(16.9%)

41 Still waiting

46 Still waiting

(23)

88%

N=129

88%

73%

N=154

Median Lamivudine

treatment 16 Ms

N=25

(24)

Multivariate Cox Regression Model

g

of Pretreatment Characteristics and

6-Month Mortality

6 Month Mortality

Variable

SE of

Risk Ratio (95% CI) P value

Variable

SE of

estimate

Risk Ratio (95% CI) P value

Creatinine

0.311 5.23 (2.84-9.63)

0.0001

Bilirubin

0.084 1.69 (1.43-1.99)

0.0001

HBV DNA (+/-)

0.751 6.13 (1.41-26.76)

0.0158

(25)

Studies of Lamivudine in Decompensated HBV Cirrhosis

Study

N

Child

B/C

Median

Follow-up

%Viral

Resista

%Survival %

Transpla

Study

N

p

(months)

nce

p

ntation

Uncontrolled, open label

Yao FY et al

13 0/100

15

7

100

15 Yao FY et al.

2000 (UCSF)

13 0/100

15

7

100

15 Kapoor D et al.

18 78/22

18

17

100

0 2001(India)

Villeneuve et al. 2000

(Canada)

35 28/72

19

13

70

20 (Canada)

Perrillo RP et al.

2001(North America)

77 NA

26

21

96

61 Controlled, open label

Yao FY et al. 2001(UCSF)

23 0/100

13

10

100

35 Fontana RJ et al 2002

162 NA

10

11

83

56 Fontana RJ et al. 2002

(North America)

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Entecavir versus lamivudine in the treatment

of chronic hepatitis B patients with hepatic

decompensation.

p

Hsu YC

,

Mo LR

,

Chang CY

,

Perng DS

,

Tseng CH

,

Lo GH

,

Tai CM

,

Lin

CW

Hsu CC

Hsu CY

Huang SC

Lin JT

CW

,

Hsu CC

,

Hsu CY

,

Huang SC

,

Lin JT

.

Department of Internal Medicine, E-Da Hospital/I-Shou University,

Kaohsiung, Taiwan.

g,

(30)

Abstract

BACKGROUND:

Lamivudine has been widely used in chronic hepatitis B patients with hepatic decompensation, but its use is limited by drug resistance. This outcome research aimed to investigate the comparative efficacy and safety of entecavir versus lamivudine in decompensated patients.

METHODS:

Between November 2004 and February 2010, 126 consecutive treatment-naive patients received either entecavir (n=53) or lamivudine (n=73) for decompensated chronic hepatitis B. All patients presented with both hyperbilirubinaemia and coagulopathy. Primary outcome was mortality within 1 year;

d l d d l l d l b h l d l l d secondary outcomes included liver-related mortality, biochemical and virological response, and improvement of hepatic dysfunction.

RESULTS:

Both treatment groups were comparable in baseline characteristics. A total of 19 (35.8%) entecavir and g p p 33 (45.2%) lamivudine receivers expired within 1 year, respectively (P=0.29, log rank test). Age (hazard ratio [HR] 1.04 per year, 95% CI 1.01, 1.06), cirrhosis (HR 2.07, 95% CI 1.02, 4.23), and international normalized ratio for prothrombin time (HR 1.44, 95% CI 1.20, 1.74) were independent baseline

predictors for all-cause mortality. Antiviral therapy was also unrelated to liver-specific death. However, p ti t t ki g t i t d d t tt i i t f li ti (76 5% 52 5% more patients taking entecavir tended to attain aminotransferase normalization (76.5% versus 52.5%; P=0.05) and viral DNA undetectability (100% versus 58.3%; P=0.06). Moreover, entecavir was

associated with significantly greater reduction of the model for end-stage liver disease scores (median 10.0 versus 4.3; P=0.02). Overall, 3 (7.5%) lamivudine but no entecavir users acquired drug resistance in 1 year (P=0.25).

in 1 year (P 0.25).

CONCLUSIONS:

Entecavir as compared with lamivudine is similar in the effect on short-term mortality but is associated with greater clinical improvement among chronic hepatitis survivors who recovered from hepatic

decompensation decompensation.

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Thanks for your attention