11/15/2005 8:00 AM - 12:30 PM
Hepatitis B Pathogenesis
Poster 1285
Abstract
ID: 62098
Category:
JO9: Hepatitis B: Pathogenesis
Significance of 'anti-HBc only' in unselected sera referred to the clinical laboratory.
J. Masurel, Université Paris-Descartes, Hôpital
Cochin, Service de Virologie, Paris,
France, O. Launay, Université Paris-Descartes, CIC
de Vaccinologie Cochin-Pasteur,
Paris, France, A. Basse-Guérineau, AP-HP, Hôpital
Cochin, Service de Virologie, Paris,
France, A. Servant-Delmas, INTS, Centre National
de Référence des Hépatites B et C en
Transfusion, Paris, France, J. Méritet, AP-HP,
Hôpital Cochin, Service de Virologie,
Paris, France, S. Laperche, INTS, Centre National
de Référence des Hépatites B et C en
Transfusion, Paris, France, P. Sogni, Université
Paris-Descartes, Hôpital Cochin, Service d'Hépatologie, Paris, France, A. R.
Rosenberg, Université Paris-Descartes, Hôpital Cochin, Service de Virologie,
Paris, France
Background & Aim:
Isolated detection of total
anti-HBc in the absence of HBsAg and anti-HBs (‘anti-HBc only’) has been
reported, particularly among patients infected with human immunodeficiency
virus (HIV) or hepatitis C virus (HCV). It remains unclear how this serological
profile should be interpreted and whether all individuals with such pattern
need to be tested for hepatitis B virus (HBV) DNA. The aim of this study was to
evaluate the significance of ‘anti-HBc only’ in unselected sera.
Methods & Results:
Of the 6431 patients that
were tested for HbsAg, anti-HBs, and total anti-HBc in the clinical laboratory
of our teaching hospital between January and
December 2003, 362 (5.6%)
had ‘anti-HBc only’. Among them, 1 was in the window period following acute
hepatitis B (positive for anti-HBc IgM). Anti-HBe was undetectable in 207 (57.2%)
sera, suggesting that some of these might be false positive. However, only 11
of these 207 sera were negative when retested using another assay for total
anti-HBc; these 11 sera had significantly lower sample/cutoff ratios when
compared to those positive with both assays (p<0.001). Two sera had
detectable HBsAg when retested with one of the most recent HBsAg assays. In
these 2 sera, HBV DNA was
detected, and sequencing of
the s gene revealed amino acid substitutions in the immunodominant epitope of HBsAg.
The remaining 348 sera with true ‘anti-HBc only’ were tested for HBV DNA using
the branched DNA-based VERSANT HBV DNA 3.0 assay (Bayer), a standardized test
with a threshold of detection (2,000 copies/ml) that might allow the screening
of clinically relevant infection. The PCR-based COBAS AMPLICOR HBV MONITOR
assay (Roche) was used as confirmation test. HBV DNA was found in 8/348 (2.3%)
patients, including 1 pregnant woman, with viral loads above 10,000 copies/ml
in 5 cases. No mutation was detected in the s gene in these 8 cases. No factor
(including HIV and HCV status) was found to be predictive of HBV DNA
positivity.
Conclusions:
Despite the use of more
sensitive HBsAg assays, ‘anti-HBc only’ is a common event in the clinical
laboratory, and is rarely due to false positivity. In view of the absence of
predictors of chronic HBV infection, the results suggest that all individuals
with ‘anti-HBc only’ should be tested for serum HBV DNA in order to identify
patients at potential risk of HBV transmission, and needing clinical and
virological follow-up.
Poster 1286
Abstract
ID: 63416
Category:
JO9: Hepatitis B: Pathogenesis
Etiopathology of HCC in Thailand
O. Galy,
INSERM U271, LYON, France, Metropolitan,
LYON
CEDEX 03, France, S. Villar, IARC Unit of nutrition and Cancer, LYON,
France,
P. Srivatanakul, National Cancer Institute Cancer Control Unit,
Carcinogenesis Unit, LYON , France
Introduction and Aim:
Hepatocellular Carcinoma is
the main primary liver cancer observed in the world representing more than 70%
of the 500 000 annual new cases of liver cancer. The major risk factor is
Hepatitis B virus (HBV) chronic infection that increases cancer-risk about 100
times. The existence of HBV occult infection (HBV DNA without HBsAg) is now
recognized but its role in liver disease, especially cirrhosis and HCC is not
clearly elucidated. Many genetic alterations were identified in HCC; pathway
involved in growth control, apoptosis or DNA repair. However, the molecular
basis of how they interfere with HBV and whether HBV occult infections follow
the same pathways in the pathogenesis of HCC is still poorly understood.
Methods:
In this study we describe
TP53 and β-catenin mutations according to HBV infection status (occult
or HBsAg+) in a high HVB prevalence zone (
pairs. 7 out of the 18 pairs
exhibited HBsAg negative status; they were categorized as “occult HBV” pairs.
HCV RNA was detected in 3 out of the 18 pairs including one case with an occult
HBV pair. This low incidence of HCV infection excludes hypothesis of silent
hepatitis due to HCV repression effect. Determination of tumour grade
(Edmondson) and Fibrosis/Activity (METAVIR) scores for surrounding area were
performed. We identified TP53 gene mutations by PCR/RFLP/Sequencing in exon 5-9
and β-catenin mutations by DHPLC/Sequencing in exon 3.
Results:
Age of patients positive for
HBV DNA ranged from 34 to 73 with an average value of 48, age of patients with
occult hepatitis was lower than with HBsAg+ Hepatitis. Tumour grade and METAVIR
scores for non tumour areas were similar in the two types of infection. TP53
mutations were detected in 7 cases; aspecific TP53 mutation at codon 249 represented
60% of those mutations but only occurred among HBsAg+ cases. β-catenin
mutations distribution was similar for occult and non-occult infection.
Conclusion:
The study suggests that
there is no significant disparity between the distributions of different
molecular events in the two HBV infection types. Thus we can conclude that HBV
occult infection could be implicated in HCC development according to mechanism
similar to those involved in non-occult infection. The possible association of
occult infection with TP53 mutation at codon 249 requires more detailed
investigation.
Poster
1289
Abstract
ID: 65055
Category:
JO9: Hepatitis B: Pathogenesis
Adefovir treatment of chronic hepatitis B patients recovers circulating numbers and function of myeloid dendritic cells.
R. G.
van der Molen, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
Rotterdam,
Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical
Center
MC,
Introduction:
Dendritic cells (DC) play an
important role in the induction of T-cell responses. The myeloid DC (mDC) and
plasmacytoid DC (pDC) are the two predominant precursor DC-subtypes present in
peripheral blood. Recently, we have shown that mDC of chronic hepatitis B virus
(HBV) infected patients are impaired in the expression of costimulatory
molecules, T-cell stimulatory capacity as well as TNFa production. In addition,
we showed a reduced IFNa production by pDC in chronic HBV patients compared to
healthy controls. The question is whether the impaired DC function contributes
to chronicity of HBV infection or whether the virus itself causes this
dysfunction of DC.
Aim:
The aim of our study was to
assess the effect of virus reduction by adefovir on function and absolute
numbers of both mDC and pDC.
Methods:
In this study, 14 chronic
HBV patients were treated with adefovir (10 mg od.) and followed during the
first 6 months of treatment.
Results:
The median serum HBV DNA
decreased significantly from 1.1x108 to 2.0x103 geq/ml within the first 3
months and remained stable thereafter. The mean ALT levels decreased from 150
to 41 U/L after 6 months. As determined by flowcytometry, a significant
increase in the absolute numbers of mDC, but not of pDC was found after 6
months of treatment compared to baseline. To determine DC function, mDC and pDC
were isolated using magnetic cell sorting techniques. The T-cell stimulatory
capacity of mDC increased significantly in 10 out of 14 patients after 3 months
of treatment. The mean IL-12 as well as the TNFa production by mDC stimulated
with poly (I:C) and IFNg significantly increased after 3 months of treatment in
these 10 patients. In 4 out of 14 patients, the T-cell stimulatory capacity
decreased after 3 months compared to baseline. At the same time, IL- 12 and
TNFa levels were reduced. Two of these patients started treatment at time of immune
activation, i.e. ALT elevated 8 and 27 times the upper limit of normal. This
indicates that their mDC might have been activated at baseline. The
longitudinal expression of costimulatory molecules CD80, CD86 and CD40
concurred with T-cell stimulation results for all patients. The mean production
of IFNa by isolated pDC stimulated with Staphylococcus aureus Cowan strain I
antigen showed a trend towards reduction after 6 months of treatment compared
to baseline.
Conclusion:
In conclusion, reducing the
viral load by adefovir recovers circulating numbers and function of mDC, but
not of pDC, suggesting that adefovir contributes to partial restoration of the
immunological control to HBV infection.
Poster
1294
Abstract
ID: 64494
Category:
JO9: Hepatitis B: Pathogenesis
The Relationship between Hepatitis B
Virus (HBV) Genotype and Hepatitis B e Antigen (HBeAg) Status in a Cohort of Alaska
S.
Livingston, Liver Disease and Hepatitis Program,
Disease
and Hepatitis Program,
Program,
CDC,
Hurlburt,
Liver Disease and Hepatitis Program,
Disease
and Hepatitis Program,
Hepatitis
Program,
Introduction:
In Alaska Natives (AN) with
chronic HBV infection, we have previously observed a 73% probability of
clearing HBeAg within 10 years of the first positive hepatitis B surface
antigen (HBsAg) specimen. Objective: To investigate the relationship between
HBV genotype (GT) and HBeAg status in this cohort.
Methods:
Followed 1536 AN with
chronic HBV infection for 12.6 years (median).
Sera were tested biannually
for HBeAg. Using stored sera, we tested for HBV GT in 1045 persons by direct
sequencing of the S gene and determined HBeAg status by GT on the initial HBsAg
+ specimen and changes in HBeAg status by GT over time.
Results:
Genotypes A, B, C, D, F and
H (1 case--omitted from further analysis) were
identified. Genotype
distribution and proportion HBeAg+ by GT is displayed in the Table. The median
age (years) at time of initial HBeAg+ specimen by GT was A, 15.1; B, 18.9; C,
19.6; D, 12.8, and F, 11.3. Fewer persons with GT A and B were initially HBeAg+
(P<.001); this remained true after adjustment for age (P<.001). Among
persons initially HBeAg+, those with GT C were significantly more likely to
remain positive on subsequent visits than those with GT A and D (P<.001),
who likewise were more likely to remain positive than those with GT B and F
(P<.001). At time of last testing, more persons with GT C, 71% (22/31), were
still HBeAg positive compared to those with GT A, B, D and F, 14% (4/28), 0%
(0/5) , 41% (63/255) and 13% (14/109) respectively (P<.001). Median age at
seroconversion is shown in the Table. Persons with GT C were significantly
older at the time of HBeAg seroconversion (P<.001). Among those initially
HBeAg+, persons with GT C
and F were more likely to revert to HBeAg+ after clearing HBeAg than those with
other GT (P<.001). Of persons initially HBeAg-, those with GT B, D and F
were more likely to remain HBeAg- than GT A and C (P=.002).
Conclusions:
Significant differences in
HBeAg seroconversion and reversion back
to HBeAg positivity were
observed between HBV GT among a homogeneous population of AN. Persons with GT C
were significantly less likely to clear HBeAg and significantly more likely to
have reversions back to HBeAg positivity than those with other GT, suggesting
that HBV GT status may be of clinical importance.
Poster
1306
Abstract
ID: 66121
Category:
JO9: Hepatitis B: Pathogenesis
Adefovir treatment of chronic hepatitis B decreases regulatory T cells and partially restores the antiviral immune response.
J. N.
Stoop, Erasmus MC,
Netherlands,
R. G. Van der Molen, Erasmus MC, University Medical Center Rotterdam,
Rotterdam,
Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical
Center
Disclosures:
The following authors have indicated they have no relationships to disclose:
Jeroen Stoop, Renate Van der Molen, Ernst Kuipers,
Robert de Man, Johannes Kusters,
Harry
Janssen
Introduction:
Adefovir is a nucleotide
analogue, which effectively suppresses viral replication in the majority of
chronic HBV infected patients. We determined whether adefovir can induce a
restoration of the immune response in patients with chronic hepatitis B. An
important mediator of impaired immune reactivity are regulatory T cells (Treg).
We previously showed that Treg are capable of inhibiting the immune response
against HBV core antigen (HBcAg).
Methods:
In the current study we
assessed the effect of adefovir therapy on the percentage of Treg and the
immune response against HBcAg. Peripheral blood mononuclear cells (PBMC) from
12 chronic hepatitis B patients were obtained at baseline and after 3 and 6
months of adefovir treatment (10 mg per os daily). All patients had serum
HBVDNA levels above 105 copies/ml and abnormal ALT levels. Six patients were
HBeAg positive and 6 anti-HBeAg positive. Samples from one patient were tested
in the same experiment. The percentage of Treg of CD4+ cells was determined by
flowcytometry with antibodies against CD4, CD25, CD45RO and CTLA-4. The
response against HBV was tested by stimulating PBMC with HBcAg. After
stimulation the IFN-g and IL10 production were determined by Elispot. The proliferation
was determined by 3[H]-thymidine incorporation.
Results:
The median drop of HBVDNA
was 5.16 log after 3 months and HBVDNA levels remained stable thereafter.
Immunological testing has been performed for 7 patients so far. The percentage
Treg of CD4+ cells at baseline was 3.60 ± 0.44 (mean ± sem) and decreased to
2.81 ± 0.22 at 3 months (P=0.028) During month 3-6 the percentage of Treg did
not change significantly. During the first 3 months of treatment the HBcAg
specific proliferation increased from 3736 CPM ± 984 to 5537 CPM ± 1350 and the
IFN-g production increased from 7.05 spots/100.000 cells ± 2.61 to 21.48
spots/100.000 cells ± 7.96. After these 3 months the proliferation and the
IFN-g production did not increase any further. Treatment with adefovir did not
affect the HBcAg specific IL10 production.
Conclusion:
In conclusion, during the
treatment with adefovir the proportion of Treg in
peripheral blood decreases
while both the IFN-g production and proliferation
against HBcAg increases. However, we did not find a decrease in the production of the anti-inflammatory cytokine IL-10. Together these data suggest that adefovir contributes to a partial recovery of the immunological control of chronic HBV infection.
Poster
1308
Abstract
ID: 67083
Category:
JO9: Hepatitis B: Pathogenesis
Models To Predict Hepatocellular Carcinoma (HCC) In Patients With Chronic Hepatitis B Infection: The R.E.V.E.A.L.- HBV Study.
C.
Chen,
University,
Research
Institute,
Research
Institute,
Introduction:
The risk of any particular
CHB patient developing HCC over a specific
period remains to be
determined. Predicting patients at risk of progressing to HCC may help in
patient counseling, risk stratification and identifying those most likely to
benefit from intervention. Our objective was to develop such a model using
readily available clinical information in CHB infected subjects.
Methods:
Information from 3,653
asymptomatic HBsAg-positive and anti-HCV-negative subjects recruited from 7
townships in
screening. In addition, the
medical charts of these subjects were reviewed using a structured abstraction
form. A diagnosis of HCC was confirmed by any one of the following: positive
cyto-histopathology; presence of two coincident, focal liver lesions by liver
imaging studies (abdominal ultrasonography, CT Scan, MRI and/or angiography);
presence of one focal liver lesion and an alpha fetoprotein (AFP) level >400
ng/ml. Logistic regression models were used to identify the predictive
variables, and the model accuracy determined by the Area Under the Receiver
Operator Characteristic curves (AUROC).
Results:
The mean follow-up time was
11 years in this cohort. The training set 1826/3851 (50%), was comparable to
the validation set for all baseline variables and HCC events (p>0.05).
Distribution of key variables in both groups were, males (62%); HBeAg-positive
(16%); ALT <1x ULN (94%); current alcohol consumption (12%). Using
multivariable logistic regression, in the best fitting model Age and HBV DNA
level were the strongest predictors of future HCC events (AUROC = 0.87);
concordant percent 95%; discordant percent 5%; model goodness of fit (p=0.33).
The strongest risk
was associated with age
60-65; OR (95% CI) was 16.1 (6.3-41.4) reference group (30- 39); and HBV DNA ³
105 copies/mL OR (95% CI) was 9.3 (4.0-21.4) [reference <300 copies/mL]. The
model had a sensitivity of 78% and specificity of 78% at a predictive
probability level of 4.3%.
Model characteristics in the
validation group were AUROC = 0.83; concordant percent =95.6; and goodness of
fit =0.3008.
Conclusion:
Risk stratification for HCC
is possible using a model comprised of readily available non-invasive clinical
information. External validation of the model will be necessary to further
evaluate its characteristics.
Poster
1309
Abstract
ID: 67282
Category:
JO9: Hepatitis B: Pathogenesis
Serum HBV DNA levels and Liver Disease
progression in patients with chronic HbeAg (-)
Hepatitis B infection. A prospective cohort study.
G.
Zacharakis,
Koskinas,
Papoutselis,
Unit of Preventive Medicine,
Preventive
Medicine,
Medicine,
Medicine,
Background:
The role of serum HBV-DNA
levels in the natural history and management of chronic HBV infection is
currently under investigation.
Aim:
To evaluate the levels of
serum HBV-DNA in association with the natural
history of chronic HBV
infection. A prospective cohort study sponsored by a grant from EC Project
Interreg I and II.
Patients/Methods:
257 adults, median age 34
years (range 20-65), with chronic HBV infection, were recruited during
1992-1994 and prospectively followed up for a period up to 12 years (median 5.3
years). Patients with HCV/HDV coinfection, alcohol consumption or treated were
excluded from the study. Viral markers, liver biochemistry and physical
examination were performed every 6 months. Liver biopsy was done at entry and
every 2-4 years. Liver histology was assessed according to Scheuer criteria.
Serum HBV-DNA levels were measured by Amplicor HBV Monitor kit (Roche
Diagnostics Systems,
Results:
14/257 (5%) patients were
HBeAg(+) with median serum HBV DNA
levels 6.9x106 copies/ml
(range 1.4x105-4x107copies/ml) At entry, 195/257 (76%) were HBeAg (-), anti-HBe
(+), with a history of normal ALT levels for at least 6 months (inactive
carries): a) 97/195(50%) individuals had undetectable serum HBV-DNA, no liver
disease and remained so at follow-up period, b) 94/195 (48%) subjects had serum
HBV-DNA levels <104 copies/ml, 91/94 (97%) normal liver histology and
remained so at follow-up period except 6 patients who lost serum HBV-DNA, and,
c) 4/195 (2%) individuals had serum HBV-DNA >104copies/ml, nearly normal
liver histology of whom 2 exhibited abnormal ALT levels after 3 years and
developed mild progression of liver disease. At entry, 48/257 (19%) patients
were HBeAg (-), anti-HBe (+), with a history of elevated ALT levels for at
least 6 months; 12/48 (25%) had an erratic ALT pattern, median HBV-DNA levels
3.5x105copies/ml (range 7.1x104 to 3.2x107) and 36/48 (75%) had persistent
elevated ALT(>1.5xUNL), median HBV-DNA levels 1.2x107copies/ml (range 2x105
to 6.9x107), (p<0.05). In this group of patients, 22/48 (46%) had
moderate/severe histology at entry and 5/48 (10%)
developed liver disease
progression during the follow-up period. Overall,
HBeAg(-) patients with
persistent serum HBV-DNA levels >104copies/ml were more likely to have liver
disease progression than those with lower or
undetectable HBV-DNA levels
(OR: 2.1).
Conclusions:
The threshold of serum
HBV-DNA associated with abnormalities
in liver biochemistry and
liver disease seems to be the level of >104copies/ml. Close monitoring of
serum HBV-DNA could be a useful clinical tool in the management of chronic HBV
patients, particularly in the HBeAg (-) group.
Poster
1310
Abstract
ID: 61212
Category:
JO9: Hepatitis B: Pathogenesis
Non-invasive assessment of liver fibrosis in chronic hepatitis B using FibroScan®.
P.
Marcellin, Hopital Beaujon,
Haut
Leveque,
Metropolitan,
M. Ziol, Hopital Jean Verdier, Bondy
Bedossa,
Hopital Beaujon,
Verdier,
Bondy
Introduction:
Previous studies have shown
that liver stiffness measurement (LSM) with the FibroScan® (Echosens®,
Aim:
The aim of this prospective
multi centre study was to evaluate the accuracy of this non-invasive method to
assess fibrosis in patients with chronic hepatitis B.
Methods:
220 patients with chronic
hepatitis B who underwent a liver biopsy during their routine follow-up were
included in the study after giving their informed consent. LSM was performed
within six months of the liver biopsy. Only LSM with at least 8 valid
measurements and an IQR/median ratio >50% were considered interpretable.
Fibrosis and activity were evaluated on the histological slides by two
pathologists using the METAVIR and Ishak scoring systems. Steatosis was graded
as follow: 0 (no steatosis), 1
(1-10%), 2 (11-30%) and 3
(>30%). Only liver samples with at least 10 portal tracts or obvious
cirrhosis were considered suitable for evaluation.
38 (17%) biopsy samples were
considered unsuitable for a reliable staging of fibrosis. LSM failed in 12 (5%)
patients. In the 170 remaining patients, LSM ranged from 2.5 to 72.5 kPa. The
distribution of METAVIR fibrosis scores was: F0 (6%), F1 (36%), F2 (30%), F3
(14%) and F4 (14%). The distribution of METAVIR activity scores was: A0 (25%),
A1 (50%), A2 (18%) and A3 (7%). As well, the distribution of steatosis scores
was 0 (50%), 2 (34%), 2 (8%) and 3 (8%). The spearman correlation coefficients
between LSM and METAVIR or Ishak fibrosis were 0.66 and 0.67 respectively (p
< 0.0001).
Results:
Multivariate analysis of LSM
versus METAVIR activity and fibrosis and steatosis scores showed that only
fibrosis stage was significantly associated with LSM. The areas under the ROC
curves (95% confidence interval) were 0.81 (0.74-0.86), 0.92 (0.86-0.95) and
0.90 (0.81-0.95) for METAVIR F >= 2, F >= 3 and F=4, respectively.
Conclusion:
In patients with chronic
hepatitis B, the accuracy (ranging from 0.81 to 0.92) of LSM to measure
fibrosis stage and to detect presence of cirrhosis was not significantly
different from that obtained in patients with chronic hepatitis C.
Poster
1312
Abstract
ID: 65486
Category:
JO9: Hepatitis B: Pathogenesis
Prevalence and clinical role of occult hepatitis B in a cohort of HIV-infected patients.
N. Marino, S.M.Annunziata Hospital, Firenze,
Italy, S. Lo Caputo, S.M.Annunziata
Hospital, Firenze, Italy, P. Pierotti,
S.M.Annunziata Hospital, Firenze, Italy, C. Blè,
S.M.Annunziata Hospital, Firenze, Italy, M.
Riccardi, Misericordia Hospital, Grosseto,
Grosseto, Italy, M. De Gennaro, Campo di Marte
Hospital, Lucca, Italy, A. Scasso,
Campo di Marte Hospital, Lucca, Italy, A. Vivarelli,
Del Ceppo Hospital, Pistoia, Italy,
D. Dionisio, Del Ceppo Hospital, Pistoia, Italy,
F. Mazzotta, S.M.Annunziata Hospital,
Background –
Hepatitis B virus is not completely eliminated after
loss of hepatitis B surface antigen (HBsAg) and clinical recovery: HBV-DNA can
be detected by polymerase chain reaction (PCR) assay in serum, liver and
peripheral blood mononuclears cells. The HBV detection rate is highest in
subjects who are anti-HBc positive/antiHBs negative (isolated anti-HBc ). Occult
hepatitis B virus infection was observed in approximately 10% of HIV-infected
patients with HBc alone. The screening of this subset of HIV+ patients may have
clinical implications.
Methods-
Consecutive HIV+ patients in the year 2003 were
chequed in 4 Infectious
Disease Units in
Results-
A total of 955 HIV-positive ( 71,3% males, median age
42,3 years, heterosexual transmission 26,7%, homosexual 30,2%, IVD 59,4%) were
evaluated for HBV infection. Based on hepatic serology 581 patients (60,8%)
were anti-HBc positive, 64 (6,7%) HbsAg positive, 361 (37,8%) anti-HBs
positive, 190 (19,9%) anti-HBc positive alone. 402 patients (42,1%) were
coinfected with HCV. Isolated antiHBc+ was not related to
sex, age, immunological status and HIV-viremia. .
Patients HCV+ were more likely to have isolated anti-HBc than were subjects
with HIV alone ( 33,6% vs. 9,9% p<0,0001). HBV-DNA was positive in 6,9% of
anti-HBc + patients. with low level of replication (from 102 to 103 copies/mL).
Patients HBV-DNA positive didn’t show either clinical or laboratory
abnormalities, no evidence of relation with CD4 count, HIV-RNA, HAART, or HCV
coinfection. Data on the follow-up (6-12-18 months) ) report that viraemia in
occult HBV infection tends to appear intermittently
with small fluctuation of very low levels of HBV replication. 17,8% of
anti-HBc+ patients was HBVDNA positive in at least 1 determination. During the
follow up period a patient who has interrupted voluntarily the HIV therapy,
including Lamivudine, has developed an acute hepatitis B.
Conclusions-
The serological pattern of isolated anti-HBc positivity
is frequent in HIV infected patients: longitudinal evaluation of HBV-DNA is
necessary for correct diagnosis of occult HBV infection. The screening of
subjects with occult hepatitis B infection could have implications in terms of
surveillance and therapy in the HIV infection.
Poster
1316
Abstract
ID: 64208
Category:
JO9: Hepatitis B: Pathogenesis
Host genetic and virus factors contribute to the clinical phenotype of hepatitis B: a twin study.
B.
Xu, Institute of Infectious Diseases of PLA,
Y.
Wang, Institute of Infectious Diseases of PLA,
Hospital,,
Aim:
To analyze the effect of host genetic and virus
factors on clinical phenotype of hepatitis B between HBV infected twins (20
pairs) and control groups (14 pairs of sex and age matched patients). Twins'
zygosity was identified by short tandem repeat genescan. Hepatitis A, B, C,
delta and E virus serological markers, HBV DNA level, ALT, AST and TBil were
detected.
Methods:
The data was analyzed by Fisher's exact test. 6
patients with high
HBV DNA level were divided into 3 groups: monozygotic
(MZ) twins, dizygotic (DZ) twins and non-twin siblings groups. The relationship
of viral quasispecies, genotype and clinical phenotype was analyzed. The
procedure was PCR-RFLP analysis of HBV S gene (HBV genotyping)-longer PCR of
HBV 3.2kb genome-TA cloning-conformation sensitive gel electrophoresis analysis
(quasispecies detection of preS1/S2 region)- sequencing.
Results:
The results were as follows: 1. 14 pairs of MZ twins
and 6 pairs of DZ twins
were identified. 2. As to the concordant rate,
diseases phenotype concordant rate and serological pattern of HBV infection, MZ
twins had significant difference compared with DZ twins and control groups
(P<0.05), but DZ twins and control groups had no significant difference
(P>0.05). In all groups, no significant difference was observed in infection
rate, HBsAg (+) rate, HBeAg (+) rate, asymptomatic carrier rate and HBV clearance
rate (P>0.05). 2 pairs of MZ twins had distinct outcomes: one died of severe
hepatitis, the other suffered from chronic infection.
3 pairs of MZ twins changed from symptomless to different outcomes with various
antiviral effects in their twenties. HBIg injection and inoculation right after
birth might prevent high-risk twins from infection. 3. 1 pair of MZ twins
infected with different HBV genotype (B and C) showed discordant phenotype,
while 1 pair of DZ twins (genotype B) and 1 pair of siblings (genotype C) infected
with similar HBV strains (genetic diversity=0.0%~3.3%) showed concordant
phenotype. 4. The long fragment gene deletions in
preS1/S2 region of HBV genotype C within the siblings pair were found.
Conclusions:
The high concordance in MZ twins indicated that the
host genetic background might influence the clinical phenotype, while other
factors such
as age, antiviral and inoculation might also effect on
clinical phenotype. The long fragment gene deletions in HBV preS1/S2 region
might be a reason for HBsAg antigenicity change and lead to immune escape and
onset of illness. In a word, the results suggest both host and virus factors
can contribute to determining the outcome of hepatitis B, and further research
is needed to decide which factor plays a dominant role.
[Key words] Hepatitis B virus; Twins; Genetics;
Phenotype
Poster 1317
Abstract
ID: 64481
Category:
JO9: Hepatitis B: Pathogenesis
Clinical Significance of Hepatitis B Virus Genotypes in Children and Adolescents with Chronic Hepatitis B.
S. Wirth, Children's Hospital, HELIOS KLinikum
Wuppertal, Witten-Herdecke Univ.,
Wuppertal, Germany, P. Oommen, Children's
Hospital, HELIOS KLinikum Wuppertal,
Witten-Herdecke Univ., Wuppertal, Germany, P.
Gerner, Children's Hospital, HELIOS
KLinikum Wuppertal, Witten-Herdecke Univ.,
Wuppertal, Germany, P. Wintermeyer,
Children's Hospital, HELIOS KLinikum Wuppertal,
Witten-Herdecke Univ., Wuppertal,
Germany, A. Jenke, Children's Hospital, HELIOS
KLinikum Wuppertal, Witten-
Herdecke Univ., Wuppertal, Germany, E. Coci,
Children's Hospital, HELIOS KLinikum
Wuppertal, Witten-Herdecke Univ., Wuppertal,
Germany
Background/Aims:
Until today the prevalence of different HBV genotypes
and their
clinical significance have only rarely been
investigated in children with chronic hepatitis B. Thus, the aim of this study
was both to ascertain epidemiological data on HBV genotype distribution in
childhood and to correlate the results with serological, virological, and
histological data in order to provide information on the therapeutic and prognostic
significance of genotypes in this age group.
Methods:
Hepatitis B virus genomes of 249 HBeAg-positive
chronic HBV carriers were genotyped based on restriction fragment length
polymorphism methodology (RFLP). Genotypes were correlated with corresponding
values for alanine aminotransferase (ALT) levels, quantitative HBV DNA and
histological findings.
Results:
162 males and 87 females at a mean age of 7.2 years
were studied. 96 % of the patients could be attributed to HBV genotypes A and D
(32.5 % and 63.5 %, respectively) wheras the remaining were classified as
genotypes B, C, E and F. ALTlevels and HBV DNA-levels were available for 237
and 176 patients, respectively. There was no significant difference in ALT
levels among different genotypes (mean 67 U/l). Similarly, no significant
genotype-difference was found for histological findings. In contrast, there was
a clear association between very high hepatitis B virus DNA levels
and individuals with HBV genotype D (p=0.006). Mean
time follow-up of 3.6 years showed that patients with genotype D tended to
seroconvert to anti-HBe later than those with genotype A (58% vs. 37 %).
Conclusion:
Children with HBV genotype D showed a significantly
higher viral load as
compared to patients with HBV genotype A. Since
children with vertical transmission and high viral replication respond
significantly poorer to treatment, individuals with genotype D have to be
monitored particularly careful. Long-term studies need to clarify, whether
these patients are prone to develop a more unfavorable outcome.
Abstract
ID: 65285
Category:
JO9: Hepatitis B: Pathogenesis
Clearance of HBsAg in a cohort of Alaska Natives with Chronic Hepatitis B.
J.
Simonetti, Liver Disease and Hepatitis Program,
Investigations
Program,
Program,
K.
Hurlburt, Liver Disease and Hepatitis Program,
Disease
and Hepatitis Program,
Hepatitis
Program,
Disclosures: The following authors have indicated they have no relationships to disclose:
Introduction:
Worldwide eight (A-H) Hepatitis B (HBV) genotypes have
been identified. The precise role that genotypes play in the natural history of
chronic Hepatitis B (HBV) remains to be elucidated. In this study we report the
relationship between genotype and clearance of HBsAg in an area where 6 HBV
genotypes have been found.
Methods:
A long-term study of 1536 HBsAg positive Alaska
Natives identified 182
persons who subsequently cleared HBsAg. All chronic
HBV carriers were tested biannually for HBsAg. Individuals were considered to
have cleared HBsAg when 2 successive specimens tested negative. Genotype, by
direct sequencing of the S-gene was determined for 137 of the HBsAg negative
individuals for whom stored serum was available. In addition, one HBV DNA level
was determined by real-time PCR for 95 individuals an average of 14.5 years
after HBsAg clearance (lower limit of detection 25 IU/ml). We analyzed the
resultant data to determine if clearance of HBsAg was associated with genotype,
age or gender and whether DNA was detectable after HBsAg clearance.
Results:
Six genotypes (A, B, C, D, F and H) were identified in
this cohort of
Natives with chronic HBV. The percentage of each
genotype that cleared HBsAg was as follows: genotype A 10.6% (13/123), genotype
B 4.7% (2/43), genotype C 11.9% (8/67), genotype D 14.7% (85/577), genotype F
13.6% (28/206) and genotype H (1/1). The single genotype H specimen was omitted
from further analysis. None of the HBV genotypes found in
Gender was not associated with HBsAg clearance
(p=0.688). HBV DNA was found in 15.7% (15/95) of the specimens tested after
clearance of HBsAg (range 28-1313 IU/ml) but was not associated with any
particular genotype (p=0.469). HCC developed in 3 individuals after they had
cleared HBsAg; two were genotype F and one was genotype A.
Conclusion:
Clearance of HBsAg was not associated with any of the
six genotypes found
in a cohort of Alaska Natives with chronic HBV, nor
with gender. Further investigations are required to determine if the viral
persistence in those individuals with detectable HBV DNA after clearance of
HBsAg is due to viral mutations. These results provide new information about
the relationship between HBsAg clearance and genotype. In addition, the
development of HCC after HBsAg clearance emphasizes the importance of sustained
monitoring after HBsAg seroconversion.
Poster
1322
Abstract
ID: 67571
Category:
JO9: Hepatitis B: Pathogenesis
Role of liver biopsy in patients with normal ALT and high HBV DNA.
M. Lai, BIDMC, Boston, MA, B. Hyatt, BIDMC,
Boston, MA, N. Afdhal, Beth Israel