David But

Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B

BACKGROUND/AIMS To determine whether gender, age, hepatitis B virus genotype, core promoter and precore mutations, HBeAg/ anti-HBe status, HBV DNA, ALT levels and cirrhosis on presentation were independent risk factors and derive a novel risk score for the development of HCC. METHODS CHB patients (820) were followed up (mean duration 76.8 months) for the occurrence of HCC. RESULTS The 5- and 10-year prevalence of HCC were 4.4% and 6.3%, respectively. Cox regression analysis showed that male gender (p = 0.025, RR 2.98), increasing age (p < 0.001, RR 1.07), higher HBV DNA levels (p = 0.02, RR 1.28), core promoter mutations (p = 0.007, RR 3.66), and presence of cirrhosis (p < 0.001, RR 7.31) were independent risks for the development of HCC. A risk score was derived and validated with sensitivity > 84% and specificity > 76% to predict the 5- and 10- year risks for the development of HCC. The AUC for the 5- and 10-year prediction were 0.88 and 0.89, respectively. CONCLUSIONS The risk score, based on age, gender, HBV DNA levels, core promoter mutations and cirrhosis, can estimate the chance of development of HCC in 5 and 10 years after presentation. It can be used to identify high-risk CHB patients for treatment and screening of HCC.

HBsAg Seroclearance in Chronic Hepatitis B in Asian Patients: Replicative Level and Risk of Hepatocellular Carcinoma

BACKGROUND & AIMS Our aims were to study the virologic, histologic, and clinical outcome in chronic hepatitis B (CHB) patients with hepatitis B surface antigen (HBsAg) seroclearance. METHODS 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. RESULTS 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 ages >or=50 years compared with those with HBsAg seroclearance at ages <50 (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 and >10 years after HBsAg seroclearance, respectively, and 82.1% patients had persistently normal alanine aminotransferase levels. CONCLUSIONS HBV persisted at low replicative and transcriptional levels after HBsAg seroclearance. HBsAg seroclearance at age <50 years was associated with a lower risk for the development of HCC.

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

Background/aim: 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. Methods: 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. Results: Genotype C, CP-MT, T1653, HBV DNA levels ⩾4 log10 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) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log10 copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA ⩾4 log10 copies/ml and cirrhosis were independent factors for HCC (all p<0.05). 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 levels ⩾4 log10 copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log10 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. Conclusions: CP-MT, T1653, HBV DNA levels ⩾4 log10 copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: Final report

Long-term immunogenicity and efficacy of HBVvaccination with different regimens of HBV vaccines (A: 2-dose recombinant vs. B: 3-dose recombinant vs. C: 3-dose plasma-derived vaccines) without booster dose were examined in 318 Chinese children. Geometric mean titer (GMTs) of anti-HBs of group A subjects was significantly lower than that of groups B and C subjects at years 1, 5, 10 and 15. At year 22, the proportion of subjects with anti-HBs > or = 10 mlU/mL for groups A, B and C were 35.3%, 76.5% and 52.4%, respectively (p < 0.05 between groups A and B) in 55 subjects. In the 22 years study period, none was found to be HBsAg positive, and 72 subjects had > or = 1 episodes of anamnestic response. In conclusion, the 3-dose regimens have a better long-term immunogenicity. In terms of protection against HBV infection, the 2-dose and 3-dose vaccines had equal efficacies.

Prevalence of Fibrosis and Cirrhosis in Chronic Hepatitis B : Implications for Treatment and Management

OBJECTIVE:To document the prevalence and factors associated with severe fibrosis and cirrhosis in a large population of Asian chronic hepatitis B (CHB) patients.METHODS:Transient elastography was performed in unselected CHB patients. Liver stiffness score of <8.1 kPa was used as a cut-off for the presence of severe fibrosis or liver cirrhosis.RESULTS:1315 patients were recruited, of which 951 (72%) were treatment-naïve. Of these, 319 (34%) had severe fibrosis, with higher prevalence seen in males compared with females (39% vs 24% respectively, p < 0.01. Severe fibrosis was seen with increasing age from 20% in patients <25 years to 81% in those >65 years. Higher prevalence of severe fibrosis was seen in HBeAg(+) patients compared to HBeAg(−) patients age >45 years (58% vs 43% respectively, p = 0.03), in patients with HBV DNA levels ≥4 log compared with <4 log copies/ml (41% vs 27% respectively, p < 0.01), and in patients with stepwise increase of ALT levels (<0.5 × ULN vs 0.5–1 × ULN vs 1–2 × ULN; 11% vs 30% vs 48% respectively, p < 0.01). After multivariate analysis, gender, age and ALT levels were significant factors associated with severe fibrosis. Patients who received antiviral treatment had lower ALT, stiffness score and prevalence of cirrhosis compared to treatment-naïve patients [25 vs 35 U/L (p < 0.01), 6.2 vs 6.7 kPa (p = 0.031) and 14% vs 22% (p = 0.008) respectively].CONCLUSION:The overall prevalence of severe fibrosis in CHB patients was 34% with higher rates seen in older age groups, males, and in patients with higher ALT levels.

Correlation of Liver Stiffness and Histological Features in Healthy Persons and in Patients With Occult Hepatitis B, Chronic Active Hepatitis B, or Hepatitis B Cirrhosis

OBJECTIVES:Liver stiffness measurement using transient elastography has become a popular tool to assess liver fibrosis. The aim of this study was to determine liver stiffness values and histological features in healthy subjects and in patients with chronic hepatitis B (CHB).METHODS:A total of 157 people were included (28 healthy subjects and 18 patients with occult hepatitis B infection, 102 with active CHB, and 9 with end-stage hepatitis B cirrhosis). Histology and liver stiffness measurements were obtained from all patients.RESULTS:The median liver stiffness in healthy subjects and in occult hepatitis B, active hepatitis B, and end-stage cirrhosis patients was 4.6, 4.2, 8.7, and 33.8 kPa, respectively. In healthy subjects and in patients with occult hepatitis B infection, none had significant fibrosis on histology, and all had liver stiffness <7.2 kPa. In patients with active CHB, 32 (31%) had liver stiffness >11.0 kPa, but only four (12%) had cirrhosis on histology. Using liver stiffness to predict cirrhosis in this group had a sensitivity of 100%, a specificity of 69%, a positive predictive value of 10%, and a negative predictive value of 100%. All nine patients with end-stage liver cirrhosis had liver stiffness >11.0 kPa. The overall area under the ROC curve (AUROC) for diagnosing cirrhosis using a cutoff of 11.3 kPa was 0.89.CONCLUSIONS:Liver stiffness measurement has an overall good diagnostic accuracy with excellent negative predictive value. However, in active CHB with elevated alanine aminotransferase (ALT) levels, the positive predictive value for diagnosing cirrhosis is poor, and further studies are needed to optimize the use of transient elastography in this important group.

Prevalence of occult hepatitis B infection in a highly endemic area for chronic hepatitis B: a study of a large blood donor population

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 ≥2 out 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.

Detection of Colorectal Adenoma by Narrow Band Imaging (HQ190) vs. High-Definition White Light Colonoscopy: A Randomized Controlled Trial

OBJECTIVES:The benefits of narrow band imaging (NBI) on enhancing colorectal adenoma detection remain questionable. We tested whether the new generation of NBI (190-NBI), which is twice as bright as the previous version, would improve adenoma detection when compared with high-definition white light (HD-WL) colonoscopy.METHODS:It was a randomized controlled trial with tandem colonoscopy. We recruited patients who underwent colonoscopy for symptoms, screening, or surveillance. Patients were randomized for the use of either 190-NBI or HD-WL on withdrawal. Tandem colonoscopy was performed by using the same assigned colonoscope and withdrawal method. Lesions detected on first-pass and second-pass examination were used for adenoma detection and miss rates, respectively. The primary outcomes were adenoma and polyp detection rates.RESULTS:A total of 360 patients were randomized to undergo either 190-NBI or HD-WL colonoscopy. Both the adenoma and polyp detection rates were significantly higher in the 190-NBI group compared with the HD-WL group (adenoma: 48.3% vs. 34.4%, P=0.01; polyps: 61.1% vs. 48.3%, P=0.02). The mean number of polyps detected per patient was higher in the 190-NBI group (1.49% vs. 1.13, P=0.07). There was no significant difference in the adenoma miss rates between the two groups (21.8% vs. 21.2%). Multivariate analysis showed that the use of 190-NBI (odds ratio (OR) 1.85; 95% confidence interval (CI) 1.10–3.12), withdrawal time (OR 1.29; CI 1.19–1.38), patients age (OR 1.04; CI 1.01–1.06), and male gender (OR 2.38; CI 1.42–3.99) were associated with adenoma detection.CONCLUSIONS:190-NBI colonoscopy was superior to the conventional HD-WL in detecting colorectal adenomas or polyps, but there was no significant difference in adenoma miss rates.

Clarithromycin-amoxycillin-containing triple therapy: a valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?

Background:  Recent studies have suggested the eradication rate for Helicobacter pylori infection with standard amoxycillin–clarithromycin‐containing triple therapy as first‐line treatment have fallen below 80%. Levofloxacin‐containing triple therapy was proposed as an alternative. The aim of this study is to compare the efficacy and tolerability of the standard 7‐day clarithromycin‐containing triple therapy against the 7‐day levofloxacin‐containing triple therapy, and to assess whether the classical triple therapy is still valid as empirical first‐line treatment for H. pylori infection in Hong Kong.

Ten day sequential versus 10 day modified bismuth quadruple therapy as empirical firstline and secondline treatment for Helicobacter pylori in Chinese patients: an open label, randomised, crossover trial

Objective Treatments with sequential therapy (SEQ) or bismuth quadruple (QUAD) therapy have been proposed as empirical firstline regimens for Helicobacter pylori. We compared the efficacy and tolerability of 10 day SEQ with 10 day modified QUAD as both firstline and secondline treatments for H pylori in a randomised crossover study. Design H pylori positive and treatment naïve patients were randomly assigned to receive either 10 day SEQ (esomeprazole for 10 days, amoxicillin for an initial 5 days, followed by clarithromycin and metronidazole for a subsequent 5 days) or modified QUAD (esomeprazole, bismuth subcitrate, tetracycline and metronidazole). H pylori eradication was confirmed by urea breath test at 8 weeks. Patients who failed the initial assigned treatment were crossed over to receive the alternate regimen. The primary outcome was eradication rates of firstline treatment by intention to treat (ITT) and per protocol (PP) analyses. Results 357 patients were randomised to receive either SEQ or QUAD. The PP eradication rates of the SEQ and QUAD groups were 95.2% and 98.8%, respectively (p=0.10). Based on ITT analysis, the corresponding eradication rates were 89.4% and 92.7%, respectively (p=0.36). Eight (4.8%) patients in the SEQ and two (1.2%) patients in the QUAD who failed the firstline treatment were crossed over to the alternate regimen with 100% retreatment success. The overall incidence of adverse events was higher in the QUAD (16.7%) than in the SEQ (8.1%; p=0.032) group. Conclusions Ten day sequential and modified bismuth quadruple therapies are both highly effective as empirical firstline therapies for H pylori in Chinese patients. ClinicalTrials.gov NCT 01760824