U.S. Akarca1, F. Gunsar1,
G. Ersoz1, T. Ozacar2, S. Erensoy2, M. Akyildiz1,
E. Kasap1, S. Akay1, F. Tekin1, Z. Karasu1,
Y. Batur1, T. İlter1
1Department of Gastroenterology, Ege University Medical School, Izmir, Turkey 2Department of Microbiology, Ege University Medical School, Izmir, Turkey
Introducion
Resistance to lamivudine is a major drawback of
treatment of chronic hepatitis B (CHB). Most of the studies have shown an equal
rate of resistance to lamivudine in HBeAg positive and HBeAg negative patients.
However, our previous reports implied that HBeAg negative patients had a lower
rate of lamivudine resistance which was attributed to the lower replicative
capacity of the HBeAg minus virus.
Aim
In this study we analyzed the cumulative probability of
biochemical breakthrough of lamivudine-treated patients by considering their
age, gender, HBeAg status, baseline ALT and HBV DNA levels.
Methods
We reviewed data on 498 patients with compensated
chronic hepatitis B who received lamivudine for up to 6 years in a single
center. Biochemical breakthrough was defined as the presence of two consecutive
ALT values more than the upper limit of normal, at least 1 month apart, after
ALT normalization. Primary resistance was defined as the persistent ALT
elevation during lamivudine treatment. To investigate the parameters which were
related to breakthrough, Kaplan-Meier analysis and log-rank test were performed
after categorization of the above parameters. Variables reaching a statistical
significance were introduced into Cox’s multiple regression analysis.
Results
Of 498 lamivudine-treated patients (346M, 152F, median
age: 41), 322 (64.7%) were HBeAg negative, 176 (35.3%) HBeAg positive. Median
ALT was 113 IU/L, HBV DNA was 312 pg/ml. Biochemical breakthrough rate at 1, 2,
3, 4, and 5 years were 9%, 21%, 36%, 49%, and 59% respectively. These values
for HBeAg positives were 13, 33, 59, 74 and 88%, for HBeAg negatives were 7,
15, 25, 35, and 41% (p<0.00001). Univariate analysis showed that baseline
ALT (p=0.036), age (p=0.0019), HBV DNA (p<0.0001) were related to
breakthrough, as well. Multivariate analysis indicated that HBeAg status, HBV
DNA and categorized ALT (<2xULN, 2-5xULN, >5xULN) were independently
related to cumulative biochemical breakthrough rate.
Conclusions
HBeAg negative patients have a lower rate of
biochemical breakthrough during lamivudine therapy comparing to HBeAg positive
patients independent of baseline HBV DNA and ALT values.
P. Fabris1, M.R. Biasin2, M.T. Giordani1, L. Berardo2, D. Infantolino2, V. Menin2,
E. Conti1, C. Stecca1, F. de Lalla1
1Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy 2Department of Pathology, Hospital of Castelfranco Veneto, Treviso, Italy
Background
The frequency and the impact of occult HBV infection in
patients with chronic hepatitis C are
still under discussion.
Aims
To evaluate the prevalence of occult
HBV infection and to assess its
impact on HCV viral titre, and liver
histology in patients with chronic hepatitis C and in HIV/HCV coinfected
patients..
Methods
One-hundred and sixty-one frozen liver biopsies from patients (74%
IVDUs) with chronic hepatitis C (Group A), 26 liver biopsies from HIV/HCV
coinfected patients (Group B) and 32 biopsies from a control group (25 HBsAg+,
4 autoimmune hepatitis and 3 cryptogenic chronic hepatitis) were studied. DNA
was extracted with QIAGEN kit method and amplified with nested PCR by
using primers for S, Core and X genes.
Liver histology was evaluated using the
Ishak’ s modified HAI.
Results
The overall HBV-DNA frequency was 14.2% (23/161) in specimens from Group A,
and in 11.5% (3/26) specimens from Group B (p=ns). In both
groups, HBV-DNA positivity was unrelated to HCV genotype, while a significant
(p<0.01) association with serological
markers of previous exposure to HBV infection was found. In Group A, HCV viral
titre was lower in HBV-DNA positive than in HBV-DNA negative patients (0.4 x 106 UI/ml vs 1.4 x 106,
p=0.06).Furthermore, grading (but not staging) was significantly higher in
HBV-DNA positive than in HBV-DNA negative patients (mean score 7.0 vs 5.2,
p=0.03). Among HCV mono-infected, 5 samples were positive for S gene, 11 for
Core gene, 5 for both S gene and Core gene, and 2 for X gene. Similar figure
was observed in liver tissue from
HCV/HIV co-infected patients.
Conclusions
In our study the prevalence of occult HBV infection
appears to be lower than previously reported, with a similar
figure in HCV mono-infected and
in HCV/HIV co-infected patients. The inverse correlation between the HBV-DNA
positivity in liver tissue and HCV viral titre seems to support an interference of occult HBV infection on HCV
replication. Although HBV-DNA positivity
appears associated with more severe liver inflammation, prospective
studies should be designed to evaluate the impact of occult HBV infection on
liver disease progression.
G. Germanidis1, S. Chevaliez2, F. Roudot-Thoraval2, M. Bouvier-Alias2, F. Guerre2, A. Miladi2, I. Makri3,
S. Manolakopoulos4, E. Pagkalos1, A. Avgerinos4, G. Dalekos3, J.M. Pawlotsky2
1Department of Internal Medicine, Papageorgiou General Hospital, Thessaloniki, Greece 2Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris 12, Créteil, France 3University of Larissa, Larissa, Greece 4Evangelismos Hospital, Athens, Greece
Introduction
The diagnostic and prognostic value of single HBV DNA
level measurements in individual patients is unknown, and no clinically
relevant thresholds have been established to make accurate clinical or
therapeutical decisions.
Objective
To determine the clinical information provided by HBV
DNA levels and identify clinically relevant HBV DNA thresholds in
HBeAg-negative, HBV genotype D-infected patients.
Methods
HBV DNA was quantified in 808 Greek patients with
chronic hepatitis B (695 HBeAg-negative, 113 HBeAg-positive as a control
group). HBV DNA levels were compared with the clinical, biochemical and
histological characteristics of infection. The HBV genotype and precore and
core promoter mutations were determined.
Results
Preliminary results are available for 241 patients (154
M, 87 F, mean age 50±14) with HBeAg-negative chronic hepatitis B, 19.5% having
cirrhosis. All but 3 were infected with HBV genotype D. The HBV DNA level
varied according to the predominant precore nucleotide at position 1896:
(wild-type: 5.9±2.1 vs precore mutant: 4.8±1.5 log IU/ml), but was unrelated to
core promoter mutations. The HBV DNA load was significantly higher in the
patients with cirrhosis (5.5±1.3 vs 4.7±1.6, p=0.006). Among 102 patients with
a Metavir score, HBV DNA load was associated with the activity grade
(p=0.0005), together with the age and serum ALT and AST levels. An HBV DNA load
of 600,000 IU/ml (5.8 log IU/ml) was the best predictor of chronic active
hepatitis, ie A2 or A3 (PPV=64.2%, NPV=75.5%). When combining the activity
grade and fibrosis score, the HBV DNA load was significantly associated with
the severity of HBV-induced liver disease (p=0.04), together with an older age
and higher AST levels.
Conclusion
In genotype D-infected, HBeAg-negative patients with
chronic hepatitis B, the HBV DNA load is significantly related to the type of
precore mutation, and increases with the severity of HBV-induced liver disease.
Combining HBV DNA load, aminotransferase levels and the patient?s age may allow
to discriminate among the patients who need and those who do not need antiviral
therapy. The final results on the full series of 808 patients will be
presented. They will help deriving a treatment decision algorithm for
HBeAg-negative, HBV genotype D-infected patients.
N. Marino1, S. Lo Caputo1, P. Pierotti1, C. Blé1, M.P. Riccardi2, M. Trezzi2,
M. Toti2, M. De Gennaro3, A. Scasso3, A. Vivarelli4, D.
Dionisio4
1Division of Infectious Diseases,S.M.Annunziata Hospital, Florence, Italy 2Division of Infectious Diseases, Misericordia Hospital, Grosseto, Italy 3Division of Infectious Diseases, Campo Di Marte Hospital, Lucca, Italy 4Division of Infectious Diseases, Del Ceppo Hospital, Pistoia, Italy
Background
70–90% of HIV-infected patients have evidence of
infection with Hepatitis B virus. Most individuals develop anti-HBs and
anti-HBc; 10-18% develop anti-HBc in absence of detectable anti-HBs and may
reflect latent HBV infection.
Methods
HIV+ consecutive patients in the year 2003 were chequed
in 4 Infectious Disease Units in Tuscany (Italy) in order to assess parameters
HIV-related (CD4 count, HIV-RNA), serological markers for HBV (HBsAg, anti-HBs,
anti-HBc , HBeAg, anti-HBe) and HCV (anti-HCV, HCV-RNA ). Polymerase chain
reaction (PCR) for HBV-DNA (Cobas Amplicor HBV Monitor ) was performed in
patients who showed only anti-HBc reactivity. Clinical and therapeutical data
were collected. T.Student test was employed.
Results
955 HIV+ patients ( 71,3% males, median age 42,3 years,
eterosexual transmission 26,7%, omosexual 30,2%, IVD 59,4%) were evaluated for
HBV infection. 581 patients (60,8%) were anti-HBc+, 64 (6,7%) were HbsAg+, 361
(37,8%) were anti-HBs+, 190 (19,9%) were anti-HBc+ alone. 402 patients (42,1%)
were coinfected with HCV. Isolated antiHBc+ was not related to sex, age,
immunological status and HIV-viremia. Patients with isolated anti-HBc were more
likely than patients anti-HBc - to be HCV seropositive ( 71% vs 17,3%
p<0,0001) . 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 of the HBV viraemic patients
report that viraemia in occult Hepatitis B is not persistent. Liver cirrhosis
was observed only in HCV+ patients and does not relate to HBV-DNA; prevalence
was higher in anti-HBc+ 15,8% vs. anti-HBc- 1,5% (p<0,0001).
Conclusions
These findings suggest that occult HBV infection is
frequent in patients HIV+, occurs more frequently in patients with chronic
hepatitis C and enhances the severity of liver disease. HBV-DNA positive in
6,9% was not related to clinical or laboratoriy. Longitudinal evaluation of
HBV-DNA is necessary for correct etiologic diagnosis of occult HBV infection.
S. Mauss1, T. Lutz2, F. van Boemmel3, F. Berger1, T. Berg3, A. Stoehr4,
A. Carlebach2, G. Schmutz1
1Center for HIV and Hepatogastroenterology, Duesseldorf, Germany 2HIV-Cohort, Frankfurt, Germany 3Medical Clinic Charite, Berlin, Germany 4Institute for Interdisciplinary Infectiology and Immunology, Hamburg, Germany
Objective
Sequential monotherapy is the standard of care in the
treatment of chronic hepatitis B. In contrast in HIV- or HCV-infection
antiviral combination therapy has been proven to be superior to monotherapy.
Methods
Patients with HBV/HIV-coinfection never pretreated with
tenofovir (TDF) and lamivudine (3TC) starting antiretroviral therapy on TDF in
combination with 3TC were compared to patients who had highly replicative
hepatitis B under treatment with 3TC and were switched to TDF as the only
active HBV-polymerase inhibitor. All patients were HBe-antigen positive. All
patients who switched to TDF as monotherapy for HBV had highly replicative
chronic hepatitis B despite 3TC therapy defined as >500.000 copies/mL
indicating 3TC resistance. The lower limit of detection of HBV-DNA was <1000
copies/mL. Results: At baseline patients on TDF + 3TC (n=8) had a median
HBV-DNA of 49.000.000 copies/mL compared to 187.000.000 copies/mL on TDF
(n=24). After 3 months on treatment median HBV-DNA decreased to 140.000 copies/mL
on TDF + 3TC compared to 30.000 copies/mL on TDF. After 12 months on therapy
median HBV-DNA was 2200 copies/mL in patients on TDF + 3TC and <1000
copies/mL on TDF. A sustained undetectable HBV-DNA <1000 copies/mL was
achieved in 6/8 (75%) patients on 3TC + TDF and in 19/24 (79%) patients on TDF.
Viral rebound was observed in 0/8 and 2/24 patients, respectively. ALT
normalised in 5/8 (63%) and 16/24 (67%) patients. ALT >2x upper limit of
normal was observed in 0/8 and 2/24 patients. A loss of HBe-antigen was observed
in 1/8 patients on TDF + 3TC and in 6/24 patients on TDF. HBs-antigen loss was
found in 0/8 and 2/24 patients.
Conclusion
In this cohort of HBe-antigen positive
HBV/HIV-coinfected individuals full virologic suppression of HBV-DNA was
achieved in the majority of patients independent of treatment allocation.
HBe-antigen loss and ALT normalisation were not in favour of the combination
therapy. From these preliminary data monotherapy with TDF seems as effective as
TDF + 3TC in coinfected patients with highly replicative hepatitis B.
F. Oliveri1, M. Puoti2, T. Santantonio3, P. Lampertico4, G. Colloredo5, G. Niro6, G. Fattovich7, F. Morisco8,
A. Marrone9, P. Costa10, M. Felder11, P.
Cacciatore12, A. Smedile13,
M.R. Brunetto1
1U.O. Gastroenterologia ed Epatologia, Azienda Ospedaliera
Universitaria Pisana, Pisa, Italy 2Clinica
Malattie Infettive e Tropicali, AO Spedali Civili, Brescia, Italy 3Clinica
Malattie Infettive, Azienda Ospedaliera Policlinico Consorziale, Bari, Italy 4Divisione
di Epatologia, IRCCS Ospedale Maggiore Policlinico, Milano, Italy 5Divisione
Medicina, Policlinico San Pietro, Ponte
San Pietro, Italy 6Gastroenterologia
Casa Sollievo Della Sofferenza, San
Giovanni Rotondo, Italy 7Dipartimento
di Gastroenterologia, Università di Verona, Verona, Italy 8Cattedra
Di Gastroenterologia, Dipartimento di Scienza Degli Alimenti, Università di
Napoli 'Federico II', Napoli, Italy 9Divisione di Medicina Interna ed Epatologia, Seconda
Università di Napoli, Napoli, Italy 10Divisione Malattie Infettive Ospedale 'C. Poma' –
Mantova 11Divisione di Gastroenterologia, Ospedale Centrale Bolzano 12Clinica
Malattie Infettive, Università Di Chieti 13UO Gastroenterologia
Ospedaliera, Ospedale S. Giovanni Battista 'Molinette', Torino, Italy, Italy
Introduction
HBeAg negative CHB is a progressive disease with low
spontaneous and drug induced resolution rates. We evaluated sustained response
(SR) to IFN and factors influencing treatment
and disease outcome in a large series of patients.
Patients
and Methods
We followed up prospectively 558 anti-HBe positive CHB
patients (451 males, 107 females; mean age 41, range 12-66 y) from 13 Italian
Centers. Patients received at least 3 months (m) of alpha-IFN from 1985 to
2001: 437 (78%) experienced single courses whereas 121 (22%) 2 or more
courses. Mean follow up after end of
treatment (EOT) 54 m (1-205 m). SR=normal ALT, HBV-DNA<10 pg/ml, IgM
anti-HBc<0.2 IMx index for at least 12 m after EOT.
Results
At baseline 150 (27%) patients had cirrhosis, 49 (9%)
moderate-severe steatosis. At first IFN treatment 319 (57,2%) patients achieved
EOT response, 96 (17,2%) were SR; after relapse 14 (2,5%) developed
persistently normal ALT and undetectable HBV-DNA (PRR=Persistent Remission after Relapse).
Long Term Response (LTR=SR+PRR) rate in naives (19,7%) was the same of that in
retreated (19,8%). At multivariate analysis (MVA) age younger than 40 y (p=0,011)
and treatment duration (p<0,000001) were independently associated with SR,
observed in 6,8%, 15.9% and 30.7% of patients treated 3-6 m, 7-12 m and more
than 1 y (mean 19 m) respectively. HBsAg clearance was observed in 47 (35%) of
134 LTR (anti-HBs seroconversion in 32). During follow up 43 (7,7%) patients
developed End Stage Complications (ESC) (jaundice, ascites, var.bleeding,
encephalopathy) and/or Hepatocellular Carcinoma (HCC in 27, 4,8%). Four
patients were transplanted because of HCC and 1 for terminal cirrhosis (t.c.);
14 (2,5%) died 15-100 m after EOT because of HCC (10), t.c.(3) and extraepatic
tumor (1). Among 43 ESC patients 31 had
baseline cirrhosis, only 1 was female. At MVA female sex, younger age,
absent-mild steatosis, absence of cirrhosis and LTR to IFN were independently
associated with a better outcome. In cirrhotics LTR was independently
associated with the absence of ESC except HCC.
Conclusions
In
HBeAg negative CHB standard IFN warrants a
20% LTR associated with a better clinical outcome. In cirrhotics IFN may
avoid clinical decompensation, but not HCC.
J.B. Trabut1, B. Nalpas1,
M.L. Chaix2, V. Verkarre3, J. Serpaggi1, H. Fontaine1, S. Pol1
1Unité D'Hépatologie-INSERM U 370, CHU Necker Enfants-Malades, Paris, France 2Laboratoire De Virologie-EA 3620, Université René Descartes- CHU Necker Enfants-Malades, Paris, France 3Laboratoire D'Anatomo-Pathologie, CHU Necker Enfants-Malades, Paris, France
Background
HBV infection is a frequent cause of morbidity and
mortality in HIV-infected patients.
Aim
The aim of our study was to analyse the factors
associated with the severity of their liver disease.
Patients
and methods
A cohort of 110 patients HBV/HIV co-infected (110
sexual contaminations and 10 unknown). Analysis of : 1. parameters
significantly associated with fibrosis score and mortality ; 2. the impact
of’interferon and lamivudine therapies.
Results
Cirrhosis was present in 25.5% of the patients. Among
the 85 patients without any anti-HBV therapies, fibrosis with the Metavir
scoring system (F3-4 vs. F0-2) was significantly more severe in the older patients
(p= 0.004), in those with the longer duration of HBV infection (p=0.006), with
a CD4+ lymphocytes count < 250/mm3 (p=0.03) and those with antiretroviral
therapy (53 vs 28%, p=0.02). Necro-inflammation correlated with severity of
fibrosis (p=0.002). In multivariate analysis, antiretroviral therapy and the necro-inflammatory activity were
significantly associated with fibrosis (p=0.04, RR=3.1 and 0.001,
respectively). Eight patients (8.7%) died (5 F4, 2 F3 and one F1) during the
follow-up, including 5 liver-related deaths ; yearly mortality was 1.7% and was
significantly higher in cirrhotics (20% vs 5%, p=0.039) and in patients with
with a CD4+< 250/mm3 (26.3 vs 4.5%, p=0.004). Mortality was reduced in
patients under antiretroviral therapy including lamivudine (p=0.04). Standard
Interferon efficacy (HBV DNA<700.000 copies/ml) was poor since only 10.5% of
treated patients had sustained virosuppression (> 6 months) and only one
(2.8%) had HBe/antiHBe seroconversion. Lamivudine, given to 51 patients, resulted
in HBeAg loss in 44.8% and a primary control of HBV replication in 95% of
patients ; 52.6% developped resistance after a mean of 23 months. Lamivudine
therapy was associated with less severe liver lesions, reduction of fibrosis
progression and a lower mortality.
Conclusion
Our study establishes that in HBV/HIV co-infection :1.
cirrhosis is frequent (25%) and severe
(20% of deaths) ; 2. antiretroviral therapies (and CD4<250/mm3)
enhance liver lesions; 3. lamivudine provides a benefit in reducing liver-related
morbidity and mortality.
O. Schildgen1, U.C. Wend7, C.K. Schewe4, M. Vogel2, M. Daeumer3, R. Kaiser3, L. Weitner4, M. Helm5, H. Hartmann6, B. Matz1, J.K. Rockstroh2, W. Gerlich7