HBV-associated Severe Liver Diseases:

Progress on Pathogenesis and Treatment

Yuming WangInstitute for Infectious Diseases of PLA

Southwest HospitalThird Military Medical University

Chongqing, P. R. China

The Progress of

Pathogenesis

Viral Factors

Evidence for the role of viral factors Long-term follow-up studies demonstrated

the close relationship between disease

severity and viral factors

NA has been showed to be effective in

prevention and treatment of hepatitis

exacerbation

HBV mutation and genotypes are closely

related to disease severity

Immune suppressed ALF: overwhelming viral

replication and immune paralysis

HBV mutation and genotyping is closely related to disease severity

Precore (G1896A) mutation /cor

e-promoter (G1762T/G1764A) mu

tations

PreS2 mutations

HBV genotypes

Fig. Frequencies of Precor

e/C-promoter mutations c

ompared between pts. wit

h FH and self-limited acute

hepatitis who were infecte

d with HBV/Bj or Ce

Ozasa A, et al. Hepatology. 2006, 44: 326-334

Outcome of acute hepatitis B virus infection

Pts with FH were older (>34y) FH was frequent (13%) and a

ssociated with Bj and Ce Lack of HBeAg High replication due to preco

re mutationOzasa A, et al. Hepatology. 2006, 44: 326-334

Pathogenesis of Special Fulminant Hepatitis----

Immunosuppression-induced ALF(Fibrosing Cholastatic Hepatitis, FCH)

Fig. Hepatitis reactivation after chemotherapy

Time after exposure (w)

0 4 8 12 16 20 24 28 32 36 52 100

chemotherapychemotherapyChronic Chronic hepatitishepatitis Liver cirrhosisLiver cirrhosis

ALTALT

RecoverRecover

Acute hepatitisAcute hepatitisHBV DNAHBV DNA

Immuno-suppression Immuno-reboundImmuno-rebound

ALFALF

DeathDeath

Meuleman P, et al. J Virol, 2006, 80(6):2797-2807.

Actually there are 2 kinds of responses: immune rebound and immune paralysis

Ocama P, et al. Am J Med, 2005, 118, Dec:e15-1413.e22

Fig. Overwhelming HBV infection with immnosuppressionA-D ALF after chemotherapy in 1 case of non-Hodgkin lymphoma E, F a case with CHB

HBsAg

HBcAg

ExtensivePositive

HBsAg

Extensive hepatocyte

injury and inflamation

Severe architectural

disruption with fibrosis

and necrosis

HBcAg

Why do the pts. in tolerance stage have no FCH manifestations ?

Immune tolerance≠ immune paralysis Immune tolerance ： virus and host ha

ve a relationship of mutually restriction

immune paralysis: host loses its restriction to the virus

Medical strategy for two categories of ALF

Immune suppression induced ALF

- Inhibition of virus

Immune mediated ALF

- Immune suppression by using steroids

- Inhibition of virus, ceasing of Immune

mediated liver necrosis

The Progress of Treatment Antiviral therapy by NA

Hospitalized pts. with HBV-associated hepatic failure in Our Dept. through 1991-2005

0

50

100

150

200

250

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

/住院重肝 肝衰竭患者

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

( 人 )

619

49

74

100

167

189 212

77

7.2%

13.9%

22.3%

42.3%

57.5%

68.7%

76.2% 77.7%

92.3%

83 137 220 175 174 243 248 273 83

1999 2000 2001 2002 2003 2004 2005 2006 20070%

20%

40%

60%

80%

100%

pe

rce

nta

ge

(%)

nucleoside analogue use none nucleoside analogue

(1-3)

Fig. Hospitalized liver failure patient of hepatitis B and nucleoside analogue usage in South-West hospital

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Outcome of severe hepatitis patients after LAM treatment

Cases Cure or improved（ % ）

Inefficacy or death（ % ）

495 （ control ） 291 （ 58.8 ） 204 （ 41.2 ）

541 （ treatment ）

p ＜ 0.0001

389 （ 71.9 ） 152 （ 28.1 ）

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Fig. Patient’s condition and prognosis of anti-HBV therapy within 1 week after onset of symptoms

*P=0.000

89. 2

18. 9

38. 1*

76. 2*

0102030405060708090

100

l i ver fai l ure survi val rate

earl y anti -HBV(N=37) non anti -HBV(N=21)

张绪清，等，待发表

Year(n)improvement/total (%)

Pstage ： early late

2000(19) 2/5(40.0) 2/14(14.3) 1.8684 0.1717

2001(49) 6/15(40.0) 4/34(11.8) 5.1048 0.0238

2002(74) 12/24(50.0)

7/50(14.0) 11.0129 0.0009

2003(100)15/31(48.4)

16/69(23.1) 6.3497 0.0117

2004(167) 28/52(53.9)

29/115(25.2)

13.0544 0.0003

2005(189)31/51(56.1)

39/132(29.5)

5.0975 0.0240

2006(212) 40/69(58.0)

49/143(34.3)

4.1704 0.0411

2

Tab. Curative effect of 810 liver failure patients of hepatitis B after nucleoside analogue treatment

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

0 100 200 300 400 500 600 700

0%

20%

40%

60%

80%

100%

Cum

Sur

viva

l

Survival Time(day)

treatment control

90d P<0.05

Fig.1 Survival Curve of 215 liver failure of hepatitis B after lamivudine treatment

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Fig. liver failure of Chronic Hepatitis B Virus Infection After Withdrawal of Lamivudine Therapy in South-West hospital

137

220

175 174

243 248

273

83

0 3 2 6 13 14 15 11

2000 2001 2002 2003 2004 2005 2006 20070

50

100

150

200

250

In p

atie

nt o

f liv

er f

ailu

re total LAM withdrawal

(1-3)

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

0w 2w 4w 8w

4.5

5.0

5.5

6.0

6.5

7.0

7.5B

V D

NA

(Lo

g 10co

pies

/ml)

LAM ETV ADV

Fig. Anti-HBV therapy by NA of 276 liver failure patients of Hepatitis after anti-HBV therapy by NA

Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Fig. The disease cause of 1 patients with severe hepatitis B after treatment

38y male ； HBsAg (+) 4 years, jaundice for 2 weeks was transferred

to our department after 8 weeks treatment from local hospital

0

200

400

600

800

1000

1200

0d 5d 10d 18d 5w 8w 10w0102030405060708090

ALTTBPTA

LAMliver failure peritonitis death admission

Zhang X, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

0123456789

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77

HBV- DNA Al t

HB

V D

NA

(lo

g10

co

pie

s/m

l)

100

200300

400500

600

700

800

IU/mlLAM 100mg/d 36m

LAM50mg/d

6m

LAM停药后复发

month

ETVADV

Fig. One pts. with decompensated liver cirrhosis showed multi-drug resistance

YVDD

Wang Y, et al. unpublished data

Target sequence: 394 bp. located in the Rt region

of the polymerase gene in HBV genome

All known mutation loci associated with nucleoside

analog resistance were included

I169T V173L L180M A181V T184

ACFGILMS

S202CGI M204I M204V N236T M250ILV

LAM ● ● ● ●

ADV ● ●ETV ● ● ● ● ● ● ● ●

L-dT ●

Fig. Nested-PCR for the amplification of P Rt sequence

Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Agarose gel electrophoresis of PCR products

TA cloning

PCR verification of white colonies

Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Patient I

Dynamics of serum HBV DNA, ALT and HBV quasispecies population

Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

‘VM’ breakthrough

Quasispecies memory

Patient J

Dynamics of serum HBV DNA, ALT and HBV quasispecies population

‘VM’ breakthrough

Quasispecies memory

Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Antiviral therapy

before and After OLTx in Pts.

with Severe Hepatitis

Terrault N, et al. Liver Transpl, 2005, 11: 716-732

Fig. Prevention and Treatment of HBV Reinfection in OLTx Patients

HBV recurrence rate between HBV DNA(+) and HBV DNA(-) pre-OLT patients

0

10

20

30

40

50

60

70

80

1 year 2 year 3 year

HBV DNA(＋)

HBV DNA(－)

（％）

8.2 （ 7/85 ）2.3 （ 2/88 ）

31.5 （ 17/54）

12.7 （ 7/55）

51.4 （ 19/37）

20.6 （ 7/37）

P＜ 0.01(post-OLT)

Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Mechanism for HBV recurrence post-OLTx

Without anti-virus treatment pre-OLT in HBV

DNA(-) patients

Insufficient anti-viral treatment pre-OLT

HBV mutations (LAM-R) pre-OLT has not been

detected by real-time PCR

Be short of profession doctor’s guidance, and

insufficient follow-up system

The problem in compliance of patientsXia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007

Conclusion: Progress of Pathogenesis

viral factors are emphasized now, which have been demonstrated by the efficacy of antiviral therapy by nucleoside analogues

Immunosuppression induced liver failure is associated with immune polarization and viral replication

NA has been shown to be effective and safe in

patients with hepatitis B including fulminant

hepatitis and decompensated liver cirrhosis

could effectively suppress HBV-induced liver

inflammation and necrosis in short term, and

prevent hepatitis flares

more experience has been accumulated in LAM

and ADV, latter is suitable for the patients with

slow progression

Conclusion: the Progress of Antiviral Therapy by NA (1)

ETV and LdT will have potential application

owing to their strong potency; iii) antiviral

indication can be extended to acute course

viral load can be flexible, and duration is

indefinite (except for patients with acute

infection)

viral resistance is not common and multi-

drug resistance is rare, but more attention

should be paid, due to the resistance related

hepatitis reactivation

Conclusion: the Progress of Antiviral Therapy by NA (1)

50-year Anniversary of Dept. of Infectious Diseases, TMMU in 2005