Clinical trial: intra dermal hepatitis B vaccination with topical imiquimod versus intra muscular hepatitis B vaccination in patients with inflammatory bowel disease.

BACKGROUND: Efficacy with conventional intra muscular (IM) hepatitis B vaccination in patients with inflammatory bowel disease (IBD) is suboptimal. AIM: To compare the immunogenicity of intradermal (ID) hepatitis B vaccination after topical imiquimod pre-treatment with IM hepatitis B vaccination in patients with IBD. METHODS: Adult IBD patients with no evidence of hepatitis B infection or immunity (negative to HBsAg/anti-HBc/anti-HBs) were randomised 1:1 to receive either ID hepatitis B vaccine with topical imiquimod pre-treatment to injection site (ID-Imq) or IM hepatitis B vaccine with aqueous cream pre-treatment (IM-Aq) at 0, 1 and 6 months. Patients and investigators were blinded to the randomisation and intervention. The primary endpoint was seroprotection rate at 12-month, defined as percentage of subjects with anti-HBs ≥10 mIU/ml. RESULTS: Between September 2019 and December 2020, 104 patients with IBD (68% male; 50% Crohn's) enrolled, and 53 assigned to ID-Imq group. The percentage of patients using steroids, immunomodulators or biologics at randomisation was 15%, 55% or 22%, respectively. Seroprotection rate at 12 months was significantly higher in the ID-Imq group than the IM-Aq group (91% vs 69%; OR 4.39, 95% CI 1.47-13.11). Multivariate analysis showed that ID vaccine with topical imiquimod and higher albumin level were associated with a higher seroprotection rate. The safety profile was similar but local reactions were more common in the ID-Imq group. CONCLUSIONS: Intradermal hepatitis B vaccination with topical imiquimod pre-treatment is safe and offers superior seroprotection to conventional IM administration in patients with IBD.

Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy.

BACKGROUND: We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development. METHODS: This is a case-control study of 104 patients [52 HCC and 52 non-HCC (matched with age, gender, cirrhosis and treatment duration)] on ≥ 3 years entecavir (ETV) with unquantifiable HBV DNA by Cobas Taqman assay v2.0 (Roche Diagnostics; lower limit of quantification [LLOQ] 20 IU/mL). Serial sera within 1, 1-2, and > 2 years prior to HCC diagnosis or last follow-up (LFU) were measured for HBV DNA and pre-genomic (pg) RNA using a highly sensitive semi-quantitative PCR assay with lower limit of detection of 10 IU/mL and LLOQ of 51.5 IU/mL, respectively. RESULTS: Among the 104 patients (80.8% male, median age 61.2 years old, 38.5% cirrhosis, median duration of ETV 45.5 months), 38.5% and 9.6% HCC patients had undetectable serum DNA and pgRNA, respectively, compared to 65.4% and 36.5% in non-HCC patients; P = 0.005 & 0.001, respectively, at the time of HCC diagnosis/LFU. Detectable HBV DNA and pgRNA were associated with a higher 2-year risk of HCC development (HR 2.79, 95% CI 1.424-5.468 & HR 4.544, 95% CI 1.07-19.289, respectively). No significant differences were observed for qHBsAg levels between HCC and non-HCC patients. CONCLUSIONS: More than 50% CHB patients on ETV with HBV DNA < LLOQ by standard assay had persistent viraemia as determined by a more sensitive assay. Detectable HBV DNA or pgRNA by more sensitive assays was associated with HCC development. More potent viral suppression is required to further reduce the risk of HCC.

Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.

BACKGROUND: Treatment cessation in chronic HBV infection may be durable in certain patient subgroups before hepatitis B surface antigen (HBsAg) seroclearance. The role of serum HBV RNA in determining treatment cessation suitability has not been well-investigated. METHODS: Nucleos(t)ide analogue (NUC) treatment was discontinued in non-cirrhotic patients with chronic HBV with serum HBsAg <200 IU/mL and fulfilling internationally recommended criteria for treatment cessation. Patients were monitored till 48 weeks with baseline and serial measurements of serum HBsAg, HBV RNA and hepatitis B core-related antigen. NUCs were resumed when HBV DNA reaches >2000 IU/mL regardless of alanine aminotransferase (ALT) levels. RESULTS: 114 entecavir-treated patients (median age 58.4 years, median serum HBsAg 54.4 IU/mL) with median treatment duration of 6.7 years were recruited. The 48-week cumulative rate of HBV DNA >2000 IU/mL was 58.1%. End-of-treatment serum HBV RNA and off-treatment serial HBV RNA were both independently associated with HBV DNA >2000 IU/mL (HR 2.959, 95% CI 1.776 to 4.926, p<0.001; HR 2.278, 95% CI 1.151 to 4.525, p=0.018, respectively). Patients with HBV RNA ≥44.6 U/mL had a cumulative 48-week rate of 93.2%, while combining HBV RNA undetectability and HBsAg <10 IU/mL had a cumulative 48-week rate of 9.1%. 24 patients (38.7%) developed off-treatment ALT elevation, highest peak ALT was 1515 U/L. 8 patients (median serum HBsAg 2.6 IU/mL) developed HBsAg seroclearance. CONCLUSION: Serum HBV RNA measurement is essential for deciding on entecavir cessation in patients with chronic HBV, especially with low HBsAg levels. Patients can be stratified on their risk of off-treatment relapse based on both viral determinants. TRIAL REGISTRATION NUMBER: NCT02738554.

Hepatocellular carcinoma: recent advances and emerging medical therapies.

Hepatocellular carcinoma remains a deadly disease with poor prognosis in patients with unresectable cancer. Trans-arterial chemoembolization is the primary locoregional therapy for intermediate-stage hepatocellular carcinoma, with an estimated median overall survival of less than two years. For almost a decade, sorafenib has been the only standard systemic treatment for metastatic disease or tumors which progress or are considered unsuitable for locoregional therapy. Major breakthroughs have been made over the past few years in the management of hepatocellular carcinoma, especially in medical therapies for advanced disease. In this article, recent advances in intra-arterial therapy, multi-kinase inhibitors, and immunotherapy will be reviewed.

Entecavir Reduced Serum Hepatitis B Core-Related Antigen in Chronic Hepatitis B Patients with Hepatocellular Carcinoma.

Serum hepatitis B core-related antigen (HBcrAg) was shown to predict the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients undergoing treatment. We investigated the longitudinal profile of HBcrAg in entecavir (ETV)-treated CHB patients with subsequent HCC development. We identified HCC cases diagnosed at ≥1 year after ETV initiation. CHB patients without HCC (matched for age, sex, cirrhosis status, baseline hepatitis B virus [HBV] DNA level, and ETV treatment duration) were identified as controls at an HCC:non-HCC ratio of 1:2. Serum samples were retrieved at baseline (ETV initiation) and at 3 and 5 years of ETV therapy for HBcrAg measurement (log IU/mL). In total, 180 patients (60 HCC patients matched with 120 CHB patients without HCC; median age, 56.5 years; 80.6% male; baseline HBV DNA, 5.9 log IU/mL; median follow-up, 6.8 years) were recruited. The median time from ETV initiation to HCC development was 3.2 years. HBcrAg levels were higher in HCC cases than in controls at all three time points: 5.69 log IU/ mL versus 5.02 log IU/mL (p=0.025), 4.23 log IU/mL versus 3.36 log IU/mL (p=0.007), and 3.86 log IU/mL versus 3.36 log IU/mL (p=0.009), respectively. ETV led to similar rates of decline in HBcrAg from baseline to 3 years in both groups (0.34 log IU/mL/year vs 0.39 log IU/mL/year, p=0.774), although the decline from 3 to 5 years was slower in the non- HCC group (0.05 log IU/mL/year) than in the HCC group (0.09 log IU/mL/year, p=0.055). ETV time-dependently reduced HBcrAg in HCC and non-HCC patients. HBcrAg interpretation should consider the antiviral treatment duration.

A large real-world cohort study examining the effects of long-term entecavir on hepatocellular carcinoma and HBsAg seroclearance.

Real-world studies examining reduction in risk of hepatocellular carcinoma (HCC) in patients receiving antivirals are limited by the small size of the studies, or by data insufficiency and heterogeneity with short follow-up duration. We aimed to examine the real-world long-term outcome of patients receiving entecavir treatment on HCC incidence and HBsAg seroclearance. The incidence of HCC in 1225 entecavir-treated patients between 2002 and 2015 was compared with the HCC incidence estimated using the REACH-B, GAG-HCC and CU-HCC scores. Standardized incidence ratios (SIR) were calculated. The impact of entecavir treatment on HBsAg seroclearance was also explored. The median follow-up of the cohort was 6.6 years, with 66 cases of HCC development. Using the REACH-B model, the reduction of HCC risk was significant from year 6 onwards with SIR of 0.68 (95% CI 0.535-0.866) at year 10. In subgroup patients without cirrhosis, consistent risk reduction was observed from the fifth year and the SIR reached 0.51 (95% CI 0.271-0.704) by year 10. Benefit in cirrhotic patients was demonstrated when using the GAG-HCC and CU-HCC score, with the SIR at year 10 being 0.38 (95% CI 0.259-0.544) and 0.46 (95% CI 0.314-0.659), respectively. The cumulative rate of HBsAg seroclearance was 5.2%. HBsAg level at third year of treatment and baseline-to-3-year percentage reduction was predictive of subsequent HBsAg seroclearance. In conclusion, long-term entecavir therapy was associated with significant reduction in the risk of HCC in the real world. However, HBsAg seroclearance rate remained low. Additional therapy may be considered in patients with adverse predictive factors for subsequent HBsAg seroclearance.

A Territorywide Prevalence Study on Blood-Borne and Enteric Viral Hepatitis in Hong Kong.

BACKGROUND: Viral hepatitis epidemiological data are important for the World Health Organization plan of eliminating viral hepatitis. We aimed to document the prevalence of viral hepatitis A to E in Hong Kong. METHODS: This community-based study was open to all Hong Kong Chinese citizens aged ≥18 years. Baseline data and risk factors were collected. Hepatitis A-E serology was measured, including hepatitis B e antigen, antibodies to hepatitis B e antigen, antibodies to hepatitis D, hepatitis B virus (HBV) DNA for hepatitis B surface antigen (HBsAg)-positive participants, and antibodies to hepatitis B surface antigen and antibodies to hepatitis B core antigen (anti-HBc) in HBsAg-negative participants. Hepatitis C virus (HCV) RNA and genotypes were determined in anti-HCV-positive participants. RESULTS: A total of 10 256 participants were recruited from February 2015 to July 2016. Overall HBsAg seroprevalence was 7.8% (95% confidence interval [CI], 7.3%-8.3%), which was reduced significantly with HBV vaccination (odds ratio, 0.15 [95% CI, .11-.21]). Among HBsAg-negative participants, anti-HBc seroprevalence increased from 5.4% (<26 years) to 60.1% (>65 years). No hepatitis D virus (HDV) cases were detected. Anti-HCV positivity was 0.5% (95% CI, .3%-.6%). Prevalence of antibodies to hepatitis A virus (anti-HAV) and hepatitis E virus (anti-HEV) was 65.2% (95% CI, 64.2%-66.1%) and 33.3% (95% CI, 32.4%-34.2%), respectively, and were influenced by age, family income, and being born in mainland China. CONCLUSIONS: HBV seroprevalence remained high despite universal vaccination. High anti-HBc seroprevalence underlines the potential issue of HBV reactivation during profound immunosuppression. HCV and HDV remained uncommon. Anti-HAV seroprevalence had decreased whereas anti-HEV seroprevalence had risen.

Attitudes and perceptions of influenza vaccination among Hong Kong doctors and medical students before the 2009 pandemic.

BACKGROUND: Vaccination is an important preventive measure for preparing against the influenza pandemics. This study investigated the attitudes and perceptions of influenza vaccination among doctors and medical students in Hong Kong. METHODS: A cross-sectional survey was conducted among 204 doctors and 242 medical students in a teaching hospital in 2009. Participants' demographic and job characteristics, and influenza experience and vaccination in the previous year were assessed in the questionnaire. Logistic regression models were used to examine the associations between uptake of influenza vaccination and the perceived benefits. RESULTS: Medical students were more likely to have receive an influenza vaccination in the previous year (66.9 vs. 39.7%) and acknowledged the related benefits than doctors. Moreover, uptake of influenza vaccine was associated with perceived benefits of vaccination in both doctors and medical students. CONCLUSIONS: The perceived benefits of influenza vaccination are an important factor in vaccine uptake for both doctors and medical students in Hong Kong, and should be reinforced in the professional training.

Laparoscopic liver resection for hepatocellular carcinoma.

OBJECTIVE: To provide an updated review on the clinical experience in laparoscopic liver resection, specifically for hepatocellular carcinoma. METHODS: A comprehensive literature search in MEDLINE was conducted for all English papers up to May 2010 on laparoscopic liver resection for hepatocellular carcinoma. Patient characteristics, perioperative results, and oncologic outcomes were compared and analysed. RESULTS: We analysed 11 clinical studies involving 466 hepatocellular carcinoma patients treated with laparoscopic hepatectomy. Thirty-seven (9%) patients underwent major resection. Cirrhosis occurred in 62%. The mean operative time was 189.5 min, and the mean blood loss was 315.6 mL. Blood transfusion was required in 14.6% of patients. There were two operative deaths. Postoperative complications included bile leakage (1%), bleeding (2.9%), liver failure (5.1%), and ascites (6%). The 1-year, 3-year, and 5-year disease-free survival rates ranged from 60% to 90%, 50% to 64%, and 31% to 50%, respectively, and the corresponding overall survival rates ranged from 85% to 100%, 67% to 100%, and 50% to 97% respectively. CONCLUSION: Laparoscopic liver resection for hepatocellular carcinoma appears to be safe and to achieve acceptable oncologic outcomes even in cirrhotic livers, but whether it is comparable to conventional open surgery needs to be evaluated in a randomized, controlled trial setting.