May 16th

 

Abstract ID: M1710

 

Do Chronic Hepatitis B Patients Have Poorer Diabetic Control and More Diabetic Complications? - a Prospective Study Of 2931 Patients

 

V.W. Wong, A.Y. Cheng, P. Tong, W. So, W. Chan, F.C. Chow, H.L. Chan, J.J. Sung, J. Chan

 

Background

Chronic hepatitis C is associated with insulin resistance and type 2 diabetes mellitus. The association is more controversial among hepatitis B patients. This study aims to investigate the metabolic profile and clinical course of diabetic patients with chronic hepatitis B (CHB).

 

Methods

2931 Hong Kong Chinese with diabetes underwent comprehensive examination for diabetic control and complications at a university hospital from February 1995 to April 1999. They were then assessed prospectively for mortality and major cardiovascular events.

 

Results

After excluding 93 patients with type 1 diabetes mellitus, 2838 patients were included in the current analysis. The mean age at baseline was 59.7 years (SD 12.9). 1669 (58.8%) patients were female. 286 (10.1%) patients had CHB. CHB patients had earlier onset of diabetes than HBsAg negative controls (mean age 51.0 versus 53.7 years, p = 0.0002). More CHB patients had glycosylated hemoglobin above 8% (40.2% versus 34.2%, p = 0.04). On the other hand, CHB patients had lower systolic blood pressure (134 versus 137 mmHg, p = 0.05), lower total cholesterol level (5.2 versus 5.5 mmol/l, p = 0.001), lower LDL-cholesterol (3.3 versus 3.5 mmol/l, p = 0.01) and lower triglycerides (1.5 versus 1.8 mmol/l, p = 0.0003). Both groups had similar body mass index and hip-waist ratio. Diabetic retinopathy is more common among CHB patients (28% versus 23%, p = 0.03). At a mean follow-up of 3.5 years (range 1.7 to 5.9 years), mortality was 7% among CHB patients and 4% among controls (p = 0.02). However, the excessive deaths were largely due to liver failure and hepatocellular carcinoma among CHB patients (3.8% versus 0.3%, p < 0.0001). There is no difference in macrovascular complications and cardiovascular events between the two groups.

 

Conclusions

CHB patients have earlier onset of diabetes and poorer diabetic control. This results in increased prevalence of diabetic retinopathy. The better blood pressure control and more favorable lipid profile among CHB patients provide protection against macrovascular complications.


 

Abstract ID: M916

 

The Effect Of Antiviral Treatment on Hepatitis B X Protein, Proliferating Cell Nuclear Antigen and P53 Protein Expression in Chronic Hepatitis B

 

c. cengiz, n. turhan, m. akdogan, d. oguz, s. kacar

 

Introduction

There is conflicting data on whether therapy for chronic Hepatitis B Virus (HBV) infection reduces the risk of developing hepatocellular carcinoma (HCC). HBV X protein (HBx), proliferating cell nuclear antigen (PCNA) and p53 protein are known to play a role in HBV related hepatocarcinogenesis. The impact of HBV therapy on these histological markers has yet to be addressed.

 

Aim

To evaluate the histological expression of HBx, PCNA and p53 in a cohort of chronic HBV patients treated with interferon (IFN) and /or lamivudine (3TC).

 

Methods

Thirty HBV monoinfected, antiviral therapy naive individuals, 18 HBe antigen negative (HBe Ag -) and 12 positive (HBe Ag +) were treated with IFN alfa-2a 9 MU 3 x weekly + 3TC 100mg daily (n = 23) or 3TC alone (n =7) for 12 months. Liver biopsies were performed pre and post antiviral therapy. End- of-treatment virological response (ETVR) was determined for each patient. Biopsies were stained for HBx, PCNA and p53 using monoclonal antibodies, and PCNA index (number of PCNA expressing hepatocytes per 1000 hepatocytes) post therapy compared to baseline (BL) was evaluated.

 

Results

Mean age of cohort was 35, 17 male, all were Caucasian. No subject had cirrhosis. HBx was expressed in 5/30 (17%) of BL biopsies, 4/5 HBx (+) biopsies were from HBe Ag (-) subjects. No biopsy was p53 (+). All biopsies (+) for HBx exhibited BL PCNA scores above the mean. Loss of HBx after HBV therapy (n = 3) was associated with decrease in PCNA index. Subjects achieving an ETVR (n = 25) had a significant decrease in PCNA index post therapy compared to baseline (p< 0.005), there was no significant difference between pre and post therapy PCNA index in those not attaining an ETVR. Large cell dysplasia (LCD) was observed in 8/30 (27%) of BL biopsies and in 3/5 (60%) of HBx (+) biopsies. LCD was associated with a higher BL PCNA index (p< 0.05). Persistant HBx expression post therapy (n = 2) was associated with LCD on BL biopsy, and failure to achieve ETVR or to reduce PCNA index.

 

Conclusion

We conclude that HBx expression is commoner in HBe Ag (-), precore mutant subjects and is associated with a higher PCNA index as well as LCD. Achieving an ETVR is associated with decrease in PCNA index. HBV therapy may provide HBx antigen loss. Further studies are indicated to determine if individuals with decreased PCNA index and/or loss of HBx expression following therapy are at lower risk of developing HCC.


 

Abstract ID: M930

 

Hepatitis B Virus X Protein Expression Increases the Level Of Damage Inducible Transcript 3 in Human Hepatoma Cell Cultures.

 

C. Madden, B. Slagle

 

Objective

The hepatitis B virus X protein (HBx) is necessary for the establishment of infection in mammals and significantly increases the level of virus produced in vitro. HBx has also been shown to influence apoptosis. The purpose of this study was to identify the impact of HBx expression on molecular pathways related to cellular proliferation, senescence, necrosis, and apoptosis.

 

Methods: We utilized membrane arrays to examine the influence of HBx expression on 96 key genes related to cell stress and toxicity. Total RNA was isolated from HepG2 cell cultures transiently transfected with an HBx expression or control plasmids.

 

Results

Of the 96 genes analyzed, the expression level of damage inducible transcript 3 (DDIT3/GADD153/CHOP) exhibited the most dramatic increase (approximately 4-fold) due to the expression of HBx. DDIT3 is a pro-apoptotic stress response protein produced in response to DNA damage, nutrient deprivation, or the accumulation of unfolded proteins. Consistent with the induction of DDIT3, intracellular localization studies performed with HBx and the green fluorescent protein (GFP) indicated that HBx/GFP fusion proteins form cytoplasmic inclusions in transfected HepG2 cell cultures. The precise nature of these inclusions is under investigation but they may represent aggregates of misfolded protein that are responsible for the increase in DDIT3.

 

Conclusions: The induction of DDIT3 may have important consequences for viral replication. DDIT3 encodes the C-EBP-homologous protein (CHOP), a stress response transcription factor. Although CHOP is often considered a pro-apoptotic tumor suppressor protein, it both positively and negatively regulates signaling by members of the C-EBP and AP-1 family of transcription factors. The ability of HBx to increase production of CHOP may serve as an important regulator of viral gene expression.


 

Abstract ID: M1224

 

Does Previous Hepatitis B Immunization Correlate With Immune Status in Asian Americans?

 

V. Warren, S. Tong, H. Liu, K.E. Kim

 

Introduction

Asian Americans have the highest rates of hepatitis B in the United States. Hepatitis B immunization has decreased the incidence of infection. Our Chicago Asian immigrant community based hepatitis B screening program have identified approximately 10% positivity rates for hepatitis B surface antigen. However, studies to date have not reported the prior immunization status in Asian community based hepatitis B screening programs.

 

Between 2001- 2003, 1019 Asian immigrants in the Chicago and metropolitan area were screened for hepatitis B (Chinese,Vietnamese, Cambodian, Lao, Korean, Indian, Pakistani, Ethiopian and Somali).

 

Methods

All screenings were performed in community based settings and were linguistically specific. All participants completed a translated survey on risk factors, health beliefs and previous immunizations.

 

94 persons were HbsAg+ for an average rate of 9.23%. (Men 13%,Women 7%). 53% were immune (anti-HBs+); 37% had no immunity (anti-HBs negative). 54% (546) were antiHBs+. 64% of persons with immunity to HBV reported no recollection of receiving HBV vaccine. 5% said they had had a past diagnosis of hepatitis. Table 1 reports the breakdown of immunization history in those positive for HBsAg.

 

In our study population, those aged 19-35 had both the highest rates of both HBsAg positivity and previous hepatitis B immunization reporting. The concern for this young Asian population is the risk of absent follow up and needed screening and/or treatment. Since greater than 60% of all Asian Americans are foreign born, immigrating from regions highly endemic for hepatitis B and where a new emphasis on immunization is increasing, this study highlights the need for aggressive screening despite immunization history. Previous immunization in Asian Americans should not deter screening and evaluation for hepatitis B risk.

 

Table 1 Sero-prevalence of HBsAg by age group and immunization history

Age Group n

HBsAg +

n (%)

Reporting No Vaccine

n (%)

Reporting Vaccine

n (%)

<18 32

1 (3.13)

21 (65.6)

11 (34.7)

19-35 209

34 (16.27)

147 ( 70.3)

62 (29.7)

36-45 251

28 (11.16)

191 (76.1)

60 (24)

46-55 195

18 (9.23)

158 (81.0)

37 (19)

56-65 215

8 (3.72)

153 (71.2)

62 (28.8)

>65 105

5 (4.76)

79 (75.2)

26 (24.8)

No age recorded 12

 

 

 

 


 

Abstract ID: M1223

 

Hepatitis B Screening in Asian Americans: the Need for Subgroup Analysis on the Prevalence, Risk and Susceptibilty for Hepatitis B

 

H. Liu, V. Warren, K.E. Kim

 

Introduction

Asian Americans have the highest rates of hepatitis B in the United States. One in ten Asian Americans have chronic hepatitis B; 25% of those with chronic hepatitis B will die from complications of the disease, including cirrhosis and hepatocellular carcinoma. Within certain Asian communities, hepatocellular carcinoma has been reported to be up to 12 times more common than in Caucasian Americans, representing the greatest cancer health disparity in the United States. Despite the availability of effective hepatitis B vaccines, studies of hepatitis B susceptibility within disaggregated Asian immigrant communities have not been well reported.  This study aims to determine the prevalence and susceptibility of hepatitis B between 7 different Asian immigrant communities in the Chicago metropolitan region.

Methods

This prospective, convenience sampled study utilized lay health educators to provide education coupled with community based hepatitis B screening programs in 7 separate Asian immigrant community centers.  Clients who regularly attended community center events were asked to participate in the study.  All screening programs were carried out in their native languages which included Korean, Chinese, Vietnamese, Laotian, Cambodian and Indo-Pakistani languages.

Results

A total of 800 clients were screened.  59% were women; the age range was 31-70, with the mean of 47.  Overall, 10% were HBsAG-positive, 53% were HBsAB-positive and 37% were neither HBsAG/HBsAB-positive (susceptible group).  There were wide variations in hepatitis B markers between Asian ethnic groups(see Table 1)

 

Hepatitis B is an extremely infectious, yet preventable disease.  Immigrants from Asia are at highest risk for chronic hepatitis B and early death.  This study shows the variations in hepatitis B prevalence, immune status and susceptibility within disaggregated Asian immigrant communities, and addresses the need for tailored, ethnic specific hepatitis B education, prevention and intervention within and between communities. Asian Americans are the most rapidly growing immigrant population in the US, and with greater than 60% of Asian Americans being foreign-born, early screening and prevention for hepatitis B must be universally instituted.

 

Table 1: Hepatitis B Screening Serology by Asian Ethnicity

 

 

 

Korean

Chinese

Vietnamese

Laotian

Cambodian

Pakistani

Indian

HBsAg+

5.70%

13.90%

11.50%

13.60%

7.00%

12.50%

1.00%

HBsAb+

52.50%

54.60%

63.10%

50%

55.80%

25%

7.60%

Susceptible

41.80%

31.50%

25.40%

36.40%

37.20%

62.50%

92.30%

 


 

Abstract ID: M1225

 

Comparison Of Histologic Activity Index in Chronic Hepatitis B Patients, Stratified By Alt Levels.

 

W. Kijkunasathian, P. Tangkijvanich, P. Kongkam, P. Komolmit

 

BACKGROUND

Several practice guidelines have been proposed to assist physicians in management of chronic hepatitis B patients. Most of them recommend that liver biopsy and treatment should be performed in patients with ALT levels > 2*ULN. However, such management in patients with ALT levels of 1-2*ULN is still controversial.

 

METHODS/AIMS

A cross-sectional analytic study was performed to characterize the histologic features of the chronic hepatitis B patients with elevated ALT levels of 1-2*ULN and levels > 2*ULN according to the Knodell histologic activity index and to determine whether there were any predictors of hepatic necroinflammation and fibrosis.

 

RESULTS

Of 104 patients, 35 patients had ALT levels of 1-2*ULN (mean ALT 1.5*ULN). 69 patients had ALT levels > 2*ULN (mean ALT 4.4*ULN). Mean necroinflammatory scores and fibrotic scores in the first group were 4.26(2.17) and 1.71(1.38), respectively and the latter group were 4.58(2.26) and 1.51(1.16), respectively. 13 patients (38.2%) in the first group had necroinflammatory scores > 3 and fibrotic scores >1. There were no statistically significant associations among age, sex, BMI, HBeAg status, HBV-DNA, bilirubin and albumin predictive of liver histology.

 

SUMMARY

There were no differences in liver histology between patients with ALT levels of 1-2*ULN and levels > 2*ULN and no statistically significant associations among characteristic of patients, virology and biochemistry to predict liver histology. CONCLUSION: ALT level alone can not be used to predict necroinflammatory and fibrotic indices in chronic hepatitis B patients.

 

ALT < 2x (n=35)

ALT > 2x (n=69)

p value

Mean necroinflammatory scores

4.26(2.17)

4.58(2.26)

p = 0.488

No. of patients

with necroinflammatory scores > 3

13 (38.2%)

33 (47.1%)

p = 0.391

Mean fibrotic scores

1.71(1.38)

1.51(1.16)

p = 0.450

No. of patients

with fibrotic scores > 1

13 (38.2%)

18 (25.7%)

p = 0.190

 

 


 

Abstract ID: M1228

 

Hepatitis B Virus Genotypes and Hepatocellular Carcinoma in Thailand

 

P. Tangkijvanich, V. Mahachai, P. Komolmit, J. Fongsaran, A. Theamboonlers, Y. Poovorawan

 

AIMS

The role of hepatitis B virus (HBV) genotypes on the clinical features and prognosis of patients with hepatocellular carcinoma (HCC) are currently unknown. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Thai patients.

 

METHODS

Patients with genotype C had a higher positive rate of HBeAg and exhibited earlier progression of cirrhosis and HCC than those with genotype B. However, there were no differences in the risk of developing HCC and its prognosis between patients with these genotypes.

 

BV genotypes were determined by PCR-RFLP in stored sera of 93 asymptomatic carriers, 103 patients with chronic hepatitis, 60 patients with cirrhosis and 76 patients with HCC. The clinical data were analyzed in relation to the HBV genotype. RESULTS: HBV genotypes C and B were predominant in Thailand, accounting for 73% and 21%, respectively. The distributions of genotypes B and C were similar in HCC patients compared to the other groups. Genotype C was significantly more common in HCC patients who were under 40 years old than genotype B (18% vs. 0%, P=0.03), but was significantly less common in patients older than 60 years (26 % vs. 56.5%, P=0.01). The positive rate of HBeAg in patients with genotype C was significantly higher than that in patients with genotype B (71.6% vs. 44.4%, P=0.03 in chronic hepatitis; 56.8% vs. 11.1%, P=0.01 in cirrhosis). There were no differences between HCC patients with genotypes B and C regarding of tumor staging by CLIP criteria and the overall median survival. Multivariate analyses showed that HBV genotype was not an independent prognostic factor of survival in HCC patients.

 

HBV genotypes were determined by PCR-RFLP in stored sera of 93 asymptomatic carriers, 103 patients with chronic hepatitis, 60 patients with cirrhosis and 76 patients with HCC. The clinical data were analyzed in relation to the HBV genotype. RESULTS: HBV genotypes C and B were predominant in Thailand, accounting for 73% and 21%, respectively. The distributions of genotypes B and C were similar in HCC patients compared to the other groups. Genotype C was significantly more common in HCC patients who were under 40 years old than genotype B (18% vs. 0%, P=0.03), but was significantly less common in patients older than 60 years (26 % vs. 56.5%, P=0.01). The positive rate of HBeAg in patients with genotype C was significantly higher than that in patients with genotype B (71.6% vs. 44.4%, P=0.03 in chronic hepatitis; 56.8% vs. 11.1%, P=0.01 in cirrhosis). There were no differences between HCC patients with genotypes B and C regarding of tumor staging by CLIP criteria and the overall median survival. Multivariate analyses showed that HBV genotype was not an independent prognostic factor of survival in HCC patients.

 

CONCLUSION

Patients with genotype C had a higher positive rate of HBeAg and exhibited earlier progression of cirrhosis and HCC than those with genotype B. However, there were no differences in the risk of developing HCC and its prognosis between patients with these genotypes.

 


 

Abstract ID: M1231

 

The Genotoxic Effects Of Hepatitis B Virus To the Host DNA

 

P. Ozkal, H. Ilgin Ruhi, M. Akdogan, S. Kacar, N. Sasmaz

 

Introduction

Chronic viral hepatitis is the main cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in the world. Hepatitis B virus (HBV) has mutagenic effects on host cell. Hepatitis B virus may be showing these mutagenic effects by its viral proteins or integrating into host DNA. The aim of this study is to detect the genotoxic effects of the hepatitis B virus (HBV) to the host DNA.

 

Material and Method

Thirty-one patients with chronic hepatitis B (CHB), 20 with HBV carriers and 20 healthy controls were included in this study. Peripheral blood lymphocytes of 31 chronic hepatitis B patients and 20 chronic HBV carriers were cultured to make cytogenetic evaluation by observing chromosome breakage and cytologic evaluation by micronucleus (MN) test. Their results were compared with healthy controls. For each individual 100 metaphase chromosome spreads were analysed. 190-1091 binucleated cells were observed and for each individual MN were scored.

 

Results

Our results showed a significantly higher frequency of chromosome breaks in patients with CHB and in HBV carriers than control group (p=0,031 and p=0,007, respectively). There was no difference between CHB patients and HBV carriers (p>0.05). Moreover we did not find any difference at MN scores between each groups (p>0.05). No correlation was found between the lenght of HBV positivity and MN scores&chrosome breaks (p>0.05).

Based on this data, we concluded that chronic HBV patients and carriers have chromosomal instability and HBV carriers are as important as patients because of their same chromosome breakage frequency.


 

Abstract ID: M940

 

The Hepatitis B Virus X Protein Enhances AP-1 Activation Through Interaction With Jab1

 

Y. Tanaka, F. Kanai, K. Tateishi, T. Ikenoue, Y. Asaoka, B. Guleng, J. Amarsanaa, M. Ohta, J. Imamura, T. Kawabe, M. Omata

 

Background/Aim

Hepatitis B virus (HBV) is closely associated with the development of acute or chronic hepatitis and hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx), one of four ORFs of HBV, is considered to be a major factor responsible for hepatocarcinogenesis, since the expression of HBx induces HCC in certain strains of transgenic mice. HBx was also shown to stimulate cytoplasmic transcription indirectly by activating cellular signal transduction pathways, including AP-1. AP-1 can display its oncogenic effects by regulating genes involved in cell proliferation, differentiation and apoptosis. However, the mechanism of AP-1 activation by HBx remains poorly understood. To investigate the molecular mechanism of HBx-mediated AP-1 activation, we tried to identify new host factors which interact with HBx. Methods: We constructed a mammalian expression vector encoding HBx with carboxyl-terminal myc and flag tag separated by a cleavage site for the TEV protease, transiently transfected 293T cells with the vector, and purified the tagged HBx with its binding proteins from the cell lysate by affinity purification. After proteins were eluted, they were separated by SDS-PAGE, silver stained and analyzed by nano LC/MS/MS. In vivo and In vitro interactions were confirmed by immunoprecipitation and GST pull-down assay, respectively. Interacting domain of HBx was determined by deletion constructs. Luciferase assay was performed to investigate the effect of the AP-1 activation. Results: We identified COP9 (constitutive photomorphogenesis 9) signalosome (CSN) subunit 3 and 4 as HBx interacting proteins by mass spectrometry. We also detected CSN subunit 5, Jab1 (Jun activation domain-binding protein 1), as a novel cellular target of HBx. HBx binds to Jab1 in vivo and in vitro, and analysis of HBx deletion constructs revealed that amino acid 30 to 125 of HBx was responsible for the binding to Jab1. Furthermore, co-transfection of HBx and Jab1 showed potent AP-1 activation compared with HBx mutant lacking Jab1 interacting domain (HBx 61-154). Conclusions: These results suggest that Jab1 binds to HBx and facilitate HBx-mediated AP-1 activation. These findings are helpful to elucidating the underlying mechanisms of viral hepatitis and hepatocarcinogenesis. Acknowledgement: This is a collaborative research with Dr. Tohru Ichimura and Dr. Toshiaki Isobe (Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan).

 


 

Abstract ID: M924

 

Viral Load Is a Strong Predictor Of Hepatocellular Carcinoma (HCC) Risk in People Chronically Infected With Hepatitis B Virus (HBV) Independent Of Serum Alanine Aminotransaminase Level (ALT)

 

U.H. Iloeje, MD, H. Yang, MSc, J. Su, MD, MSc, C. Jen, MSc, E. Kuo, MD, S. You, PhD, C. Chen, PhD

 

Introduction

Treatment guidelines exclude chronic hepatitis B patients with normal serum ALT from therapy. This study was carried out to examine the risk of HCC in this population of patients with emphasis on the role of serum HBV DNA level.

 

Methods

A cohort of 3,851 participants with chronic HBV infection was recruited from seven townships in Taiwan between 1991 and 1992. Cohort entry serum samples were tested for HBsAg, HBeAg, HBV DNA by PCR, and serum ALT. The diagnosis of HCC was ascertained through data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.

 

Results

Overall, during 43,993 person-years of follow-up, 176 patients were newly diagnosed with HCC among the 3,851 participants. Of the 3,851 participants, 3,270 (85%) were seronegative for HBeAg, of which 1121 (34%) had serum HBV DNA level 104 copies/mL and 1052 (94%) of them had a normal serum ALT level. 581 participants (15%) were HBeAg positive of which 557 (96%) had serum HBV DNA 104 copies/mL at cohort entry and 463 (83%) of them had normal serum ALT levels. There was a dose dependent relationship between HBV DNA and HCC risk in people with normal serum ALT variably defined as either <1 x ULN or <2 x ULN.

 

Adjusted Relative Risk of Liver Cancer for Various Serum HBV DNA and ALT Levels

 

HBV DNA Levels

ALT

No. of Subjects

No. of Liver Cancer Cases

Adjusted Relative Risk (95% CI)

Undetectable<3102

<2ULN

939

15

1.0

<105

<2ULN

1870

39

1.5 (0.8-2.7)

105

<2ULN

968

115

10.1 (5.9-17.4)

Undetectable<3102

2ULN

12

1

2.8 (0.4-23.0)

<105

2ULN

16

1

4.0 (0.5-30.2)

105

2ULN

46

5

7.9 (2.8-21.7)

 

 

 

 

 

Undetectable<3102

<1ULN

908

13

1.0

<105

<1ULN

1825

37

1.6 (0.9-3.0)

105

<1ULN

868

93

10.2 (5.7-18.4)

Undetectable<3102

1ULN

43

3

4.3 (1.2-15.9)

<105

1ULN

61

3

4.3 (1.2-15.1)

105

1ULN

146

27

16.9 (8.1-33.7)

P<0.05, P<0.001

 

Conclusion

Elevated serum HBV DNA is a strong predictor of HCC in patients regardless of serum ALT.


 

Abstract ID: M932

 

Serum Hepatitis B Virus Markers (HBVm) in Postransfusional Chronic Hepatitis C (pt Chc)

 

M. MARTIN ARRANZ, R. BARCENA MARUGAN, G. MORALEDA, S. DEL CAMPO, J. MORENO, J. SEGURA CABRAL

 

BACKGROUND

The prevalence of past infection by HBV in the population is high, especially among those patients with CHC.

 

AIMS

To analyze the incidence and influence of HBV markers in patients with post-transfusional CHC and verify whether latent HBV infection is still present.

 

PATIENTS AND METHODS

203 patients (>18 years) with PT CHC, without previous antiviral treatment were studied. The exclusion criteria were: intravenous drug abuse, HIV infection, history of liver disease previous to the transfusion, two or more major surgeries prior to transfusion and positive HBsAg. Liver biopsy was obtained. HBsAg, anti-HBs, anti-HBc and HBV-DNA were analyzed (ELISA and nested PCR). Relaxed circular (RC) and covalently closed circular (ccc) HBV-DNA was analysed in liver by nested-PCR.HCV-RNA was analyzed by qualitative and quantitative PCR assay.

 

RESULTS

Anti-HBc was detected in 41/203 patients (20.2%) with or without anti-HBs (Group I); 28/41 (68.3%) were anti-HBs positive.162 patients were anti-HBc negative (group II).There were no significant differences in demographic and clinical characteristics between both groups, except age (Group I: 51.9 11.7 vs Group II: 46.1513.9; p<.005).Group I had more fibrosis (2.26 1.56 vs 1.49 1.18; p<.005).51.4% in group I had fibrosis III or IV (34% cirrhosis) vs 9.4% in group II (p<.001). No significant differences in inflammatory activity were observed. Finally, 71.4% of the patients with fibrosis III-IV/IV had anti-HBc vs 28.6% of patients with fibrosis 0-II/IV (p<.001).The multivariate analysis showed that the age ( p=.002, OR 1.045), male sex (p=.028, OR 2.203) and anti-HBc (p=.003, OR 3.107) were 3 independent factors associated with higher fibrosis. Serum HBV-DNA was negative in patients from group I and in 40 analyzed patients from group II.HBV-DNA in liver was observed in 10% of patients from group I (20 liver samples were analyzed) and in any patient from group II (25 liver biopsies were analyzed). No differences between both groups regarding to the HCV viremia were found. In the two patients with DNA-HBV in liver, HCV viral load was nearest the media of population.

 

CONCLUSION

Prevalence of serum HBVm in PT CHC patients was 20.2%.Presence of anti-HBc had a relationship with fibrosis and were more frequent in patients with severe fibrosis or cirrhosis. HBV latent infection is still present in the 10% of them. Serum HBVm do not seem to influence HCV viral replication or necroinflammatory activity.


 

Abstract ID: M925

 

Serum Hepatitis B Virus (HBV) DNA Level Predicts the Incidence Of Liver Cirrhosis in Persons Chronically Infected With HBV

 

U.H. Iloeje, MD, H. Yang, MSc, J. Su, MD, MSc, C. Jen, MSc, E. Kuo, MD, S. You, PhD, C. Chen, PhD

 

Introduction
Chronic hepatitis B patients are at increased risk of developing liver cirrhosis. Cirrhosis develops as a result of hepatic inflammation and subsequent fibrosis. Ongoing viral replication is associated with hepatic inflammatory activity and suppression of viral replication in clinical trials is associated with improvements in liver histology. An association between elevated HBV DNA level and progression to cirrhosis has not been shown in a large epidemiological setting. This study was carried out to examine if increasing levels of HBV DNA is associated with increasing risk of cirrhosis.

 

Methods

A population based prospective cohort study of 3,851 HBV infected subjects was established from seven townships in Taiwan between 1991 and 1992. Cohort entry serum samples were tested for HBV DNA by PCR, and the diagnosis of cirrhosis was by ultrasonography and ascertained by medical records review. Cirrhosis 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 Coxs proportional hazard models.

 

Results

Of the 3,851 subjects, 75 subjects diagnosed with cirrhosis within 6 months of enrollment were excluded leaving 3,774 subjects. During 42,114.9 person-years of follow-up, 395 cirrhosis cases were newly diagnosed. The incidence rate of cirrhosis ranged from 386.1/100,000 PYFU for those with HBV DNA <300 copies/ml to 2,575.7/100,000 PYFU for those with HBV DNA 106 copies/mL (test of trend: p<0.0001) in a dose dependent manner. With the undetectable group as reference, and adjusting for gender, age, habits of cigarette smoking, and alcohol consumption, and antibodies against hepatitis C virus, the risk of cirrhosis started increasing at HBV DNA level of 104 RRadj 2.4 (95%CI 1.6-3.5) and was 9.3 (95% CI 6.5-13.1) for those who had serum HBV DNA level > 106 copies/ml.

 

Conclusion

HBV DNA level is a strong predictor of cirrhosis risk. The incidence of cirrhosis increases with HBV DNA level in a dose dependent manner. It is expected therefore that reducing the HBV DNA should conversely decrease cirrhosis risk in chronic Hepatitis B patients.

 


 

Abstract ID: M947

Progression To Decompensated Cirrhosis in Chronic Hepatitis B Virus Infected Persons Is Strongly Associated With Baseline Viral Load

 

H. Yang, MSc, U.H. Iloeje, MD, J. Su, MD, MSc, C. Jen, MSc, E. Kuo, MD, S. You, PhD, C. Chen, PhD

 

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 Coxs proportional hazard models.

 

Results

Of the 3,851 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 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 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.

 

ID: M933

Combination Therapy Of Pegylated Interferon Alfa 2b and Adefovir Dipivoxil in Chronic Hepatitis B (CHB) Patients Leads To a Strong Suppression Of Cccdna and High Rates Of Hbe and Hbs Seroconversion

 

J. Petersen, P. Buggisch, B. Zoellner, M. Zankel, C. Fischer, S. Xiong, G. Currie, C. Brosgart, K. Wursthorn

 

Introduction

HBV targeted antiviral therapy with adefovir dipivoxil (ADV) results in a significant reduction of intrahepatic HBV DNA and cccDNA, serum HBsAg, and serum HBV DNA (Werle-Lapostolle, Gastroenterology 2004). Pegylated interferon alfa (Peg IFN) improves serological outcome in HBeAg positive and HBeAg negative patients (Lau, AASLD 2004; Marcellin, New Engl J Med 2004).

 

Aim

To determine the virological and serological outcome in patients with chronic Hepatitis B treated with Peg IFN alfa 2b and ADV.

 

Methods

26 patients with chronic Hepatitis B were included in a single center open label pilot study. Patients received a 48 week course of antiviral combination therapy with 12kDa pegylated interferon alfa 2b 1.5g/kg sq qw and ADV 10mg qd. 23/26 patients were analyzed at the time of abstract submission, final data will be available as of December 2004. Intrahepatocellular cccDNA, serum HBsAg, and serum HBV DNA was quantified as described previously (Werle-Lapostolle, Gastroenterology 2004).

 

Baseline characteristics:

Median age, years:

33

Male:

14

Caucasian:

21

Asian:

5

HBeAg +:

15

HBeAg :

11

HBV DNA, PCR:

5 x 106
(log10 copies/ml, median)

ALT (xULN, median):

3,1

 

Results at week 48, compared to week 0:

cccDNA reduction (median) from paired biopsies:

-2.2log

Serum HBsAg titer reduction (median):

- 44%

Serum HBV DNA reduction (median):

-4.7log

Serum HBV DNA <100 copies/ml:

12/23 (52%)

(LLoD, LightCycler, Roche)

 

HBeAg loss:

7/13 (54%)

HBeAg seroconversion:

5/13 (38%)

HBsAg seroconversion:

4/23 (17%)

ALT normalisation:

10/23 (43%)

ALT improvement:

19/23 (83%)

METAVIR histology score improved:

13/21 (62%)

 

Conclusion

Administration of 48 weeks of Peg IFN alfa 2b and adefovir dipivoxil resulted in a strong suppression of cccDNA, high rates of HBsAg seroconversion, HBeAg seroconversion and loss, respectively. Combination therapy was safe and well tolerated. No unexpected adverse events were reported. All patients are continuing in study on additional 96 weeks of ADV monotherapy followed by a third liver biopsy.