OCCULT HEPATITIS B VIRUS INFECTION IS
ASSOCIATED WITH CARCINOGENESIS OF
HEPATOCELLULAR CARCINOMA IN PATIENTS WITH LIVER CIRRHOSIS IN CHRONIC HEPATITIS
C VIRUS CARRIERS
S. Adachi, A. Shibuya, A. Takeuchi, T. Nakazawa, Y. Miura, M. Watanabe, K. Saigenji
Department of Gastroenterology, Kitasato
University East Hospital, Agamihara, Japan
Background and Aims
Occult hepatitis B virus (HBV) infection correlates with liver cirrhosis (LC) in chronic hepatitis C virus (HCV) carriers and is a risk factor for development of hepatocellular carcinoma (HCC). Here we examined the prevalence and the status of occult HBV in patients with LC related to HCV, and analyzed risk factors statistically for carcinogenesis of HCC among these patients.
Materials and Methods
One hundred thirty-eight patients (82 men and 56 women; median age, 60 years) with LC which were positive for HCV-antibodies but negative for HBs-antigen were studied prospectively. Median observed periods were 45,5 months. All patients were examined by regular follow-up images for the detection of HCC. We tested HBV-X gene from serum samples of all patients with LC as occult HBV infection by using nested polymerase chain reaction techniques. Univariate and multivariate analyses were performed to examine risk factors for carcinogenesis of HCC including occult HBV infection.
Results:
Eighty-eight patients with HCC were observed during follow up periods (64%). Forty-seven patients (34.1%) showed the positive for occult HBV infection. Univariate and Multivariate analyses revealed that more than 80 IU/l of the mean value of alanine aminotransferase(ALT),more than 20ng/ml of the mean value of α-fetoprotein(AFP), and HBV-DNA positive were independent risk factors significantly(P=0.031, P=0.046, and P=0.037, respectively).
Conclusions
The mean value of ALT and AFP, and occult
HBV infection were associated with carcinogenesis of HCC. Therefore, the
patients with LC related to HCV are required to examine occult HBV infection
for developing HCC.
CLINICAL
SIGNIFICANCE OF HEPATITIS B VIRUS GENOTYPES IN KOREA
S.H. Ahn1,2, J.M. Lee1,
H.Y. Chang1, S.P. Hong3, S.G. Hwang4, N.K. Kim4,
K.S. Rim4, S.O. Kim3, Y.H. Paik1,2, K.H. Han1,2,
C.Y. Chon1,2, Y.M. Moon1,2
1Department of Internal Medicine, Yonsei University College of
Medicine, Seoul, Korea
2Institute of Gastroenterology,
Yonsei University College of Medicine, Seoul,
Korea
3GeneMatrix Inc, Seoul, Korea 4Pochon
CHA University College of Medicine, Pundang,
Korea
Background/Aims
Recent studies have shown that hepatitis B virus (HBV)
genotypes may correlate with clinical significance in natural history and
treatment outcome. Korea is a high endemic area of HBV infection. However, data
regarding HBV genotypes and clinical significance is still scarce. We first
investigated the frequency and the clinical impact of Korean HBV genotypes in a
large population.
Patients
and Methods
A total of 476 carriers of HBV infection were enrolled
in this study. The new technology of restriction fragment mass polymorphism
(RFMP) using MALDI-TOF mass spectrometry (J Hepatol 2004;40:837-844) was performed
for HBV genotyping based on the specific sequence polymorphism of surface
protein (amino acids 44-49). The results from direct sequencing and INNO-LiPA
HBV genotyping line probe assay were compared with our assay results. Clinical
features including virological status and disease progression were evaluated.
Results
The median age of total patients was 35.5 years (M:F =
4.9:1). Out of 476 patients, inactive carriers were 151 (31.7%), chronic
hepatitis 179 (37.6%), liver cirrhosis 78 (16.4%) and hepatocellular carcinoma
(HCC) 68 (14.3%). There were 464 (97.5%) of genotype C, 11 (2.3%) of A, and 1
(0.2%) of B. Comparing genotype A and C, genotype A patients were all inactive
carriers, whereas genotype C patients included chronic hepatitis, liver cirrhosis
(p<0.001). No HCC was found in patients with genotype A. HBV genotype A
isolates in Korea was comparable to those found in European countries rather
than in sub-Saharan Africa without T1809/T1812 and A1896 mutations.
Conclusions
HBV genotype C is highly prevalent in Korea. The strong
relationship of Korean HBV Genotype A with benign clinical course needs further
comparative studies with same genotype of other countries and molecular
characterization.
FACTORS ASSOCIATED WITH LIVER DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS B
Y. Benhamou1, J.J. Quioc1,
D. Thabut1, V. Thibault2, T. Poynard1
1Service D'Hepato-Gastroenterologie, Hopital Pitie Salpetriere, Paris,
France
2Laboratoire de Virologie,
Hopital Pitie Salpetriere, Paris, France
Objective/
Methods
To examine factors associated with liver decompensation
in a cohort of HBsAg carriers refered in our liver disease department. All the
HBsAg carriers seen between January 1990 to June 2004, with no history of liver
decompensation at the first visit and a follow up period of more than 2 weeks
were included. Factors associated with liver decompensation were identified
using the Kaplan-Meier survival and the Cox regression analyses.
Results
461 HBsAg positive patients were included. HIV positive
patients (n=164) and patients positive for Delta virus (n=43) serological
markers were excluded. The median follow up was 55.6 (48.3-62.3) months. The
mean age was 37.6±12.8
years, 73.2% were male. HBeAg seropositivity was found in 49.9% of the
patients, 37.8% had an HBV DNA >6 log copies/mL at study entry. Cirrhosis
was found in 16% of the patients. During the follow up period, 46.4% and 25.4%
received adefovir/lamivudine and/or a course of interferon therapy,
respectively. The liver decompensation rate was 7.2%. In univariate analysis
male gender (p=0.008), age older than 35 years (p=0.003) and alcohol
consumption >40g/day (p<0.0001) were associated with a higher risk of
liver decompensation. ALT, HBV lamivudine resistance and serum HBV DNA level at study entry were not associated with
a significant risk of liver decompensation. Using multivariate analysis,
alcohol consumption (p=0.03), negative HBe serology (p=0.001) and no anti-HBV
therapy (p=0.03) remained associated with a risk of liver decompensation.
Conclusion
In patients with chronic hepatitis B, reduction of
alcohol consumption is strongly advised and HBeAg negative patients should be
actively considered for anti-HBV therapy. Anti-HBV therapy (IFN, adefovir and
lamivudine) may prevent the risk of HBV-related liver decompensation.
LACK OF A PHARMACOKINETIC INTERACTION WHEN ENTECAVIR IS CO-ADMINISTERED WITH LAMIVUDINE, ADEFOVIR, OR TENOFOVIR
M. Bifano, J.H. Yan, J. Xie, S. Rahim,
E. Elefant, D. Zhang, D. Grasela, F. LaCreta
Bristol-Myers Squibb Pharmaceutical
Research Institute, Princeton NJ, USA
Background
Entecavir (ETV) is a potent and selective
anti-hepatitis B agent. The
pharmacokinetic (PK) effects of co-administering ETV and lamivudine
(LVD) (ETV-058); ETV and adefovir (ADV) (ETV-063); and ETV and tenofovir (TDF)
(ETV-066) were evaluated in three separate Phase I studies.
Methods
All studies were open-label, multiple dose, sequential
design trials in healthy subjects that evaluated the steady-state PK of each
drug alone and in combination. Blood and urine samples were collected for PK
analyses pre- and post-dosing. ETV, ADV, TDF, and LVD concentrations were determined using
validated LC/MS/MS or HPLC/UV methods. PK analyses were conducted using
non-compartmental methods.
Results
PK parameters of ETV, LVD, ADV and TDF given alone and
in combination are shown in the associated table. There was no effect of co-administration
of LVD, ADV, or TDF on ETV pharmacokinetics. Similarly, ETV had no effect on
the pharmacokinetics of LVD, ADV, or
TDF. For all combinations tested, the adjusted geometric means for AUC(TAU),
Cmax, and Cmin of each drug when co-administered were similar to those values
for the drug alone: in every case, the corresponding 90% C.I.s satisfied the
pre-specified criteria (0.80-1.25) for lack of effect.
Conclusion
ETV may be co-administered with LVD, ADV, or TDF
without dose modification of either ETV or the co-administered drug.
COST-EFFECTIVENESS OF TWO ORAL ANTIVIRAL THERAPIES, LAMIVUDINE AND ADEFOVIR DIPIVOXIL OF HBEAG-NEGATIVE CHRONIC HEPATITIS B
M. Buti1, M.A. Casado2,
J.L. Calleja3, J. Salmerón4, J. Aguilar5, M. Rueda6, R. Esteban1
1Department of Hepatology, Hospital Vall D'Hebrón, Barcelona,
Spain 2Health Outcomes Research Unit, Pharmacoeconomics & Outcomes Research
Iberia, Madrid, Spain 3Department of Digestive Diseases, Hospital Puerta
Hierro, Madrid, Spain 4Department of Digestive Diseases, Hospital Clínico San
Cecilio, Granada, Spain 5Department of Digestive Diseases, Hospital Virgen Del
Rocio, Seville, Spain 6Medical Department, Gilead Sciences Inc., Madrid, Spain
Aim:
To estimate the cost-effectiveness of lamivudine and
adefovir dipivoxil for 3 years in HbeAg-negative chronic hepatitis B.
Methods
A treatment algorithm using a decision analysis model
has used to perform a cost-effectiveness analysis of the long-term use of
lamivudine and adefovir dipivoxil (time horizon three year). Data were obtained
from clinical trials and the study was performed from the perspective of
Spanish Public Health System. Only direct health costs associated with treatments
were included (discount rate = 3%).
Results
For the base case, the total estimated cost per patient
treated with lamivudine or adefovir for the 3 years was 7,912 and 17,088 Euros
respectively, with a 3% annual discount. Virological response at year 3 of
lamivudine therapy was 35.1% and of 77% to adefovir dipivoxil. The average
cost-effectiveness ratio (cost per responding patient at year 3) was 22,571
Euros for lamivudine and 22,185 Euros for adefovir dipivoxil. The incremental
cost-effectiveness ratio of adefovir dipivoxil vs. lamivudine (cost per
additional responding patient with adefovir dipivoxil) was 21,863 Euros,
demonstrating that this cost was even lower than the average cost-effectiveness
ratios of adefovir dipivoxil or lamivudine. The sensitivity analyses
demonstrated the robustness of the model being the adefovir price and the
response to lamivudine at year 3, the factors that most influence the
cost-effectiveness.
Conclusions
Long-term adefovir therapy has a similar
cost-effectiveness than lamivudine for HBeAg-negative patients.
VIRAL LOAD IS A STRONG PREDICTOR OF LIVER CIRRHOSIS RISK IN PEOPLE CHRONICALLY INFECTED WITH HEPATITIS B VIRUS REGARDLESS OF HEPATITIS B E ANTIGEN STATUS
C.J. Chen1, H.I. Yang1,
J. Su2, C.L. Jen1, E. Kuo3, S.L. You1,
U.H. Iloeje2
1National Taiwan University, Taipei, Taiwan 2Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, USA 3Bristol-Myers Squibb, Taipei, Taiwan
Introduction
HBeAg is considered a marker of active viral
replication often associated with high levels of viremia. This study was
carried out to examine the impact of HBV DNA level on the risk of disease
progression to cirrhosis stratified by HBeAg status.
Methods
A population based prospective cohort of 3,851 subjects
chronically infected with HBV was established was from seven townships in
Taiwan between 1991 and 1992. Subjects were prospectively followed by
hepatologists by clinical examinations including ultrasonography through June
30th 2004. The diagnosis of cirrhosis was based on ultrasonographic findings.
All cirrhosis cases diagnosed within 6 months of enrollment were excluded from
analyses. Multivariable adjusted relative risks (RRadj) were derived using Cox
proportional hazard models.
Results
Overall, 3774 subjects with 42,115 person years of
follow up contributed data to this analysis. There were 395 cases of cirrhosis.
Of the 3774 participants, 3,214 (85%) were seronegative for HBeAg, of which
1082 (34%) had serum HBV DNA level ³104 copies/mL; 560 (15%) were HBeAg
positive of which 538 (96%) had serum HBV DNA ³104 copies/mL at enrollment.
There was a dose dependent relationship between HBV DNA and cirrhosis risk
within the HBeAg strata. With the HBeAg negative undetectable DNA group as
reference, the highest risk of progression was found in the HBeAg positive
group with HBD DNA over 105 copies/mL.
Conclusion
Elevated serum HBV DNA is a strong predictor of
cirrhosis risk in HBV infected persons regardless of HBeAg status. Effective
suppression of HBV DNA to very low levels especially in HBeAg negative persons
could reduce progression of CHB to cirrhosis.
VIRAL LOAD AS A
PREDICTOR OF MORTALITY FROM HEPATOCELLULAR CARCINOMA AND CHRONIC LIVER DISEASE IN CHRONIC HEPATITIS B INFECTION
G. Chen1, W.Y. Lin2,
F.M. Shen3, U.H. Iloeje4, W.T. London1, A.A. Evans1
1Fox Chase Cancer Center, Philadelphia PA,
USA
2Haimen City Center for
Disease Control, Haimen City, China 3Fudan University School of Public Health, Shanghai, China 4Pharmaceutical
Research Institute Bristol-Myers Squibb, Wallingford,
USA
Objective
To assess prospectively the relationship between past
hepatitis B virus (HBV) viral load and mortality from HCC and chronic liver
disease (CLD) over a 10-year period in adult HBsAg-positive residents of Haimen
City, China.
Methods
The cohort was recruited in 1992-93. Ten years later,
we examined the association of HBV viral load at cohort entry to subsequent HCC
and CLD mortality through 2003 in 2354 subjects in 9 townships who had chronic
HBV infection at cohort entry and were not lost to follow-up. Viral load was
assayed by real-time PCR using banked samples from cohort entry. For this analysis,
viral load was divided into three categories: undetected (LOQ: 1.6x103
copies/mL ); low titer (<105 copies/mL); high titer (³105 copies/mL). Cox
proportional hazards models, adjusted for age and sex, were used to estimate
the relative risk (RR) of liver related mortality for the low viral load
(<105 copies/ml) and high viral load (³105 copies/ml) individuals vs. those
with undetectable serum HBV DNA.
Results
A total of 448 deaths were reported in 10 years’
follow-up (231 from HCC, 85 from CLD and 132 from non-liver causes). There was
no association between viral load and non-liver-related mortality. For HCC
mortality, there was a statistically significant (p<0.01) increase in risk
across viral load categories. With the
undetected HBV DNA group as the reference, the RR (95% CI) for the low viral
load group was 1.8 (0.5-5.8) and 9.9 (3.2-31.0) for the high viral load group.
For CLD mortality the trend was also significant (p<0.01) and the
corresponding RRs (95% CIs) were 1.5 (0.2-11.8) and 13.4 (1.9-97.1). The relative risk associated with high viral
load did not appear to change with increased length of follow-up.
Conclusion
Our results indicate that high viral load is associated
with increased mortality from HCC and CLD in patients chronically-infected with
HBV. Combined with other known risk factors for HCC and CLD mortality, viral
load can help to identify individuals most at risk for serious sequelae of HBV
infection.
ENTECAVIR (ETV) RESISTANCE IS NOT OBSERVED IN NUCLEOSIDE-NAÏVE SUBJECTS AND IS OBSERVED INFREQUENTLY BY WEEK 48 IN LAMIVUDINE-REFRACTORY SUBJECTS WITH CHRONIC HBV INFECTION
R.J. Colonno, R.E. Rose, S.M. Levine, K. Pokornowski, M. Plym, C.F. Yu, C.J. Baldick, S. Zhang, A.W. Walsh, L. Discotto, C. Muzzucco, J. Fang, D.R. Langley, D.J. Tenney