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 :THE FIRST LARGE-SCALE KOREAN STUDY

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