Transcript Zhang N, et al. Oral presentation at the Annual Conference of

HBV-associated Severe Liver Diseases:
Progress on Pathogenesis and Treatment
Yuming Wang
Institute for Infectious Diseases of PLA
Southwest Hospital
Third 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
/core-promoter (G1762T/G1764A)
mutations
 PreS2 mutations
 HBV genotypes
Fig. Frequencies of
Precore/C-promoter
mutations compared
between pts. with FH and
self-limited acute hepatitis
who were infected 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
associated with Bj and Ce
 Lack of HBeAg
 High replication due to
precore mutation
Ozasa 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
Death
ALF
chemotherapy
Chronic
hepatitis
HBV DNA
ALT
Immunosuppression
0
4
8
12
Liver cirrhosis
Acute hepatitis
Immuno-rebound
16
20
24
28
32
36
Actually there are 2 kinds of responses:
immune rebound and immune paralysis
Recover
52
100
Time after exposure (w)
Meuleman P, et al. J Virol, 2006, 80(6):2797-2807.
Severe
architectural
disruption
with fibrosis
and
necrosis
Extensive
hepatocyte
injury
and inflamation
Extensive
Positive
HBcAg
HBsAg
HBcAg
HBsAg
Fig. Overwhelming HBV infection with immnosuppression
A-D ALF after chemotherapy in 1 case of non-Hodgkin lymphoma
E, F a case with CHB
Ocama P, et al. Am J Med, 2005, 118, Dec:e15-1413.e22
Why do the pts. in tolerance stage
have no FCH manifestations ?
 Immune tolerance≠ immune paralysis
 Immune tolerance：virus and host
have 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
住院重肝/肝衰竭患者
(人)
250
200
150
100
50
0
11991 1992
2 1993
3 19944
5
6
7
1995 1996 1997 1998
2001 2002 2003 2004 2005
81999 92000 10
11 12 13 14 15
nucleoside analogue use
none nucleoside analogue
100%
83
137
220
175
174
243
248
273
83
92.3%
77
80%
percentage(%)
68.7%
76.2%
77.7%
189
212
167
57.5%
60%
100
42.3%
40%
74
22.3%
20%
13.9%
7.2%
0%
49
19
6
1999 2000 2001 2002
2003 2004 2005 2006 2007(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）
389（71.9）
152 （28.1）
p＜0.0001
Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007
100
90
80
70
60
50
40
30
20
10
0
89.2
76.2*
38.1*
18.9
liver failure
early anti-HBV(N=37)
survival rate
non anti-HBV(N=21)
Fig. Patient’s condition and prognosis of anti-HBV
therapy within 1 week after onset of symptoms
*P=0.000
张绪清，等，待发表
Tab. Curative effect of 810 liver failure patients of
hepatitis B after nucleoside analogue treatment
Year(n)
improvement/total (%)
stage： early
late
2
P
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
Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007
100%
treatment
control
Cum Survival
80%
90d P<0.05
60%
40%
20%
0%
0
100
200
300
400
500
600
700
Survival Time(day)
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
273
250
total
LAM withdrawal
248
243
In patient of liver failure
220
200
175
150
174
137
100
83
50
0
0
3
2
6
2000
2001
2002
2003
13
2004
14
2005
15
2006
11
2007(1-3)
Fig. liver failure of Chronic Hepatitis B Virus Infection After
Withdrawal of Lamivudine Therapy in South-West hospital
Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007
LAM
ETV
ADV
7.5
BV DNA (Log10copies/ml)
7.0
6.5
6.0
5.5
5.0
4.5
0w
2w
4w
8w
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
liver failure LAM peritonitis admission death
1200
90
80
70
60
50
40
30
20
10
0
1000
800
600
400
200
0
0d
5d
10d
18d
5w
8w
ALT
TB
PTA
10w
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
Zhang X, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007
停药后复发
LAM
ADV
LAM
ETV
50mg/d
HBV DNA (log10 copies/ml)
LAM 100mg/d 36m
6m
9
8
7
6
5
4
3
2
1
0
IU/ml
800
YVDD
700
600
500
400
300
200
100
1
month
5
9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77
HBV-DNA
Alt
Fig. One pts. with decompensated liver cirrhosis showed
multi-drug resistance
Wang Y, et al. unpublished data
I169T
LAM
V173L
L180M
●
●
T184
ACFGILMS
S202CGI
M204I
M204V
●
●
●
ADV
ETV
A181V
●
●
●
N236T
M250ILV
●
●
●
●
●
●
●
L-dT
Fig. Nested-PCR for the amplification of P Rt sequence
 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
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
‘VM’ breakthrough
Quasispecies memory
Dynamics of serum HBV DNA, ALT and HBV quasispecies population
Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007
Patient J
‘VM’ breakthrough
Quasispecies memory
Dynamics of serum HBV DNA, ALT and HBV quasispecies population
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
Fig. Prevention and Treatment of HBV Reinfection in OLTx Patients
Terrault N, et al. Liver Transpl, 2005, 11: 716-732
80 （％）
HBV DNA(＋)
70
HBV DNA(－)
60
51.4（19/37）
50
40
31.5（17/54）
30
20.6（7/37）
20
12.7（7/55）
8.2（7/85）
10
0
2.3（2/88）
1 year
2 year
3 year
(post-OLT)
P＜0.01
HBV recurrence rate between HBV DNA(+) and
HBV DNA(-) pre-OLT patients
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 patients
Xia 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
Conclusion: the Progress of
Antiviral Therapy by NA (1)

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
50-year Anniversary of
Dept. of Infectious Diseases, TMMU in 2005