Transcript Nessun titolo diapositiva

HBV-DNA detection by hybridization assay
in the serum of anti-HBe positive HBV carriers
HBV-DNA +
11/19
7/13
16/32
14/24
28/106
8/30
10/153
14/78
58%
54%
50%
58%
26%
27%
7%
18%
116/455 25%
Chronic Hepatitis
11/14 79%
14/18 78%
28/46 65%
8/21 38%
1/5
20%
10/38 26%
72/139 52%
Bonino 1980
Scotto 1983
Liebermann 1983
Hadziyannis 1983
Bonino 1984
Lok 1984
Tur Kaspa 1984
Wu 1986
Chronic anti-HBe positive hepatitis B was born in
1980 in the Mediterranean area
< 2% - Low
2-7% - Intermediate
> 8% - High
Chronic anti-HBe positive hepatitis B
Features
Virological :
mean viremia levels lower than those observed
in HBeAg positive patients
Clinical:
progressive liver disease with low rate of
spontaneous resolutions, in spite of temporary
remissions
high relapse rate after the end of IFN, in spite
of the response obtained during treatment
Brunetto MR, Hepatology 1989
HBeAg positive
infection
Anti-HBe positive
infection
Identification of 1896 G to A switch
as causative agent of
anti-HBe positive chronic hepatitis B
Brunetto MR et al, Ital. J Gastro 1989
Carman A et al, Lancet 1989
Santantonio T et al, Virology 1991
NUCLEOCAPSID PROTEINS: HBeAg
PRE-C
CORE
29 aa
183 aa
E.R.
10 aa
149 (154) aa
17 kDa non particulate, secreted HBeAg
Substitution of 7cys restores particle formation
and HBcAg antigenicity
Hepatitis B Virus
Sequence of
pre-core codon 15
CCC
Genotype
A
B
Best
CCC/U matching C
with
D
CCU
codon 28
E
CCU
F
CCC/U
CCU
Size of gene
(nucleotides)
core
Pre-S
555
519
549
519
549
519
549
486
549
486
549
486
Li J-S et al, J Virol 1993
Genotype D is the prevailing HBV genotype in
the Mediterranean area where Chronic anti-HBe
positive hepatitis B was originally described
< 2% - Low
2-7% - Intermediate
> 8% - High
Reports from South Europe on the various
features, the outcome and response to IFN
of HBeAg negative/anti-HBe positive CHB,
mainly concern 1896 GtoA ,genotype D CHB
and do not necessarily apply to other
geographical areas where other virologic
form of HBeAg-negative CHB may prevail
Hadziyannis SJ, J Hep 2002
Modulation of HBeAg expression
Transcriptional
Basic core promoter mutants
HDV super/co-infections
Pre-core mutants:
Translational
1896
1817
1897
1816
1815
G
C
G
G
T
to
to
to
to
to
A
T
A
T
C
Stop at codon 28
Stop at codon
2
Stop at codon 28
Elimination of
start codon
1
Anti-HBe positive chronic hepatitis B:
1896 G to A switch by oligohybridization assay
161 / 164 (98.2%)
52 (31.7%)
13 (7.9 %)
All patients were of
Italian origin
99 (60.4%)
Brunetto MR,1999
Anti-HBe positive chronic hepatitis B:
pre-core heterogeneity by direct sequencing
in 18 patients from Tuscany
1762
1764
1896
1899
A-T
G- A
G- A
G- A
12/18
12/18
11/18
6/18
66.6% 66.6%
+
-
+
-
61.1% 33.3%
-
-
in 5 patients
in 2 patients
Moscato G, 2001
Chronic HBsAg Hepatitis in Italy
834 cases in 14 centres
anti-D+ 7%
anti-D+/
anti-HCV+
1%
anti-HCV+
6%
HBeAg+
9%
anti-HBe+
77%
Gaeta et al.
Year of analisys:1997
Change of HBeAg and anti-HBe Distribution
in positive HBsAg Carriers in Italy
HBeAg pos.ve
anti-HBe pos.ve
Cases = 538
Cases = 718
11%
58%
42%
89%
Giusti et al.
1975-85
Gaeta et al.
1997
Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a
progressive accumulation of cases in the population
- increase in the diagnostic accuracy
(more sensitive assays, more diagnostic
accuracy by the clinicians)
Geographic Distribution of HBsAg Carriers
< 2% - Low
2-7% - Intermediate
> 8% - High
Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a
progressive accumulation of cases in the population
- increase in the diagnostic accuracy
(more sensitive assays, more diagnostic
accuracy by the clinicians)
Outcome of Chronic Anti-HBe Positive Hepatitis B
High intrafamiliar infection (43.9%)
Low parenteral exposure (13.4%)
Small number of patients with history
of acute hepatitis (4.8%)
or HBeAg pos. (2.4%)
INFECTION
DIAGNOSIS
High rate of asymptomatic
carriers among relatives
High rate of acute hepatitis
in sexual partners
CIRRHOSIS
asymptomatic
HBeAg minus
selection
36 - 40 y.
0
10
20
30
40
45 y.
50
Age (years)
60
70
80
Outcome of chronic anti-HBe positive hepatitis B
102 patients (mean age 36 y) with chronic hepatitis at histology
Median follow-up 6y. (mean 5.9y.; range 2-12y.)
7.8%
Biochemical
and Clinical
Outcome
Steadyness
6.9%
85.3%
2nd Biopsy
63/87
72.4%
38.1%
49.2%
Amelioration
Cirrhosis
4 Signs of portal
hypertension
2 Died
1 OLT
12.7%
Worsening
Cirrhosis
Steadyness
Prevalence of Chronic anti-HBe positive
Hepatitis B by Age
20 years old
50 years old
20
50
80
%
Hepatitis
Hepatitis
Gaeta et al. 2000
50
%
Healthy
Healthy
Hepatitis
Healthy
Chronic anti-HBe positive hepatitis B
Reasons for the increase of its prevalence in Italy:
- reduction of HBeAg positive cases
- long lasting unresolving disease inducing a
progressive accumulation of cases in the population
- increase in the diagnostic accuracy
(more sensitive assays, more diagnostic
accuracy by the clinicians)
Outcome of Chronic Anti-HBe Positive Hepatitis B
Biochemical patterns in 164 untreated patients
after 23 months (range 12-36) monthly monitoring
400
With flares
and normalization
73 pts
( 44.5% )
300
200
Asymptomatic
flare-up:
90% of cases
100
0
400
A
L
T
Without flares
59 pts
( 36.0% )
300
200
100
0
400
With flares and
without normalization
32 pts
( 19.5% )
300
200
100
0
0
12
months
24
Flare-up yearly
frequency:
once 57.1%
twice 20%
< once 22.8%
Anti-HBe positive chronic hepatitis B:
virological patterns in 164 patients
23 months (range 12-36) monthly monitoring
Viremia profile
persistently > 106 gen/ml
occasionally < 106 gen/ml
frequently < 106 gen/ml
persistently < 106 gen/ml
persistently > 7 PEI I.U. 110 (67.1%)
fluctuations < 7 PEI I.U. 54 (32.9%)
fluctuations
< 4 PEI I.U.
5
( 9.1%)
(31.7%)
(53.1%)
( 6.3%)
Chronic
Hepatitis Cirrhosis
ALL
IgM anti-HBc
profile
15
52
87
10
57.9%
42.1%
82.2%
17.8%
( 3.0%) c2 9.332, p = 0.002
Brunetto MR,1999
A favoring condition due to the changed
HBV epidemiology in Italy
A better understanding of what we
are looking for and how to do it
Are the major factors responsible for the increased
prevalence of anti-HBe positive CHB in Italy
AKNOWLEDGEMENT
Anna Maria Maina
Filippo Oliveri
Piero Colombatto
Giovanna Moscato
Barbara Coco
Ferruccio Bonino