Ka-Shing Cheung

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 virus core-related antigen as a surrogate marker for covalently closed circular DNA

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core‐related antigen (HBcrAg) is a novel marker for HBV disease. We aimed to determine whether HBcrAg could be a surrogate marker for intrahepatic cccDNA.

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).

Wisteria floribunda agglutinin-positive human Mac-2 binding protein predicts liver cancer development in chronic hepatitis B patients under antiviral treatment

AIM The risk factors for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients with undetectable serum HBV DNA under nucleos(t)ide analogue (NA) therapy are not well defined. We aimed to examine the relationship between Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) and HCC development in these patients. Results There was a significant difference in the median levels of pre-treatment WFA+-M2BP between the HCC and control groups (0.67 vs 0.41 COI, respectively, p < 0.001). Among patients with cirrhosis, the median level of WFA+-M2BP was higher in HCC group than in control group (0.74 vs 0.47 COI, respectively, p = 0.014). Among patients without cirrhosis, the median level of WFA+-M2BP of HCC group was also higher (0.48 vs 0.28 COI, respectively, p = 0.002). With a cutoff value of 0.69, the AUROC of pre-treatment WFA+-M2BP to predict HCC development for the whole cohort was 0.70. With cutoff values of 0.69 and 0.34, the AUROCs to predict HCC were 0.67 and 0.77 for patients with and without cirrhosis, respectively. Materials and Methods Fifty-seven NA-treated patients with undetectable HBV DNA who developed HCC were compared with 57 controls (matched with demographics and treatment duration). WFA+-M2BP levels were measured, and expressed as cutoff index (COI). Subgroup analyses were also performed in patients with and without cirrhosis. Conclusions A higher pre-treatment WFA+-M2BP level was associated with an increased risk of HCC development in patients with undetectable HBV DNA under NA therapy. Further longitudinal studies are required to examine the role of WFA+-M2BP as an accessory risk marker for HCC development.

Epidemiology and Natural History of Primary Biliary Cholangitis in the Chinese: A Territory-Based Study in Hong Kong between 2000 and 2015

Objectives:Studies on the epidemiology of primary biliary cholangitis (PBC) in the Chinese population are lacking. We aimed to determine the epidemiology of PBC in Hong Kong (HK) with a population of 7.3 million.Methods:We retrieved data from the electronic database of the HK Hospital Authority, the only public healthcare provider in Hong Kong. PBC cases between 2000 and 2015 were identified by International Classification of Diseases (ICD)-9 code. We estimated the age-/sex-adjusted incidence rate and prevalence of PBC, and analyzed the adverse outcomes (hepatocellular carcinoma (HCC), liver transplantation, and death).Results:One thousand and sixteen PBC patients aged ≥20 years were identified (female-to-male ratio 4:1; median age 60.6 years, interquartile range (IQR) 51.8–72.6 years; median follow-up 5.6 years, IQR 1.6–8.7 years). The average age/sex-adjusted annual incidence rate and prevalence were 8.4 per million person-years and 56.4 per million, respectively. Between 2000 and 2015, the age/sex-adjusted annual incidence rate increased from 6.7 to 8.1 per million person-years (Poisson P=0.002), while age/sex-adjusted prevalence increased from 31.1 to 82.3 per million (Poisson P<0.001). Fifty patients developed HCC, and 49 underwent liver transplantation. Case fatality risk decreased from 10.8 to 6.4% (Poisson P=0.003). The 5- and 10-year overall survival rates were 81.5 and 78.3%, whereas the transplant-free survival rates were 78.0% and 74.3%, respectively. Increasing age, cirrhosis and being treatment-naïve were associated with lower transplant-free survival.Conclusions:There is a considerable increase in the incidence and prevalence of PBC in the Chinese population over the past 16 years, with significant morbidity and mortality.

Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy

We examined the relationship between hepatitis B surface and core‐related antigens (HBsAg, HBcrAg) and hepatocellular carcinoma (HCC) development in patients with undetectable serum HBV DNA receiving nucleos(t)ide analogue (NA). Seventy‐six HBV carriers with undetectable HBV DNA (<20 IU/mL) who subsequently developed HCC were compared with 152 matched controls. Clinical and laboratory parameters (including novel assays to measure linearized HBsAg [HQ‐HBsAg] and HBcrAg) were analysed. There were no significant differences in HBsAg/HQ‐HBsAg levels between the two groups. There was a significant difference in the median values of both pre‐ and post‐NA HBcrAg levels between the HCC and control groups (pre‐treatment: 279.0 vs 35.4 kU/mL, P=.005; post‐treatment: 10.2 vs 1.7 kU/mL, P=.005, respectively). For the whole HCC group, a cut‐off value of post‐treatment HBcrAg level ≥7.8 kU/mL yielded an area under receiver operating curve (AUROC) of 0.61 with a negative predictive value (NPV) of 77.0%. The OR of HCC development was 3.27. For noncirrhotic patients, the median values of post‐treatment HBcrAg level of HCC group and controls were 10.2 and 1.0 kU/mL, respectively (P=.001). A cut‐off value of HBcrAg level ≥7.9 kU/mL yielded an AUROC of 0.70 with a NPV of 80.6%. The OR of HCC development was 5.95. A higher pre‐ and post‐NA treatment HBcrAg level (but not HBsAg) was associated with an increased risk of HCC development in patients achieving undetectable serum HBV DNA while on NA therapy. HBcrAg may serve as a novel risk marker for HCC in this group of patients.

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.

Prognostic Factors for Transplant-Free Survival and Validation of Prognostic Models in Chinese Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid

OBJECTIVES: We aimed to validate the prognostic models for primary biliary cholangitis (PBC) in Chinese patients receiving ursodeoxycholic acid (UCDA), and to compare their performances in predicting the long‐term survival. METHODS: Chinese patients with PBC from a tertiary center were identified via electronic search of hospital medical registry. Risk factors associated with adverse events (liver transplantation or death from liver‐related causes including hepatocellular carcinoma (HCC) and liver decompensation) were determined. Transplant‐free survival was defined as survival free of liver‐related death or transplantation. RESULTS: Of the 144 patients, 41 (28.5%) had baseline cirrhosis. The median age at diagnosis was 57.8 years. During a median follow‐up of 7.0 years, 40 patients died (21 liver‐related; 19 non‐liver‐related), 12 developed HCC, and 10 underwent transplantations. The 5‐, 10‐, and 15‐year transplant‐free survival probabilities were 91.0%, 78.1%, and 58.9%, respectively. Independent risk factors for adverse events were increasing age (hazard ratio (HR) 1.05), cirrhosis (HR 8.53), and suboptimal treatment response (HR 3.06). Aspartate aminotransferase/platelet ratio index at 1 year (APRI‐r1) in combination with treatment response optimized the risk stratification. The performances of the GLOBE, UK‐PBC scores, Rotterdam criteria, and APRI‐r1 were comparable in predicting adverse events. The area under receiver operating curves within 5, 10, and 15 years were as follows—GLOBE score: 0.83, 0.85, and 0.85, respectively; UK‐PBC score: 0.89, 0.83, and 0.79, respectively; Rotterdam criteria: 0.82, 0.76, and 0.80, respectively; APRI‐r1: 0.80, 0.83, and 0.77, respectively. CONCLUSIONS: The UK‐PBC, GLOBE scores, Rotterdam criteria, and APRI‐r1 had good and comparable prognostic prediction values for Chinese PBC patients receiving UCDA.

Prevention and management of hepatitis B virus reactivation in cancer patients

Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with solid tumor or hematological malignancies. It is associated with significant morbidity and mortality due to hepatitis flare and/or hepatic decompensation. These consequences arising from HBV reactivation are, however, largely preventable. Routine screening for HBV serologic status is recommended for all cancer patients undergoing chemotherapy or biologics. By recognizing different serological patterns (which represent either overt or occult HBV infection) and the types of immunosuppressive therapies prescribed, a risk-adapted approach can be established. Prophylactic therapy with nucleos(t)ide analogues (prior to or concomitantly with the commencement of immunosuppressive therapies) is more effective than pre-emptive therapy (starting antiviral when HBV DNA level is rising) in high-risk individuals. Entecavir has been proven to be more effective than lamivudine according to recent studies. Close monitoring of serum HBV level is the preferred strategy in low-risk patients. However, the optimal interval of DNA monitoring and the duration of therapy remain unknown.

Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re-evaluation of HBsAg seroclearance

Serologic profiles after hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B (CHB) have not been well‐studied.