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Background Independent risk factors associated with hepatitis B (HBV)-related hepatocellular carcinoma (HCC) after resection remains unknown. An accurate risk score for HCC recurrence is lacking. Methods We prospectively followed up 200 patients who underwent liver resection for HBV-related HCC for at least 2 years. Demographic, biochemical, tumor, virological and anti-viral treatment factors were analyzed to identify independent risk factors associated with recurrence after resection and a risk score for HCC recurrence formulated. Results Two hundred patients (80% male) who underwent liver resection for HBV-related HCC were recruited. The median time of recurrence was 184 weeks (IQR 52–207 weeks) for the entire cohort and 100 patients (50%) developed HCC recurrence. Stepwise Cox regression analysis identified that one-month post resection HBV DNA >20,000 IU/mL (p = 0.019; relative risk (RR) 1.67; 95% confidence interval (C.I.): 1.09–2.57), the presence of lymphovascular permeation (p100ng/mL before resection (p = 0.021; RR 1.63; 95% C.I.: 1.08–2.47) were independently associated with HCC recurrence. Antiviral treatment before resection (p = 0.024; RR 0.1; 95% C.I.: 0.01–0.74) was independently associated with reduced risk of HCC recurrence. A post-resection independent predictive score (PRIPS) was derived and validated with sensitivity of 75.3% and 60.6% and specificity of 55.7% and 79.2%, to predict the 1- and 3-year risks for the HCC recurrence respectively with the hazard ratio of 2.71 (95% C.I.: 2.12–3.48; p

The kinetics of hepatitis B surface antigen (HBsAg) levels preceding spontaneous HBsAg seroclearance has not been fully investigated. The kinetics of HBsAg and hepatitis B virus (HBV) DNA of 203 treatment-naive, hepatitis B e antigen (HBeAg)-negative patients with spontaneous HBsAg seroclearance were compared with 203 age- and sex-matched HBeAg-negative controls. Serum samples at 3 years, 2 years, 1 year, and 6 months before HBsAg seroclearance and at the time of HBsAg loss were tested. Median HBsAg levels at these respective time points before HBsAg seroclearance were 23.5, 3.51, 0.524, and 0.146 IU/mL. For all time points, patients with HBsAg seroclearance had significantly lower median HBsAg and HBV DNA levels, compared to those of the controls (all P < 0.001). Median HBsAg and HBV DNA levels declined significantly until HBsAg seroclearance (P < 0.001). Although median HBsAg levels also decreased significantly with time (P = 0.006) in controls, median HBV DNA levels remained similar (P = 0.414). Serum HBsAg levels, followed by HBsAg log reduction, were the best predictors of HBsAg seroclearance, with an area under the receiving operator characteristic (AUROC) of 0.833 (95% confidence interval [CI]: 0.792-0.873) and 0.803 (95% CI: 0.755–0.849), respectively. The optimal cut-off HBsAg level and HBsAg reduction to predict HBsAg seroclearance were

Background We investigated the differences in HBsAg kinetics at different levels of viremia in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). Methods We compared HBsAg levels among HBeAg-negative CHB patients with persistently undetectable HBV DNA (≤20 IU/mL; Group A, n = 100), HBV DNA 20–2,000 IU/mL (Group B, n = 100), and HBV DNA >2,000 IU/mL (Group C, n = 100). HBsAg and HBV DNA levels were measured at three consecutive time points during follow-up (median 21.4 months). Results Median HBsAg levels were significantly lower in Group A than in Groups B and C at all time points (p r = 0.180 and 0.151 for Groups B and C, respectively). Among patients with HBsAg p = 0.002). Among Group A patients with HBsAg 1 log annual HBsAg reduction; 10–100 IU/mL HBsAg was the optimal level for prediction (sensitivity 90 %; specificity 74.6 %). Serum HBsAg/HBV DNA ratios were significantly higher in Group B than in Groups A and C (p Conclusions HBV DNA and HBsAg were weakly correlated. Only patients with undetectable HBV DNA showed decline in HBsAg levels during follow-up. The greatest reduction in HBsAg levels occurred in patients with baseline HBsAg

Background Possible serologic activity after hepatitis B surface antigen (HBsAg) seroclearance documented by conventional assays in chronic hepatitis B (CHB) has not been thoroughly investigated. Methods We determined the levels of serum hepatitis B virus (HBV) DNA, hepatitis B core-related antigen (HBcrAg), and linearized HBsAg (CLEIA prototype) in 329 CHB patients (72.0% male) after HBsAg seroclearance was documented by a conventional HBsAg assay. Results The median interval between presentation and HBsAg seroclearance was 69.4 months. The median age at HBsAg seroclearance was 50 years. Assays for serum HBV DNA, HBcrAg, and linearized HBsAg were performed at a median time interval of 11.2 months after HBsAg loss. Linearized HBsAg and HBcrAg were detectable in 85 (25.8%) and 69 (21%) patients, respectively, and one or both serologic markers were detectable in 133 patients (40.4%). Serum HBV DNA was detectable in only 7 patients (2.1%). There was no correlation between linearized HBsAg and HBcrAg levels (r = 0.095, p = 0.924). The incidences of detectable linearized HBsAg and HBcrAg did not differ between patient samples taken at 6–12 and >12 months after HBsAg seroclearance (p = 0.146 and 0.079, respectively). Among patients with detectable serologic markers, median levels of linearized HBsAg (p = 0.581) and HBcrAg (p = 0.951) did not significantly change with time after HBsAg seroclearance. Conclusion Using novel HBcrAg and linearized HBsAg assays, viral serologic activity after HBsAg seroclearance was demonstrated in more than 40% of CHB patients. These tests have potential applications in diagnosing and prognosticating CHB patients with HBsAg seroclearance.

Background and aims The aim of the present study was to determine the population prevalence of occult hepatitis B (OHB) infection and its clinical profile in a highly endemic area of chronic hepatitis B virus disease. Methods OHB was first identified by individual sample testing for hepatitis B surface antigen (HBsAg) followed by nucleic acid testing (NAT) and vice versa for 3044 (cohort 1, stored sera from donation within 1 year) and 9990 (cohort 2, prospective study) blood donors, respectively. OHB was confirmed meticulously by $ 2o ut of 3 tests with detectable hepatitis B virus (HBV) DNA using a sensitive standardised assay. Detailed serology and viral load in the serum and liver were studied. Results The prevalence of OHB was 0.13% (4/3044) and 0.11% (11/9967) for cohort 1 and 2, respectively. In cohort 2, 10 out of 11 OHB samples were positive for anti-HBc (hepatitis B core antigen) antibody (all were immunoglobulin G). Seven had detectable anti-HBs. The serum HBV DNA levels were extremely low (highest 14.1 IU/ml). Of the six donors who underwent liver biopsies, all had normal liver biochemistry, extremely low liver HBV DNA (highest 6.21 copies/cell) and nearly normal liver histology. For those with viral sequence generation, none had the common HBsAg mutant G145R. Conclusions The prevalence of OHB in a highly endemic area of chronic HBV was very low, thus implying a low impact on transfusion services. To implement universal screening, the high cost of NAT should be taken into account. OHB blood donors had very low HBV replication, and normal liver biochemistry and histology, conferring a favourable prognosis.

Background This study aimed to identify the baseline hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) levels and on-treatment HBV DNA levels for favourable outcome in patients receiving 5-year lamivudine. Methods Virological, serological and biochemical parameters were assessed in 74 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients at year 5 of therapy. Results Patients with baseline HBV DNA levels 10 copies/ml and ALT≥2x the upper limit of normal (ULN) had a significantly higher chance of HBV DNA suppression to 10 copies/ml (76.5%) and HBeAg seroconversion (82.4%), and a lower chance of YMDD mutations (35.3%) compared with patients with HBV DNA10 copies/ml and ALT10 copies/ml (all P10 copies/ml achieved HBV DNA10 copies/ml, 60%, 80% and 90% of patients had HBV DNA10 copies/ml and 10 copies/ml, respectively at year 5. Overall, 90% of patients had HBeAg seroconversion and only 10% had YMDD mutations. Conclusions For HBeAg-positive patients with baseline HBV DNA10 copies/ml and ALT≥2xULN, lamivudine could be initiated. For those with HBV DNA10 copies/ml at week 4 or 10 copies/ml at week 24, continuation of lamivudine treatment would be more likely to result in a good long-term response.

UNLABELLED Abstract Aim: To correlate liver stiffness with demographical factors and routine liver biochemistry and to assess the predictive value of these as potential markers of fibrosis. METHODS Transient elastography was performed in 1268 chronic hepatitis B (CHB) patients. According to a previous validated study for CHB, liver stiffness of >8.1 and >10.3 kPa were used as cut-off values for defining severe fibrosis and cirrhosis respectively. RESULTS Liver stiffness correlated positively with bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin, alpha-fetoprotein (AFP) and HBV DNA levels and negatively with albumin and platelet levels (P

Background Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease. Methods One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually. Results Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls ( P=0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC ( P=0.024) and a greater HBV DNA reduction ( P=0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation. Conclusions Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.

Summary Aim To investigate the level of hepatitis B virus (HBV) DNA in Chinese chronic hepatitis B (CHB) patients below which hepatocellular carcinoma (HCC) is unlikely to occur. Methods A total of 92 CHB patients diagnosed with HCC were recruited; 184 CHB patients without HCC, matched for age, sex and HBeAg status were included as controls. HBV DNA levels were performed at the time of HCC development and at the same age time points for control group. Results The median HBV DNA level in HCC patients was 1.7 × 106 copies/mL compared with 2.2 × 105 copies/mL in controls (P = 0.006). In HCC patients, 21 (22.8%) were HBeAg(+), with no significant difference in HBV DNA levels compared with controls. Seventy-one (77%) HCC patients were HBeAg(−) with median HBV DNA level of 3.2 × 105 copies/mL, compared with 6.0 × 104 copies/mL in controls (P = 0.006). In HBeAg(−) patients, the control group had significantly greater proportion of patients having HBV DNA levels 104 copies/mL. However, 15% of the patients with HCC had HBV DNA levels

To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis.HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls.Genotype C, CP-MT, T1653, HBV DNA levelsor=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNAor=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levelsor=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions.CP-MT, T1653, HBV DNA levelsor=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Aim To determine differences in Chinese patients treated with adefovir (ADV) monotherapy or ADV in combination with lamivudine (3TC) after development of resistance to 3TC, with respect to biochemical improvement, HBV DNA suppression and development of subsequent ADV resistance. Methods All hepatitis B patients with 3TC resistance treated with ADV for 3 months or more at our centre were included, and monitored 3–6 monthly for biochemical and virological response, and development of ADV resistance. Results A total of 56 patients were included, 50% switched to ADV monotherapy and 50% received combination 3TC/ADV therapy. Median follow-up was 15.5 months. Normalization of alanine aminotransferase (ALT) occurred in 25 (89%) patients in the ADV group compared with 24 (86%) in the 3TC/ADV group (P=0.686). Virological response (VR) was achieved in seven (35%) patients in the ADV group at 12 months compared with five (28%) in the 3TC/ADV group (P=0.637). By 24 months, seven (64%) patients in the ADV group achieved VR compared with two (40%) in the 3TC/ADV group (P=0.377). Cumulative probability of developing genotypic ADV resistance in the ADV group at 24 months was 18% compared with 7% in the 3TC/ADV group (P=0.94). Conclusions There was no obvious improvement in ALT normalization and virological suppression or reduction in the development of ADV-resistant mutations with 3TC/ADV therapy compared with ADV monotherapy. Further studies with longer follow-ups are required to determine whether combination 3TC/ADV therapy will reduce the emergence of ADV resistance compared with ADV monotherapy.

Background LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317. Aims/Methods This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period. Results The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported. Conclusion LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.

To determine the effect of 1-yr lamivudine treatment on serum covalently closed-circular DNA (cccDNA) level.Serum total HBV DNA and cccDNA levels at baseline, week 24, and week 52 were measured in 82 lamivudine-treated patients, 17 of whom received 1-yr placebo and acted as controls.There was a significant reduction in the cccDNA levels from baseline (median 3.0 x 10(6) copies/ml) to week 24 (33,476 copies/ml) and week 52 (48,694 copies/ml) (p0.001 for both). The median reduction in cccDNA level at week 24 and 52 were 2.21 and 2.12 logs, respectively, which were significantly greater than those of controls (0.31 log, p0.001; 0.2 log, p0.001, respectively). Fifteen patients (18.3%) developed YMDD mutations by week 52. Compared to patients without YMDD mutations, patients with YMDD mutations had significantly less median reduction of total HBV DNA level (4.44 vs 3.65 logs, respectively, p= 0.02) and cccDNA level (2.27 vs 1.65 logs, respectively, p= 0.016) at week 24 and significantly less median reduction of cccDNA at week 52 (2.35 vs 0.8 logs respectively, p0.001).One-year lamivudine treatment decreased serum cccDNA level by 2 logs. The chance of YMDD mutations at week 52 was related to the magnitude of viral suppression at week 24.

Summary Background : Long-term effect of YMDD mutations on liver histology in Chinese hepatitis B patients is unknown. Aim : To examine the effect of prolonged lamivudine treatment on liver histology in Chinese patients with and without YMDD mutations. Methods : Liver histology was assessed in 85 patients on long-term lamivudine at baseline and year 1, and at year 3 for 25 patients. Results : Comparing patients with and without YMDD mutations at year 1, the former had higher baseline median necroinflammatory (11 vs. six respectively, P = 0.014) and fibrosis scores (three vs. one respectively, P = 0.001). The proportion of patients with improvement in necroinflammation and worsening of fibrosis was comparable for patients with and without YMDD mutations at year 1 (57.1%, 14.3% vs. 55%, 15% respectively) and year 3 (57.9%, 26.3% vs. 50%, 16.7% respectively). Comparing the histology at year 1 and 3, more patients with YMDD mutations developing after year 1 had worsening of necroinflammation than patients with persistent YMDD wild type (53.8% vs. 25% respectively). Conclusions : Patients who developed YMDD mutations had higher baseline histological scores. With YMDD mutations, the liver histology became less favourable after 3 years than at the first year, although there was still improvement when compared with that at baseline.

Quantitation of low hepatitis B virus (HBV) DNA levels in patients with chronic hepatitis B is important for monitoring natural history of disease and treatment efficacy. This study aimed to compare the quantitation range and analytical sensitivity of the newly developed COBAS TaqMan HBV test (TaqMan test) with the COBAS Amplicor HBV Monitor Test (Amplicor test), using the Eurohep HBV reference plasma and serum samples from patients. Serial dilutions (2.7x10(1)-2.7x10(8) copies/ml) of the Eurohep HBV reference plasma and 50 serum samples from chronic hepatitis B patients were tested by both assays. The TaqMan test could detect seven (2.7x10(2)-2.7x10(8) copies/ml) of eight dilutions of the reference plasma, while the Amplicor test could only detect three of them (2.7x10(3)-2.7x10(5) copies/ml). The HBV DNA values measured by the TaqMan test correlated very well with the theoretical Eurohep standard values (r=0.998, P

The aims of this study were to compare chronic hepatitis B (CHB) patients with genotypes B and C for the probability of HBeAg seroconversion, hepatitis activity, and viral replication before and after HBeAg seroconversion and to compare the prevalence of core promoter and precore mutations. A total of 180 asymptomatic Chinese patients with CHB were monitored for a median of 53.8 months, and 38 patients with cirrhosis-related complications were studied. Hepatitis B virus (HBV) DNA levels were measured in 16 patients with HBeAg seroconversion at 3 months before, during, and 3 months after HBeAg seroconversion and in all patients at the last follow-up. Hepatitis B genotypes and core promoter and precore mutations were determined. Compared to patients with genotype C (n = 109), patients with subtype Ba (n = 69) had a higher rate of anti-HBe positivity on presentation (P = 0.05). HBeAg-positive patients with subtype Ba had a higher cumulative rate of HBeAg seroconversion than patients with genotype C (P = 0.02). However, there were no differences between the two groups with regard to the median HBV DNA levels before, during, and after HBeAg seroconversion; the probability of having persistently normal or elevated aminotransferase levels; and the median HBV DNA levels and liver biochemistry at the last follow-up. There was no difference in the prevalence of genotypes and core promoter and precore mutations between patients with and without cirrhosis-related complications. Though patients with subtype Ba had earlier HBeAg seroconversion, the liver biochemistry, HBV DNA levels in different phases of the disease, and the probability of development of cirrhosis-related complications were the same with genotypes Ba and C., published_or_final_version

Background/Aims : To study the outcome and the virologic profiles of severe hepatitis exacerbations due to YMDD mutants in lamivudine-treated patients. Methods : Eighteen lamivudine-treated patients with severe hepatitis exacerbations due to YMDD mutants were recruited. Laboratory and clinical parameters were monitored. Viral genotypes and YMDD mutations were determined. Results : None of the 18 patients had YMDD wild-type during exacerbations. Three (17%) and 15 (83%) patients had genotypes B and C, respectively. Elevated bilirubin levels and prolonged prothrombin time were found in 11 (61%) and six patients (33%) respectively. Three patients (17%) had adverse outcome with the development of ascites and/or encephalopathy. One of these patients required liver transplantation and one died. Both patients had evidence of cirrhosis before treatment and hepatitis B e antigen (HBeAg) seroreversion from anti-HBe positivity. The remaining 16 patients (89%) have no evidence of pre-existing cirrhosis. Thirty seven percent of patients had normal alanine aminotransferase levels at the last follow-up. The median HBV DNA level at the last follow-up was significantly lower than the pre-treatment level ( P = 0.009 ). Conclusions : Though the majority of patients with severe hepatitis exacerbations due to YMDD mutants had uneventful course, early liver transplantation should be considered in patients with pre-existing cirrhosis and HBeAg seroreversion.

A total of 455 patients were recruited to study the prevalence of hepatitis GB virus-C/hepatitis G virus viremia in Hong Kong. There was no significant increase in the prevalence of hepatitis GB virus-C viremia in asymptomatic hepatitis B virus- and hepatitis C virus-infected patients compared to that of controls (1.56% and 7.14%, respectively, vs 3.85%, both P = NS). Renal patients as a whole had a significantly higher prevalence of hepatitis GB virus-C viremia compared to that of controls (13.95% vs 3.85%, P = 0.0271). The duration of the replacement therapy, especially for patients with peritoneal dialysis was associated with a higher chance of hepatitis GB virus-C viremia. Among renal patients, renal transplanted patients had the highest prevalence of hepatitis GB virus-C viraemia (19.1%) probably because of a higher susceptibility as a result of immunosuppression. However, hepatitis GB virus-C viraemia did not cause liver biochemistry derangement in renal transplanted patients.

Background There is a paucity of data on the long-term efficacy of combination lamivudine and adefovir therapy in patients with lamivudine-resistant chronic hepatitis B. Methods We determined the cumulative virological, serological and biochemical outcomes of 165 lamivudine-resistant chronic hepatitis B patients on lamivudine and adefovir for up to 5 years. Resistance profiles using a line probe assay were determined among patients with detectable viraemia. The significance of different baseline and on-treatment virological parameters was analysed. Results The median age and duration of follow-up were 45.1 years and 37.1 months, respectively. The cumulative rates of HBV DNA undetectability (0.5 mg/dl was 4.1%. Conclusions Combination lamivudine and adefovir therapy for up to 5 years achieved modest rates of virological suppression, but resistance developed in only 10.2% of patients. Week 24 HBV DNA

We aimed to determine the antiviral potency, viral resistance rate, and clinical safety of 3-year continuous entecavir treatment.We determined the cumulative rates of undetectable hepatitis B virus DNA (HBV DNA) levels (12 IU/ml), hepatitis B e antigen (HBeAg) seroconversion, alanine aminotransferase (ALT) normalization, and entecavir signature mutations (using the sensitive line probe assay) and monitored any side effects for 222 treatment-naïve chronic hepatitis B (CHB) patients (40.5% HBeAg positive) on continuous entecavir treatment for 3 years.The median age and follow-up duration were 45 years and 25.1 months, respectively. In all, 222, 188, and 101 patients had been followed up for at least 1, 2, and 3 years, respectively. There were incremental increases in the rates of HBV DNA undetectability, HBeAg seroconversion, and ALT normalization reaching to 92.1, 43.9, and 90.4% at year 3, respectively. In all, 100 and 76.5% of patients with baseline HBV DNA levelsand ≥ 8 logs copies/ml, respectively, had undetectable HBV DNA at year 3. The cumulative rate of entecavir-resistant mutations was 1.2% at year 3. Three patients experienced virologic breakthrough, one with resistance development, one with subsequent HBeAg seroconversion, and one with subsequent decline in HBV DNA. Two patients with baseline rt204I mutations responded to entecavir treatment. There were no serious adverse events.Using very sensitive HBV DNA and viral resistance assays, continuous entecavir treatment for treatment-naïve CHB patients for 3 years was associated with90% chance of undetectable HBV DNA and only 1.2% chance of emergence of entecavir-resistant mutations.

The significance of early HBV DNA suppression during telbivudine treatment in predicting long-term outcomes needs further investigation.We determined the cumulative rates of HBeAg seroconversion, ALT normalization, HBV DNA suppression (12IU/ml) and telbivudine resistant mutations (using the highly sensitive line probe assay) for 117 treatment-native chronic hepatitis B (CHB) patients (61.5% HBeAg-positive) on telbivudine for 3years. The significance of serum HBV DNA at week 12 and 24 was compared.The median age and duration of follow-up were 39years and 24.2months, respectively. 117, 105, 69, and 43 patients had been followed up for at least 6months and 1, 2, and 3years, respectively. The cumulative rates of HBeAg seroconversion, ALT normalization, HBV DNA undetectability were 46.8%, 80.5%, and 51.2%, respectively, at 3years. There was an incremental increase in virologic breakthroughs to 39.5% by year 3. The cumulative rate of telbivudine resistant mutations was 4.8%, 17.6%, and 34.0% for year 1, 2, and 3, respectively. Week 12 HBV DNA of200IU/ml was predictive of a higher chance of HBV DNA undetectability (p=0.022) and lower chance of resistance (p=0.001) by year 3. Undetectable HBV DNA at week 24 was predictive of viral suppression at year 2 (p0.001) but not at year 3 (p=0.241).Continuous telbivudine resulted in improved biochemical and virologic outcomes, although there was an incremental increase in cumulative rate of resistance up to year 3. Week 12 HBV DNA of200IU/ml was predictive of favorable long-term outcomes.

Aim: To correlate liver stiffness with demographical factors and routine liver biochemistry and to assess the predictive value of these as potential markers of fibrosis.Transient elastography was performed in 1268 chronic hepatitis B (CHB) patients. According to a previous validated study for CHB, liver stiffness of8.1 and10.3 kPa were used as cut-off values for defining severe fibrosis and cirrhosis respectively.Liver stiffness correlated positively with bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin, alpha-fetoprotein (AFP) and HBV DNA levels and negatively with albumin and platelet levels (P0.05 for all correlations). From 13 parameters (age, sex, platelet, AST, ALT, GGT, AFP, albumin, globulin, bilirubin, ALP, HBV DNA and hepatitis B e-antigen), four best parameters (AST, platelet, GGT and AFP) were used to derive a liver stiffness model. Using log (index)=1.44+0.1490(GGT)+0.3308 log (AST)-0.5846 log (platelets)+0.1148 log (AFP+1) to predict both severe fibrosis and cirrhosis had area under the receiver operating characteristics curve of 0.85.Routine liver biochemistry correlated well with liver stiffness in Asian CHB patients. A model using simple serum markers can predict liver stiffness, and further studies are required to validate the usefulness of these simple tests as non-invasive markers of fibrosis in CHB.

Our aims were to study the virologic, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance.We determined the age of HBsAg seroclearance that is associated with a lower risk for hepatocellular carcinoma (HCC) in 298 CHB patients (median follow-up, 108 months). The following virologic and histologic features were also determined: liver stiffness (n = 229), liver histology, serum HBV DNA levels over time (n = 265), intrahepatic HBV DNA with covalently closed circular DNA (cccDNA) levels, and messenger RNA (mRNA) expression.The median age of HBsAg seroclearance was 49.6 years. Seven (2.4%) patients developed HCC. Cumulative risk for HCC was higher in patients with HBsAg seroclearance at agesor=50 years compared with those with HBsAg seroclearance at ages50 (P = .004) years. Of these 2 groups of patients, 29.5% and 7.9%, respectively, had significant fibrosis by liver stiffness measurement (P = .001), and 15.4% of patients had mild histologic fibrosis. Intrahepatic total HBV DNA and cccDNA were detected in 100% and 79.3% of patients, respectively. All patients had undetectable surface and precore/pregenomic RNA transcripts. One (9.1%) patient had X mRNA expression. Serum HBV DNA were detectable in 13.4%, 6.1%, and 3.7% of patients within 1 year and 5-10 and10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels.HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age50 years was associated with a lower risk for the development of HCC.

The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)–positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. Conclusion: The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target. (HEPATOLOGY 2007.)

Background/Aims This study aimed to measure the intrahepatic total hepatitis B virus (HBV) DNA and covalently closed circular DNA (cccDNA) levels in tumor and non-tumor tissues in hepatocellular carcinoma (HCC) patients. Methods Intrahepatic total HBV DNA and cccDNA were measured in 25 HCC patients (21 hepatitis B surface antigen [HBsAg]-positive and 4 HBsAg-negative) by the Invader ® assay. Results A low level of intrahepatic HBV DNA was detectable in all HBsAg-negative patients. For HBsAg-positive patients, the intrahepatic total HBV DNA levels in the tumor and non-tumor tissues were comparable ( P =0.903). However, the tumor tissues had significantly higher levels of cccDNA (0.35 vs. 0.16copies/cell, P =0.030) and higher proportion of intrahepatic HBV DNA in the form of cccDNA (100% vs. 84%, P =0.004) than the non-tumor tissues. Seventeen out of 21 (81%) tumor tissues had intrahepatic HBV DNA solely in cccDNA form. Analysis of HBV mRNA expression indicated that HBV replication appeared to be lower in the tumor tissues than the non-tumor tissues. Conclusions Compared to the non-tumor tissues, the levels of HBV replication in the tumor tissues appeared to be lower, and cccDNA was the predominant form of HBV DNA in the tumor tissues.

Background: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria. Aim: To determine risk factors for the development of complications in Asian CHB patients. Patients and methods: A total of 3233 Chinese CHB patients (mean follow up 46.8 months) were monitored for liver biochemistry, viral serology, hepatitis B virus (HBV) DNA levels, acute exacerbation, hepatitis B e antigen (HBeAg) seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. Results: Median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years, respectively. Patients with alanine aminotransferase (ALT) levels of 0.5-1 times the upper limit of normal (ULN) and 1-2 × ULN had an increased risk for the development of complications compared with patients with ALT levels, published_or_final_version

To determine the relationship between hepatitis B virus (HBV) DNA levels and total histologic activity index (HAI), necroinflammation (HAI-NI), and fibrosis (HAI-F) scores.Liver histology and HBV DNA levels were determined in 94 patients with chronic hepatitis B.There was no association between HBV DNA levels and liver histology in hepatitis-B-e antigen-positive patients (n = 43). In anti-HBe-positive patients (n = 51), HBV DNA levels correlated positively with HAI-NI (r = 0.31, p= 0.014) and HAI-F (r = 0.33, p= 0.017) scores. Though the majority of anti-HBe-positive patients with HBV DNA levels10(5) copies/ml had mild necroinflammation and no fibrosis, 14.3% had established fibrosis. Anti-HBe-positive patients with core promoter mutations had a poorer histology compared to those without. There was no difference in the histology between anti-HBe-positive patients with and without precore mutations. Alanine aminotransferase (ALT) level correlated positively with HAI-NI score. Patients with persistently normal ALT levels had a significantly lower median HAI-NI score compared to patients with either persistently or intermittently elevated ALT levels.In anti-HBe-positive patients, though HBV DNA level10(5) copies/ml was associated with better histology, 14.3% patients had established fibrosis. Further studies to define a better cut-off HBV DNA level to differentiate low- and high-risk patients for disease progression are required.

The role of hepatitis B virus (HBV) genotypes, core promoter (CP) and precore mutants on hepatocellular carcinoma (HCC) is still controversial. We aimed to determine their role on the development and clinical features of HCC. HBV genotypes and CP/precore mutations were determined in 90 HCC patients and 180 matched control patients. In the 90 HCC patients, 22 (24.4%) and 68 (75.6%) had subtype Ba and genotype C, respectively. The prevalence of genotype C and CP mutations was significantly higher in HCC patients compared with controls (75.6 versus 57.8%, P = 0.004; 90.9 versus 74.8%, respectively, P = 0.007). Among carriers of genotype C, 91.8% of the HCC patients and 88.8% of controls had CP mutations. Among carriers of subtype Ba, HCC patients had a higher prevalence of CP mutations compared with controls (88.2 versus 54.5%, respectively, P = 0.02). By logistic regression analysis, the only factor associated with HCC was a mutation of the CP region (P = 0.032). There were no differences in the clinical features on presentation, the chance of receiving treatment and the cumulative survival rate for chemoembolization-treated patients between patients with subtype Ba and genotype C. There was too small a number of CP wild-type to do a similar comparison with CP mutants. In conclusion, there was a significantly higher prevalence of both genotype C and CP mutations in patients with HCC. The association between HBV genotype C and HCC was probably not genuine but was due to the high percentage of CP mutations in patients with genotype C.

A total of 455 patients were recruited to study the prevalence of hepatitis GB virus-C/hepatitis G virus viremia in Hong Kong. There was no significant increase in the prevalence of hepatitis GB virus-C viremia in asymptomatic hepatitis B virus- and hepatitis C virus-infected patients compared to that of controls (1.56% and 7.14%, respectively, vs 3.85%, both P = NS). Renal patients as a whole had a significantly higher prevalence of hepatitis GB virus-C viremia compared to that of controls (13.95% vs 3.85%, P = 0.0271). The duration of the replacement therapy, especially for patients with peritoneal dialysis was associated with a higher chance of hepatitis GB virus-C viremia. Among renal patients, renal transplanted patients had the highest prevalence of hepatitis GB virus-C viraemia (19.1%) probably because of a higher susceptibility as a result of immunosuppression. However, hepatitis GB virus-C viraemia did not cause liver biochemistry derangement in renal transplanted patients.

This journal suppl. entitled: Abstracts of the 42nd Annual Meeting of the European Association for the Study of the Liver ... 2007

INTRODUCTION: There is no data on the relationship between hepatitis B surface antigen (HBsAg) levels and liver fibrosis in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB). METHODS: Serum HBsAg and HBV DNA levels in HBeAg-positive CHB patients with liver biopsies were analyzed. The upper limit of normal (ULN) of alanine aminotransferase (ALT) was 30 and 19 U/L for men and women respectively. Histologic assessment was based on Ishak fibrosis staging for fibrosis and Knodell histologic activity index (HAI) for necroinflammation. RESULTS: 140 patients (65% male, median age 32.7 years) were recruited. 56 (40%) had ALT 1, had significantly higher median HBsAg levels (50,320 and 7,820 IU/mL respectively, p/= 25,000 IU/mL was independently associated with fibrosis score, published_or_final_version

OBJECTIVE: We determined the association between various clinical parameters and significant liver injury in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. METHODS: From 1994 to 2008, liver biopsy was performed on 319 treatment-naive CHB patients. Histologic assessment was based on the Knodell histologic activity index for necroinflammation and the Ishak fibrosis staging for fibrosis. RESULTS: 211 HBeAg-positive and 108 HBeAg-negative patients were recruited, with a median age of 31 and 46 years respectively. 9 out of 40 (22.5%) HBeAg-positive patients with normal ALT had significant histologic abnormalities (necroinflammation grading >/= 7 or fibrosis score >/= 3). There was a significant difference in fibrosis scores among HBeAg-positive patients with an ALT level within the Prati criteria (30 U/L for men, 19 U/L for women) and patients with a normal ALT but exceeding the Prati criteria (p = 0.024). Age, aspartate aminotransferase and platelet count were independent predictors of significant fibrosis in HBeAg-positive patients with an elevated ALT by multivariate analysis (p = 0.007, 0.047 and 0.045 respectively). HBV DNA and platelet count were predictors of significant fibrosis in HBeAg-negative disease (p = 0.020 and 0.015 respectively). An elevated ALT was not predictive of significant fibrosis for HBeAg-positive (p = 0.345) and -negative (p = 0.544) disease. There was no significant difference in fibrosis staging among ALT 1-2 x upper limit of normal (ULN) and > x 2 ULN for both HBeAg-positive (p = 0.098) and -negative (p = 0.838) disease. CONCLUSION: An elevated ALT does not accurately predict significant liver injury. Decisions on commencing antiviral therapy should not be heavily based on a particular ALT threshold., published_or_final_version