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.

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.

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.

Rates of metachronous adenoma after curative resection for left-sided or right-sided colon cancer.

BACKGROUND/AIMS: We determined the rates of metachronous colorectal neoplasm in colorectal cancer (CRC) patients after resection for right (R)-sided or left (L)-sided cancer. METHODS: Consecutive CRC patients who had undergone surgical resection for curative intent in our hospital between 2001 and 2004 were identified. R-sided colonic cancers refer to cancer proximal to splenic flexure whereas L-sided cancers include rectal cancers. Patients were included only if they had a clearing colonoscopy performed either before or within 6 months after the operation. Findings of surveillance colonoscopy performed up to 5 years after colonic resection were included in the analysis. RESULTS: Eight hundred and sixty-three CRC patients underwent curative surgical resection during the study period. Three hundred and twenty-seven patients (107 R-sided and 220 L-sided) fulfilled the inclusion criteria and had at least 1 postoperative surveillance colonoscopy performed. The proportion of patients who had polyp and adenoma on surveillance colonoscopy was significantly higher among patients with L-sided than R-sided cancers (polyps: 30.9% vs. 19.6%, P=0.03; adenomas: 25.5% vs. 13.1%, P=0.01). The mean number of adenoma per patient on surveillance colonoscopy was also higher for patients with L-sided than R-sided tumors (0.52; 95% confidence interval [CI], 0.37-0.68 vs. 0.22; 95% CI, 0.08-0.35; P<0.01). Multivariate analysis showed that L-sided cancers, age, male gender and longer follow-up were independent predictors of adenoma detection on surveillance colonoscopy. CONCLUSIONS: Patients with Lsided cancer had a higher rate of metachronous polyps and adenoma than those with R-sided cancer on surveillance colonoscopy.

Seven-Year Treatment Outcome of Entecavir in a Real-World Cohort: Effects on Clinical Parameters, HBsAg and HBcrAg Levels.

OBJECTIVES: We aimed to determine the levels of alanine aminotransferase (ALT), hepatitis B virus DNA (HBV DNA), HBsAg, and a novel viral marker (hepatitis B core-related antigen (HBcrAg)); hepatitis B e antigen (HBeAg) seroconversion and drug resistance rates after 7 years of entecavir treatment in chronic hepatitis B (CHB) patients. METHODS: Two hundred and twenty-two Chinese CHB patients on continuous entecavir treatment were recruited. Serologic, virologic, biochemical outcomes, and the occurrence of entecavir signature mutations were determined. RESULTS: The rates of ALT normalization, HBeAg seroconversion, and undetectable HBV DNA were 98.3%, 82.1%, and 98.7%, respectively, after 7 years of entecavir treatment. The genotypic resistance rate was 1.2%. Decline of HBsAg level was modest with a median decline rate of 0.107 log IU/ml/year. Among patients with baseline HBsAg <1,000 IU/ml and annual HBsAg decline rate of ≥0.166 log IU/ml, all have HBsAg of <200 IU/ml (a level highly predictive for HBsAg seroclearance) at year 7. In contrast, in patients with baseline HBsAg ≥1,000 IU/ml and annual HBsAg decline rate of <0.166 log IU/ml, 95.5% had HBsAg of ≥200 IU/ml at year 7. Decline of HBcrAg levels was moderate with a median decline rate of 0.244 log kU/ml/year. Forty-seven patients (32.0%) had undetectable HBcrAg level at year 7. CONCLUSIONS: Long-term entecavir therapy continued to have good responses with low drug resistance rate. However, the decline of HBsAg with treatment was suboptimal. HBcrAg level declined at a relatively better rate. Baseline HBsAg level of <1,000 IU/ml and annual decline of 0.166 log IU/ml could be used to predict HBsAg response.

Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study.

Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg-negative, anti-HBc-positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≥10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg-negative, anti-HBc-positive, of whom 62 were recruited and monitored for a median of 48 (4-104) weeks. The 2-year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8-100) weeks. Multivariate analysis showed that age ≥50 years (P = 0.004, hazard ratio = 8.2) and chronic graft-versus-host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft-versus-host disease, compared with the remaining patient cohort, had a significantly lower 2-year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. CONCLUSION: HBsAg-negative, anti-HBc-positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≥50 years and chronic graft-versus-host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451-1461).

Association of Hepatitis B Core-Related Antigen With Hepatitis B Virus Reactivation in Occult Viral Carriers Undergoing High-Risk Immunosuppressive Therapy.

OBJECTIVES: Hepatitis B core-related antigen (HBcrAg) is a novel serum marker that correlates with intrahepatic hepatitis B virus (HBV) activity. Its association with HBV reactivation in hepatitis B surface antigen (HBsAg)-negative antibody to hepatitis B core antigen (anti-HBc)-positive patients undergoing high-risk immunosuppressive therapy is undefined. METHODS: HBcrAg was measured in HBsAg-negative, anti-HBc-positive Asian patients with undetectable HBV DNA, who participated in two prospective studies investigating HBV reactivation during rituximab-containing chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Patients were monitored every 4 weeks for up to 2 years, with entecavir started when HBV reactivation, defined as HBV DNA ≥10 IU ml-1, developed. RESULTS: One hundred and twenty-four HBsAg-negative, anti-HBc-positive patients (rituximab, N=62; allogeneic HSCT, N=62) with a median follow-up of 64 weeks (range: 4-104 weeks) were studied. HBV reactivation occurred in 31 patients, with a 2-year cumulative reactivation rate of 40.4%. Serum HBcrAg was detected in 43 (34.7%) patients. Baseline HBcrAg positivity was significantly associated with HBV reactivation (P=0.004, hazard ratio (HR): 2.94, 95% confidence interval (95% CI): 1.43-6.07). HBcrAg-positive patients had a significantly higher 2-year HBV reactivation rate than HBcrAg-negative patients (71.8 vs. 31%, P=0.002). In the rituximab cohort, the HRs for positive HBcrAg and negative antibody to HBsAg for HBV reactivation were 3.65 and 2.84, respectively (P=0.011, 95% CI: 1.35-9.86 and P=0.032, 95% CI: 1.10-7.37, respectively). CONCLUSIONS: Serum HBcrAg positivity is a significant risk factor of HBV reactivation in HBsAg-negative, anti-HBc-positive patients undergoing high-risk immunosuppressive therapy and can potentially have a role in identifying patients who will best benefit from prophylactic nucleoside analogue treatment.

Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study.

PURPOSE: Patterns of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) -negative, antihepatitis B core antigen antibody (anti-HBc) -positive patients with lymphoma receiving rituximab-containing chemotherapy have not been well described. PATIENTS AND METHODS: HBsAg-negative, anti-HBc-positive Chinese patients with undetectable serum HBV DNA (< 10 IU/mL), diagnosed with hematologic malignancies and receiving rituximab-containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Entecavir was started when HBV reactivation (defined as detectable HBV DNA) was encountered. RESULTS: Among 260 patients receiving rituximab-containing chemotherapy, 63 patients (24.2%) who were HBsAg negative and anti-HBc positive underwent follow-up for a median of 70 weeks (range, 6 to 104 weeks). The 2-year cumulative rate of HBV reactivation was 41.5%, occurring at a median of 23 weeks (range, 4 to 100 weeks) after rituximab treatment. The median HBV DNA level at reactivation was 43 IU/mL (range, 14 to 920 IU/mL). A baseline undetectable antibody to HBsAg (anti-HBs; < 10 mIU/mL) was the only significant risk factor that was positively associated with HBV reactivation (hazard ratio, 3.51; 95% CI, 1.37 to 8.98; P = .009). Patients with negative baseline anti-HBs, compared with those with positive anti-HBs, had a significantly higher 2-year cumulative rate of HBV reactivation (68.3% v 34.4%; P = .012). At HBV reactivation, all patients had normal ALT, and all patients but one were HBsAg negative. Entecavir successfully controlled HBV reactivation in all patients. CONCLUSION: A high rate of HBV reactivation was observed in HBsAg-negative, anti-HBc-positive patients undergoing rituximab-containing chemotherapy, with the risk of reactivation significantly higher in anti-HBs-negative patients. Periodic HBV DNA monitoring was an effective strategy in preventing HBV-related complications.

Changes of HBsAg and HBV DNA levels in Chinese chronic hepatitis B patients after 5 years of entecavir treatment.

BACKGROUND AND AIM: Hepatitis B surface antigen (HBsAg) kinetics during long-term entecavir therapy has not been well investigated. METHODS: We described the cumulative serologic, virologic, and biochemical outcomes and the occurrence of signature entecavir mutations among 222 Chinese treatment-naïve chronic hepatitis B (CHB) patients receiving entecavir for up to 5 years. RESULTS: The median rate of HBsAg reduction over 5 years was 0.125 log IU/mL/year. Patients with high baseline HBV DNA levels (≥ 8 log copies/mL or ≥ 7.3 log IU/mL), when compared with those with baseline hepatitis B virus (HBV) DNA < 7.3 log IU/mL, had a significantly greater median rate of HBsAg reduction (0.178 and 0.102 log IU/mL/year, respectively, P < 0.001). The difference in HBsAg decline was most prominent in the first year (0.324 and 0.062 log IU/mL/year, respectively, P < 0.001). Greater median rates of HBsAg reduction were also found in hepatitis B e antigen (HBeAg)-positive patients when compared with HBeAg-negative patients (0.144 and 0.098 log IU/mL/year, P = 0.015), and in patients with high baseline HBsAg levels (≥ 3 log IU/mL), when compared with patients with low baseline HBsAg < 3 log IU/mL (0.131 and 0.045 log IU/mL/year, respectively, P = 0.001). The 5-year cumulative rate of HBV DNA undetectability (< 20 IU/mL) was 97.1%. There were two cases of entecavir resistance, resulting in a 5-year cumulative resistance rate of 1.2%. CONCLUSION: In contrast to the profound HBV DNA suppression, long-term entecavir treatment achieved only a slow decline in serum HBsAg. Although certain patient subgroups exhibit a more rapid HBsAg reduction, additional therapeutic agents are needed to increase the chance of HBsAg seroclearance in CHB.

HLA-DP and γ-interferon receptor-2 gene variants and their association with viral hepatitis activity in chronic hepatitis B infection.

BACKGROUND AND AIM: Studies show that polymorphisms in human leukocyte antigen (HLA)-DP loci and certain γ-interferon (IFN-γ) signaling pathway genes are related to persistence of hepatitis B virus (HBV) infection and viral load in chronic HBV (CHB) infection respectively. Our study aims to determine whether single-nucleotide polymorphisms (SNPs) linked to HLA-DP loci and IFN-γ signaling pathway are associated with HBV activities. METHODS: We compared the SNPs in the HLA-DPA1 gene (rs3077) and the IFN-γ receptor-2 gene (rs2284553 and rs9808753) of 100 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients with undetectable HBV DNA with 100 age- and sex-matched controls with HBV DNA > 2000 IU/mL. RESULTS: The median age of the study group was 47.9 years, and 61% were male patients. The distribution of the three polymorphisms was in Hardy-Weinberg equilibrium. Both rs3077 and rs2284553 polymorphisms were not associated with HBV viral load in terms of allelic frequency, genotypic frequency, dominant/recessive gene action. rs9808753 (G allele) was associated with a reduced chance of "undetectable HBV DNA" for patients below the age of 50 years in allelic frequency analysis (odds ratio 0.562; 95% confidence interval, 0.326-0.967; P value = 0.037). IFN-γ receptor-2 gene haplotype block (rs2284553/rs9808753) was not associated with HBV viral activity. CONCLUSION: There was no significant association between HLA-DP polymorphism (rs3077) and IFN-γ receptor-2 gene polymorphism (rs2284553) with viral activity in HBeAg-negative CHB patients. Further studies are required to confirm the association between IFN-γ receptor-2 gene polymorphism (rs9808753) and reduced chance of having "undetectable HBV DNA" in young CHB patients.

Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety.

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.