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. Ahn^1,2, J.M. Lee¹, H.Y. Chang¹, S.P. Hong³, S.G. Hwang⁴, N.K. Kim⁴, K.S. Rim⁴, S.O. Kim³, Y.H. Paik^1,2, K.H. Han^1,2, C.Y. Chon^1,2, Y.M. Moon^1,2

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

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford CT, USA

Background

Entecavir (ETV) is a potent and selective antiviral with demonstrated efficacy in all HBV patient populations. Previous analyses indicate that high level ETV resistance (ETV-R) requires the presence of LVD-resistant (LVD-R) substitutions (rtL180 and/or rtM204) in the HBV reverse transcriptase (RT) and additional substitutions at residues rtT184, rtS202 and/or rtM250.

Methods

Samples from >600 subjects completing at least 1 yr of 0.5 mg ETV therapy in nucleoside naïve (219 HBeAg pos, 211 HBeAg neg) and 1.0 mg ETV in lamivudine (LVD) refractory (171) subjects were monitored for ETV resistance and characterized by genotypic and phenotypic analysis.

Results

ETV treatment resulted in reductions in HBV DNA levels to below 200 copies/ml in 78% of nucleoside naïve subjects by Week 48. None of 659 subjects experienced a virologic rebound due to resistance, and ETV-R associated substitutions at residues rtT184, rtS202 and rtM250 were not observed in any of the 430 randomly selected nucleoside naïve subjects examined. Virologic rebound due to ETV-R was observed in 1% of ETV treated LVD-refractory subjects, with emergence of rtT184, rtS202 and/or rtM250 substitutions found in 6% of ETV-treated subjects by Week 48. ETV-R substitutions only appeared in clinical isolates containing pre-existing LVD-R changes. Unexpectedly, substitutions at residues rtT184, rtS202 or rtM250 were noted in 22 LVD-refractory subjects at baseline, indicating that LVD alone can pre-select for these changes. Despite the presence of ETV-R substitutions at baseline, treatment with ETV did not lead to rapid ETV-R emergence or lack of virologic response, and various substitutions resulted in a range of ETV susceptibility changes. Mechanistic studies using a model based on the HIV-1 RT structure, predicted at least 2 distinct mechanisms by which ETV-R substitutions can result in decreased ETV susceptibility.

Conclusions

An extensive genotypic analysis of ETV treated subjects showed no evidence of ETV-R emergence by Week 48 in nucleoside naïve subjects and resistance related virologic rebounds in only 1% of LVD-refractory subjects. Clinically relevant ETV-R requires the pre-existence of LVD-R substitutions, and the presence of ETV-R substitutions do not necessarily lead to virologic rebound. Two mechanistic pathways of ETV-R have been identified, requiring multiple RT substitutions.

PREDICTORS OF A PEJORATIVE OUTCOME IN PATIENTS TREATED WITH ADEFOVIR DIPIVOXIL FOR REACTIVATION OF CHRONIC HEPATITIS B DUE TO LAMIVUDINE-RESISTANT HEPATITIS B VIRUS MUTANTS

Y. Consigny¹, A. Plessier¹, M. Martinot¹, B.N. Pham², C. Castelnau¹, V. Paradis³, F. Durand¹, F. Degos¹, D. Valla¹, P. Marcellin¹

¹Service D'Hépatologie, Hôpital Beaujon, Clichy, France ²Service D'Immunologie Biologique, Hôpital Beaujon, Clichy, France ³Service D'Anatomopathologie, Hôpital Beaujon, Clichy, France

Introduction

Adefovir is highly effective in lamivudine-resistant chronic hepatitis B patients. However, we have observed some cases of severe liver failure despite treatment with adefovir.

Aim

The aim of our study was to analyse the factors associated with a pejorative outcome.

Methods

We retrospectively included all chronic hepatitis B patients with lamivudine resistance, defined by at least a 1 log increase in viral load during lamivudine treatment (100 mg/day) and evidence of YMDD mutation. They were all given adefovir (10 mg/day) while maintaining lamivudine. Factors influencing outcome were assessed by Cox regression (age, sex, treatment delay, transaminases, prothrombin time, bilirubin, creatinin, HBeAg, viral load, genotype).

Results

29 patients were included: Median age 44 (IQR 37 to 54), 18 (62%) HBeAg negative and 10 (34%) had cirrhosis. Adefovir was given with a median delay of 11 months (IQR 2 to 19). When adefovir was introduced, 25 (86%) patients had a viral load >7 log copies/mL. With adefovir, viral load decreased to less than 6 log copies/ml (bDNA assay) in 26 (90%) patients. Despite this, 5 patients had subfulminant hepatitis: 3 underwent successful liver transplantation, 2 died. Four patients had extensive assessment of liver histology (3 explants, 1 necropsy): all had intense and diffuse cholestasis with severe lobular necrosis, 2 patients did not have cirrhosis (Metavir F1 or F2) and 2 patients had cirrhosis (Metavir F4). Univariate Cox regression showed that the only predictors of a pejorative outcome just before initiation of adefovir were a low viral load (Hazard Ratio, HR for a 1 log decrease 2.5, 95% CI 1.1 to 5.0) or high total bilirubin level (HR for a 1 µmol/l increase 1.006, 95%CI 1.002 to 1.01: in patients with pejorative outcome, 60% had HBV DNA level <7 log and median bilirubin was 317 µmol/L (IQR 68 to 570) versus 4% and 17 µmol/L (IQR 13 to 21), respectively, in patients with favorable outcome.

Conclusion

In patients with reactivation due to lamivudine-resistant mutants, severe liver failure may progress despite virological response to adefovir therapy. Patients with low viral load or severe cholestasis should be cautiously monitored and evaluated for liver transplantation.

LONG-TERM RESULTS OF INTERFERON ALFA TREATMENT IN CHILDREN WITH CHRONIC HEPATITIS B

H. Demir, N. SaltıK-Temizel, Y. Usta, H. Özen, F. Gürakan, A.L. Yüce, N. Koçak

Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University School of Medicine, Ankara, Turkey

Background & Aim

Data on long-term effects of interferon (IFN)-alfa treatment in children with chronic hepatitis B is limited. We aimed to evaluate the long-term virological response to IFN-alfa therapy in patients with chronic hepatitis B.

Patients

Fifty HBsAg, HBeAg,and HBV-DNA positive children (aged from 2 to 15 years, mean 7.6+/-3.3 years) were enrolled in a study where they received IFN-alfa subcutaneously 3 times weekly for 24 weeks. Thirty three of them were treated with an IFN-alfa dosage of 10 MIU/m2 and remaining 17 received 5 MIU/m2. Response to treatment was defined as loss of HBeAg and development of antiHBe during therapy or within 12 months after the end of therapy. The patients were followed for a range of 24 to 79 months (mean, 42.8+/-14.2 months) after the end of treatment.

Results

Eighteen (36%) of the patients responded to treatment, 14 cases during therapy and 4 cases within 12 months after therapy withdrawal. During the follow-up period additional 17 (34%) patients had HBeAg seroconversion. Twelve of them seroconverted at 12 to 24 months’ time after cessation of IFN-alfa, and 5 later. All responders also cleared HBV-DNA from their sera. No statistical difference was found between low and high dose IFN-alfa receivers’ seroconversion rates. Total number of responders at the end of follow up was 35 (70% of all patients). Loss of HBsAg occured in 6 (12%) patients. All 6 were among 18 responders who cleared HBeAg during treatment or 12 months after cessation of therapy. None of the responders relapsed during the follow-up period.

Conclusions

IFN-alfa therapy in children with chronic hepatitis B seems to continue inducing HBeAg seroconversion after therapy, especially within 24 months after cessation of IFN-alfa .Therefore, other therapeutic regimens might be considered for non-responders, only after 2 years have passed.

ENTECAVIR (ETV) IS SUPERIOR TO LAMIVUDINE AND ADEFOVIR IN TRIALS OF HBEAG-POSITIVE AND -NEGATIVE CHRONIC HEPATITIS B INFECTION: A CROSS-STUDY ANALYSIS WITH PUBLISHED REPORTS

J.L. Dienstag¹, L.J. Wei², D. Xu³, A. Cross⁴, B. Kreter⁴, R. Wilber⁴

¹Massachusetts General Hospital, Boston MA, USA ²Harvard University, Boston MA, USA ³Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford CT, USA

Background

The oral antiviral agents LVD and ADV were approved for treatment of chronic hepatitis B based on results from placebo-controlled trials. ETV is a new oral antiviral found in clinical trials to be superior to LVD. No head-to-head comparison of all three therapies has been done, and differing virologic assays used among the trials of each agent complicate inter-study comparisons.

Aim

Apply established statistical techniques using a prospectively defined analysis protocol to compare Phase III ETV data with combined data from published histologic, biochemical, serologic, and virologic trial results of LVD, ADV and placebo.

Methods

After a comprehensive search of electronic databases, abstracts, and regulatory submissions according to predefined inclusion (prospective, randomized trials of at least one monotherapy arm and a control arm or prospectively followed case series) and exclusion criteria (foreign language, pediatric trials, trials not performed in humans, trials of other therapies, retrospective reports, trials with inadequate description of methods, lamivudine-resistant patients or patients with viral coinfection or significant comorbidities, etc.), independent reviewers extracted Week 48/52 histologic, virologic, biochemical, and serologic endpoints, which were subjected to statistical analysis by a fixed effects model.

Results

Of 612 potential publications/data sources identified, 28 satisfied inclusion/exclusion criteria. LVD, ADV, and ETV were superior to placebo for all efficacy measures (HBeAg+/-). ETV was superior to ADV for all efficacy measures in HBeAg+ patients and virologic endpoints in HBeAg- patients (other endpoints comparable). LVD was superior to ADV in HBeAg+ patients for all efficacy measures except ≥2 point histologic activity index improvement and ranked assessment of necrosis/inflammation (NI), and in HBeAg- patients for virologic endpoints (other endpoints comparable). ETV was superior to LVD for all efficacy measures except ranked assessment of NI and fibrosis (HBeAg+/-), and HBeAg+ seroconversion (other endpoints comparable).

Conclusions

For virologic endpoints, ETV is superior to LVD, which is superior to ADV. Based upon controlled trials of ETV and LVD and analyses of multiple studies in which LVD and ADV were analyzed individually, ETV consistently ranks highest among the three drugs across multiple endpoints for both HBeAg+ and HBeAg- patients with chronic hepatitis B.

HEPATIC FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION CAN BE PARTIALLY REVERSED BY IFN-GAMMA

S. Dooley¹, B-E. Wang³, J-D. Jia³, W-F. Wu⁴, J-Z. Xiang⁴, P.R. Mertens⁵, W-M. Cai², H-L. Weng²

¹Medical Clinic II, University-Hospital Mannheim, University of Heidelberg, Heidelberg, Germany ²Institute of Infectious Diseases, First Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China ³Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Science, Beijing, China ⁴Eighth Hospital of Guangzhou, Guangzhou, China ⁵Department of Nephrology and Immunology, University Hospital, RWTH, Aachen, Germany

Background

Hepatic fibrosis due to chronic hepatitis B virus (HBV) infection has an enormous socio-economic impact. Besides strategies aiming at virus elimination, prevention or reversal of liver fibrosis is amenible. Given the antifibrotic activity of IFN-γ, a randomized open-labeled multicenter trial was initiated to test IFN-γ in HBV infection.

Methods

HBs-antigen positive patients with biopsy proven hepatic fibrosis (n=99, stages 2-4 according to Scheuer criterion) were treated with diammone glycyrrhizinate and potassium magnesium aspartate. Treatment with 50 mg IFN-γ i.m. on a daily basis for three months and on alternate days the subsequent six months was performed in 66 randomly assigned patients. Efficacy was evaluated by liver biopsy and serologic markers.

Results

54 patients in the IFN-γ group and 29 patients in the control group completed the study protocol. The hepatic fibrosis score was significantly reduced in 63 percent of IFN-γ treated patients compared to 24.1 percent in the control group as assessed by a semiquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for total fibrosis score decreased from 13.8 ± 5.8 to 10.1 ± 5.1 in the IFN-γ group, whereas they were unchanged in controls (13.2 ± 6.8 versus 12.6 ± 4.8 after 9 months). The Scheuer fibrosis scoring system revealed 12 out of 54 patients improved ≥ 1 stage(s) in the IFN-γ compared to 1/29 in the control group. Antifibrotic activity may be attributed to decreased TGF-β signaling via phospho-Smad2 and reduced number of activated, α smooth muscle actin positive hepatic stellate cells.

SUSTAINED RESPONSE OFF-TREATMENT TO ENTECAVIR AND LAMIVUDINE AFTER 48 WEEKS OF TREATMENT IN NUCLEOSIDE-NAÏVE, HBEAG(+) PATIENTS: 24-WEEK FOLLOW-UP RESULTS OF PHASE 3 STUDY ETV-022

R.G. Gish¹, R.A. De Man², C. Pedersen³, J. Bialkowska⁴, T.T. Chang⁵, D. Apelian⁶, J. Zhu⁶, A. Cross⁶, R. Wilber⁶

¹California Pacific Medical Center, San Francisco CA, USA ²Erasmus Medical Center, Rotterdam, The Netherlands ³Odense Universitetshospital, Odense, Denmark ⁴Klinika Chorob Zakaznych, Lodz, Poland ⁵National Cheng Kung University Hospital, Tainan, Taiwan ⁶Bristol-Myers Squibb Pharmaceutical Research Institute,, Wallingford CT, USA

Background

Entecavir (ETV) is a potent and selective HBV antiviral which demonstrated superior efficacy to lamivudine (LVD) through 48 weeks of treatment in a Phase 3 trial in 709 HBeAg(+), nucleoside-naïve patients with chronic hepatitis B.

Methods

Patients who achieved protocol-defined complete response (CR: <0.7 MEq/mL by bDNA assay and HBeAg loss) to ETV (0.5 mg QD) and LVD (100 mg QD) by Week 48 discontinued therapy and were evaluated off-treatment for an additional 24 weeks according to several sustained response endpoints.

Results

At Week 48, more patients in the ETV than the LVD group had serum HBV DNA levels of < 0.7 MEq/mL (bDNA: 91% vs 65%, p < 0.0001) or < 400 copies/mL (PCR: 69% vs 38%, p < 0.0001), or ALT <1.25xULN (78% vs 70%, p = 0.0136). HBeAg loss rates were similar (22% (n=74) vs. 20% (n=67) respectively), and 21% of ETV patients vs 19% of LVD patients achieved CR and discontinued study medication. See table for the proportion of patients achieving sustained response endpoints at 24 weeks off-treatment. Kaplan-Meier estimates of the proportion of patients with sustained responses up to 24 weeks showed a separation among the 3 endpoints in favor of ETV that began between week 8 and 12 during the follow-up period.

Conclusions

Over 70% of patients with CR after 48 weeks of ETV therapy sustained their responses off-treatment through 24 weeks. By suppressing HBV DNA, causing loss of HBeAg, and reducing ALT levels with 1 year of treatment, ETV has the potential to sustain CR when therapy is discontinued.

ADEFOVIR DIPIVOXIL (ADV) DEMONSTRATES SUSTAINED EFFICACY IN HBEAG- CHRONIC HEPATITIS B (CHB) PATIENTS

S. Hadziyannis¹, N. Tassopoulos², T.T. Chang³, J. Heathcote⁴, G. Kitis⁵, M. Rizzetto⁶, P. Marcellin⁷, S.G. Lim⁸, S. Arterburn⁹, J. Ma⁹, S. Xiong⁹, C.L. Brosgart⁹, G. Currie⁹

¹Henry Dunant Hospital, Athens, Greece ²Western Attica Hospital, Athens, Greece ³National Cheng Kung Hospital, Taipei, Taiwan ⁴Toronto Western Hospital, Toronto ON, Canada ⁵Georgios Papanikolaou Hospital, Thessaloniki, Greece ⁶Azienda Ospedaliera San Giovanni Battista, Torino, Italy ⁷Hopital Beaujon, Clichy, France ⁸National University, Singapore, Singapore ⁹Gilead Sciences, Inc., Foster City CA, USA

Background

Adefovir Dipivoxil (ADV) demonstrated efficacy and safety in 184 HBeAg- CHB patients enrolled in a 96-week randomized, placebo-controlled trial. Patients on ADV in the second 48 weeks were offered up to 3 additional years of ADV.

Objective

To evaluate the safety and efficacy of ADV over 192 weeks.

Results

Baseline characteristics for patients randomized to receive ADV for 1st 96 weeks (n=79) and continuing open label ADV : 81% male; 70% Caucasian; 26% Asian; median age 47 years; median serum HBV DNA 7.08 log10 copies/mL; median ALT: 99 IU/L (2.3 x ULN). 70 and 67 patients continued ADV up to week 144 and week 192 respectively. Three patients had confirmed elevations in serum creatinine ≥ 0.5 mg/dL over 192 weeks. All resolved, one on treatment and two following discontinuation. No patients had phosphorus levels < 1.5 mg/dL over 192 weeks. The cumulative incidence of adefovir resistance at weeks 48 (n=184), 96 (n=134), 144 (n=123) and 192 (n=67) is 0 %, 3.0% and 11% and 18%, respectively using life table analysis. HBsAg seroconversion was observed in 4 of 79 patients (5%).

Conclusions

Treatment with ADV 10 mg over 192 weeks resulted in significant and sustained reductions in HBV DNA levels with the majority of patients achieving prolonged HBV DNA suppression and sustained ALT normalization. ADV was generally well-tolerated with long-term treatment.

LAMIVUDINE THERAPY FOR SEVERE ACUTE HEPATITIS B

F. Hasan¹, S. Owaid¹, M. Ali², H. Asker¹, J. Alkhaldi¹, R. Varghese¹

¹Department of Medicine, Faculty of Medicine, Health Sciences Center, Safat, Kuwait ²Department of Microbiology, Faculty of Medicine, Health Sciences Center, Safat, Kuwait

Background

Severe acute hepatitis B can lead to fulminant hepatic failure (FMF) and death.

Objective

To assess the efficacy and safety of lamivudine for the treatment of severe acute hepatitis B in immunocompetent patients.

Patients and methods

In a 6 year period 17 consecutive immunocompetent patients ( 15 males; mean age 32 ± 6.4 years) with acute hepatitis B and an INR ≥ 1.5 were treated with lamivudine 100 mg/day for 6 months. Treatment was started within 10-33 days of the onset of illness. HBV-DNA was monitored with a b-DNA assay. Direct sequence analysis was carried out in 4 patients.

Results

Prior to treatment, three patients had grade I-II hepatic encephalopathy. The mean serum alanine aminotransferase (ALT) was 3223 ±1405 iu/L, mean serum total bilirubin was 415 ± 144 umol/L, and mean HBV-DNA was 15.6 X 106 ± 9 X 106 copies/ml. Sixteen patients (94%) had a virologic response with loss of HBsAg, HBV-DNA, and seroconversion to anti-HBe positive status within 4 weeks of therapy. Serum ALT and bilirubin normalized within 8 weeks. Anti-HBs was detected in 10 patients within 12-24 weeks of illness. One patient with encephalopathy prior to therapy died because of FHF. DNA sequence analysis did not reveal significant amino acid substitution in the precore and core regions.

Conclusion

Lamivudine therapy results in a prompt clinical, biochemical and virologic response in patients with acute severe hepatitis B. Larger controlled studies are needed to further assess the value of lamivudine in preventing the progression to FHF.

LONG-TERM FOLLOW-UP OF CHILDREN WITH HBV INFECTION TREATED WITH INTERFERON ALFA

M. Woynarowski, K. Piwczynska, M. Wozniak, J. Socha, G. Oracz

Department of Gastroenterology Hepatology and Immunology, Warsaw, Poland

BACKGOUND

Up to 50% of children treated with interferon for HBV infection clear HBe antigen and normalize ALT activity at one year after interferon discontinuation. Long term efficacy data of interferon treatment in pediatric population are limited.

MATERIAL AND METHODS

We collected the follow-up data on 170 HBV patients (M-108, F-62) treated with interferon alfa 3 MU, TIW for 20 weeks at our institution between 1990 and 1997. The age at the beginning of interferon therapy was 1.33-16,69 years (5,65+/-3,5) mean ALT activity was 3,4 times above ULN and all children had biopsy proven, HBeAg positive chronic hepatitis. Children were observed for 1,3-13,5 years (mean 7+/-3.2) after interferon discontinuation.

RESULTS

At one year after interferon treatment HBeAg was negative in 56,1%, HBs was negative in 11,5% and 75% of children had normal ALT activity (mean 0,98 above ULN). At the end of follow-up 24 (14,1%) children were still HBeAg positive. 11 of them received lamiwudine and most of the remaining 13 were lost from follow-up. Calculated annual HBeAg loss after one year from interferon discontinuation is around 5.5%. The rate of patients with negative HBsAg increased to 17%. 84,6% of children had normal ALT activity (0,87+/-1.07 above ULN). We did not observe progression to liver cirrhosis nor any clinical signs nor symptoms of liver disease. We did not recognize any late interferon related adverse events.

CONCLUSIONS

After mean period of 7 years from interferon discontinuation the number of patients positive for HBe decreased to 14% and number of children HBsAg negative increased to 17%. No negative late effects of interferon therapy on growth or development of children were observed.

EFFECTS OF RENAL IMPAIRMENT ON SINGLE-DOSE PHARMACOKINETICS OF ENTECAVIR

J.H. Yan, M. Bifano, J. Xie, J. Freund, S. Rahim, D. Zhang, D. Grasela, F. LaCreta

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton NJ, USA

Background

Entecavir (ETV) is a potent anti-hepatitis B agent which is primarily eliminated via renal excretory pathways. This Phase I study assessed the effect of renal impairment on the pharmacokinetics (PK) of ETV after a single oral dose.

Methods

ETV-011 was an open-label, parallel group study in which 34 subjects were assigned to 1 of 6 groups based on renal function: A = normal (CLcr > 80 mL/min); B = mild impairment (CLcr > 50 < 80 mL/min); C = moderate impairment (CLcr 30-50 mL/min); D = severe impairment (CLcr < 30 mL/min) not requiring dialysis; E = severe impairment, managed with hemodialysis; and F = severe impairment, managed with continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral dose of ETV 1.0 mg. Group E received a single oral dose of ETV 1.0 mg on 2 separate occasions: prior to hemodialysis (E1) and, after a washout period, following hemodialysis (E2). PK samples were collected pre-dose and up to 336 hours (blood) or 168 hours (urine) post-dose. ETV concentrations were determined using validated LC/MS/MS methods. PK analyses for ETV were conducted using non-compartmental methods.

Results

Summary statistics for selected PK parameters are listed in the associated table. Relative to healthy subjects with normal renal function, subjects with mild to severe renal impairment, including those requiring dialysis, have ETV Cmax increased between 29% and 106%, and ETV AUC(0-T) increased between 84% and 738%.

Conclusion

Dosage adjustment of ETV is warranted when administered to patients with renal impairment.

PROGRESSION TO DECOMPENSATED CIRRHOSIS IN CHRONIC HEPATITIS B VIRUS INFECTED PERSONS IS STRONGLY ASSOCIATED WITH BASELINE VIRAL LOAD

H.I. Yang¹, U.H. Iloeje², J. Su², C.L. Jen¹, E. Kuo³, S.L. You¹, C.J. Chen¹

¹National Taiwan University, Taipei, Taiwan ²Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, USA ³Bristol-Myers Squibb, Taipei, Taiwan

Introduction

Progression to decompensated cirrhosis is associated with severe morbidity and increased cost of care in CHB patients. In the absence of transplant there is a 40% annual mortality from decompensated cirrhosis. Since high levels of viral replication is associated with poor outcomes in persons treated with anti-viral therapy we studied the relationship between viral load and progression to decompensated cirrhosis among persons with chronic HBV infection.

Methods

A large prospective population based epidemiology study was established in Taiwan between 1991 and 1992. Cohort entry serum samples were tested for HBV DNA by PCR. The diagnosis of cirrhosis was by ultrasonography and ascertained by medical records review. Decompensated cirrhosis was ascertained by the presence of at least one of the following, ascites, variceal hemorrhage, hepatic encephalopathy and hepato-renal syndrome. The event incidence rate per person year of follow-up (PYFU) for each strata of HBV DNA was calculated. The multivariable adjusted relative risk (RRadj) was derived from Cox’s proportional hazard models.

Results

Of the 3851 subjects with 44,247 PYFU, 50 cases of decompensated cirrhosis were identified. The incidence rate of decompensated cirrhosis ranged from 72.2/100,000 PYFU for those with HBV DNA <300 copies/ml to 332.4/100,000 PYFU for those with HBV DNA ³ 106 copies/mL (test of trend: p<0.001) in a dose dependent manner. With the undetectable group as reference, and adjusting for gender, age, cigarette smoking, alcohol consumption, and antibodies against hepatitis C virus, the risk of decompensated cirrhosis was highest, RRadj was 7.0 for those with serum HBV DNA level > 106 copies/ml. In a multivariable model additionally including HBeAg status and serum ALT, the RRadj was 3.1(95% CI 1.4-6.6) for HBV DNA ³ 105 copies/mL.

Conclusion

HBV DNA level strongly predicts progression to decompensated cirrhosis. The relationship between HBV DNA and decompensated cirrhosis follows a biologic gradient. These data support the predictive value of high viral replication for poor patient outcomes.

ALANINE AMINOTRANSFERASE (ALT) FLARES ARE UNCOMMON BOTH ON- AND POST-TREATMENT IN ENTECAVIR TREATED HBEAG(+) PATIENTS

C. Yurdaydin¹, R.G. Gish², T.T. Chang³, M. Sherman⁴, D. Apelian⁵, R. Hindes⁵, A. Thiry⁵, A. Cross⁵, R. Wilber⁵

¹Ankara University Medical School, Ankara, Turkey ²California Pacific Medical Center, San Francisco CA, USA ³National Cheng Kung University Hospital, Tainan, Taiwan ⁴Toronto General Hospital, Toronto, Canada ⁵Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford CT, USA

Background

Entecavir (ETV) is a potent and selective HBV antiviral. ALT flares either on- or post-treatment are of concern in patients receiving chronic hepatitis B therapy.

Methods

ALT elevations were analyzed in two randomized Phase 3 trials in HBeAg(+) patients. ETV-022 randomized 709 nucleoside-naïve patients to ETV 0.5mg QD or lamivudine (LVD) 100mg QD for up to 96 weeks. ETV-026 randomized 286 LVD-refractory patients to ETV 1.0mg QD or continued LVD 100mg QD for up to 96 weeks. For both studies, patients with HBVDNA < 0.7 MEq/mL and HBeAg loss at 48 weeks discontinued treatment and were followed 24 weeks off-treatment. ALT flares on-treatment were defined as ALT > 2 x baseline and > 10 x ULN.

Results

On-treatment ALT flares were observed for 12 (3%) ETV and 23 (6%) LVD patients in ETV-022, and in 1 ETV and 16 (11%) LVD patients in ETV-026. All ETV flares were associated with a >=2 log10 reduction in HBVDNA that preceded or coincided with ALT elevation and was maintained for the treatment period, with 12/13 flares resolving on-treatment. One subject discontinued ETV due to ALT flare (HBVDNA undetectable by PCR). All 16 flares on LVD in ETV-026 and 12/23 (52 %) in ETV-022 were associated with increasing or stable HBVDNA that preceded or coincided with ALT elevation. Eight patients discontinued LVD due to flare. Among ETV-022 patients with on-treatment flares, 1/12 ETV and 5/23 LVD patients experienced a clinical or laboratory abnormality consistent with hepatic dysfunction (INR/PT, bilirubin, or albumin), and one LVD patient died of hepatic failure. ALT flares during off-treatment follow-up were observed in 3 (2 %) ETV and 9 (6 %) LVD patients and in 9/12 cases were associated with a return of serum HBVDNA toward baseline levels. No off-treatment ETV flares resulted in hepatic decompensation.

Conclusion

ALT flares require frequent monitoring in HBeAg(+) patients. However, ALT flares on ETV are uncommon and generally associated with declines in serum HBVDNA and a benign clinical course. In contrast, ALT flares on LVD are frequently associated with loss of therapeutic effect, as measured by HBVDNA.

HBV VIRAL DYNAMICS OF TELBIVUDINE VS. LAMIVUDINE AND THE COMBINATION: RELEVANCE OF EARLY VIRAL SUPPRESSION TO BETTER LONG-TERM CLINICAL RESPONSE

X.J. Zhou¹, R.E. Boehme¹, G. Chao¹, N.A. Brown¹, C.L. Lai²

¹Idenix Pharmaceuticals, Cambridge MA, USA ²University Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong

Introduction

Telbivudine demonstrated significantly greater viral suppression and ALT normalization compared to lamivudine in a 1-year phase IIb trial in 104 patients with chronic hepatitis B (CHB) (Lai, AASLD 2003).

Aim

A viral dynamic (VD) analysis was performed to better understand observed differences in response and to delineate the relationship between early viral suppression and long-term clinical outcome.

Methods

This trial compared telbivudine 400 or 600 mg/day, and telbivudine 400 or 600 mg/day + lamivudine 100 mg/day, to lamivudine 100 mg/day, in adults with HBeAg+ CHB. VD was modeled using PCR-derived serum HBV DNA data through Week 12.

Results

A biphasic exponential VD model was fitted to the viral load data. The estimated median half-life (T1/2) of the first phase of viral suppression, representing clearance of free HBV virions, was ~1 day for all treatment groups. The observed duration of the first-phase decline of viral load was ~10 days for all groups, but median viral load reduction during this first phase was greater in the telbivudine-containing arms compared to lamivudine: 3.43 vs. 3.04 log10. During second-phase clearance, the median estimated infected cell clearance rate constant was greater in the telbivudine arms vs. lamivudine (0.06 vs. 0.04 hr–1), leading to a significantly shorter estimated infected cell T1/2 (12.1 vs. 19.4 day; P<0.001). VD parameters of the second phase viral clearance (rate constant and infected cell T1/2) estimated using early viral load data correlated with long-term virologic and clinical response, i.e., patients who became PCR negative and/or normalized ALT at 1 year had faster second phase viral clearance.

Conclusions

Greater viral load reduction in the telbivudine-containing arms, compared to lamivudine, was demonstrated within 2 weeks after initiation of treatment. This was associated with faster second-phase viral clearance in the telbivudine arms, a difference maintained through Week 52. VD analysis confirmed that earlier and more profound viral suppression is associated with better efficacy on long-term viral and clinical endpoints.

ADEFOVIR DIPIVOXIL (ADV) IS EFFECTIVE FOR THE TREATMENT OF PATIENTS WITH LAM-R CHRONIC HEPATITIS B (CHB) IN CIRRHOTIC AND ELDERLY PATIENTS

F. Zoulim¹, P. Marcellin², J.P. Zarski³, P. Parvaz⁴, M. Beaugrand⁵, Y. Benhamou⁶, S. Benoliel⁷, F. Allaert⁸, A. Trylesinski⁷, V. Sitruk⁷

¹Hépato-Gastro-Entérologie/Hôpital Hôtel Dieu, Service INSERM U271, Lyon, France ²Service Hépatologie/Hôpital Beaujon, Clichy, France ³Service Hépato-Gastro-Entérologie/CHU Grenoble Vercors Michallon, Grenoble, France ⁴Clinical Virology Laboratory/Lyon-Nord Hospital, Lyon, France ⁵Service Hépato-Gastro-Entérologie/Hôpital Jean Verdier, Bondy, France ⁶Service Hépato-Gastro-Entérologie/Hôpital Pitié Salpétrière, Paris, France ⁷Medical Affairs/Gilead Sciences, Paris, France ⁸Cenbiotech, Dijon, France,

Background

Adefovir (ADV) was studied in a broad range of CHB (HBeAg positive, pre-core mutant, wild type and LAM R) with a significant and consistent efficacy and is indicated for the treatment of chronic hepatitis B (CHB).

Objective

Evaluate efficacy of ADV 10 mg in LAM-resistant CHB patients in 2 subpopulations.

Methods

94 CHB patients with lamivudine-resistant HBV treated with ADV, followed routinely between June 2001 and 2003, with HBV DNA >100 000 copies/mL ADV and one of the following criteria: clinical or histological cirrhosis or age >65 years were retrospectively monitored. Serum HBV DNA was evaluated at a central laboratory with the VERSANT HBV DNA 3.0 Assay, Bayer, LLQ 357 IUs/mL) (values presented as medians)

Results

At baseline (n=94 pts: 86 cirrhotic and 8 elderly. 19 pts were cirrhotic and elderly ): 80% of male patients;42% HBe Ag negative; prior LAM treatment duration 28 months; age 57.5 years; ADV treatment duration 11.2 months (2.8-25.9); serum HBVDNA 8.15 log10 copies/mL and ALT 2.22 ULN. 3 patients reported SAE: 2 death (1 with aneurysm rupture and 1 with hepatic carcinoma and ascitic decompensation) the 3rd pt was co-infected HBV/HCV with nephrotic syndrome secondary to Alport syndrome, he received ADV 1 tab every 48h.

Conclusion

In cirrhotic and elderly CHB patients failing LAM therapy treated in clinical practice with ADV was safe and effective. These results are consistent with the published results from ADV clinical trials