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Background/Aims: We aimed to determine the association between blood urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic liver disease (CLD) patients.Methods: The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then, the above associations were evaluated by urea level within intervals.Results: Among 4,282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6–9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR], 4.15; 95% confidence interval [CI], 1.68–10.24) and ≥10 mmol/L (aHR, 5.22; 95% CI, 1.86–14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR, 3.24; 95% CI, 1.50–6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level, and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12,476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR, 1.27; 95% CI, 1.03–1.57).Conclusions: We identified a U-shaped relationship between the urea level and liver fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD.

BACKGROUND AND AIMS The uptake of antiviral treatment for patients with chronic hepatitis B (CHB) has been suboptimal. We aimed to determine the secular trend of treatment uptake in the territory-wide CHB cohort in Hong Kong from 2000 to 2017 and the factors for no treatment despite fulfilling treatment criteria. METHODS Chronic hepatitis B patients under public clinics and hospitals were identified through electronic medical records. The treatment indications were defined according to the Asian-Pacific guidelines published at the time of patients' first appearance in four periods: 2000-2004, 2005-2009, 2010-2013, and 2014-2017. RESULTS There were 135 395 CHB patients were included; 1493/12472 (12.0%), 7416/43426 (17.1%), 10 129/46559 (21.8%), 8051/32 938 (24.4%) patients fulfilled treatment criteria in the four periods, respectively. The treatment uptake rate increased with time: 35.1%, 43.4%, 60.2%, and 68.6% respectively. High fibrosis indices (APRI, FIB-4, and Forns indices) appeared to be the main factors for treatment indication in non-cirrhotic patients, with over 90% fulfilling treatment criteria due to high fibrosis indices alone. Of those fulfilling treatment criteria by high fibrosis indices, less than 60% of patients (25.2%, 36.1%, 46.0%, and 58.9%, respectively) had antiviral treatment initiated. Normal platelet count (odds ratio 0.42, P

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P

Background/Aims: Serum fibrosis scores comprised of common laboratory tests have high utility to assess severity of liver fibrosis. We aimed to derive and validate a hepatocellular carcinoma (HCC) risk score based on serum fibrosis scores to predict HCC in treatment-naïve chronic hepatitis B (CHB) patients.Methods: Fifteen thousand one hundred eighty-seven treatment-naïve adult CHB patients were identified to form the training cohort in this retrospective study. Individual fibrosis score was included to construct a new HCC prediction score. The score was externally validated in an independent treatment-naïve Korean CHB cohort.Results: 180/15,187 patients (1.2%) in training cohort and 47/4,286 patients (1.1%) in validation cohort developed HCC during a mean follow-up of 52 and 50 months, respectively. The newly developed HCC risk score, Liang score, is composed of gender, age, hepatitis B virus DNA, fibrosis-4 (FIB-4) index, and ranges from 0 to 22. Area under the time-dependent receiver operating characteristic curve of Liang score was 0.79 (95% confidence interval, 0.70–0.89). A cutoff value of nine provided an extremely high negative predictive value of 99.9% and high sensitivity of 90.0% at 5 years in the validation cohort. Patients with Liang score ≤9 had HCC incidence

Background & Aims PAGE-B and modified PAGE-B (mPAGE-B) scores were developed to predict the risk of hepatocellular carcinoma (HCC) in patients on nucleos(t)ide analogue therapy. However, how and when to use these risk scores in clinical practice is uncertain. Methods Consecutive adult patients with chronic hepatitis B who had received entecavir or tenofovir for at least 6 months between January 2005 and June 2018 were identified from a territory-wide database in Hong Kong. The performance of PAGE-B and mPAGE-B scores for HCC prediction at 5 years was assessed by area under the time-dependent receiver operating characteristic curve (AUROC), and different cut-off values of these 2 scores were evaluated by survival analysis. Results Of 32,150 identified patients with chronic hepatitis B, 20,868 (64.9%) were male. Their mean age was 53.0 ± 13.2 years. At a median (IQR) follow-up of 3.9 (1.8–5.0) years, 1,532 (4.8%) patients developed HCC. The AUROCs (95% CI) for the prediction of HCC at 5 years were 0.77 (0.76–0.78) and 0.80 (0.79–0.81), with PAGE-B and mPAGE-B scores, respectively (p Conclusions PAGE-B and mPAGE-B scores can be applied to identify patients on antiviral therapy who are at low risk of developing HCC. These patients could be exempted from HCC surveillance due to their very low HCC risk. Lay summary Risk scores have been developed to predict the likelihood of patients with chronic hepatitis B developing hepatocellular carcinoma (HCC). We investigated the role of 2 such scores, PAGE-B and modified PAGE-B, in predicting the risk of HCC in 32,150 nucleos(t)ide analogue-treated patients with chronic hepatitis B. These scores identified a group of patients at very low risk of developing HCC who could therefore be exempted from HCC surveillance.

Background & Aims: Accurate hepatocellular carcinoma (HCC) risk prediction facilitates appropriate surveillance strategy and reduces cancer mortality. We aimed to derive and validate novel machine learning models to predict HCC in a territory-wide cohort of patients with chronic viral hepatitis (CVH) using data from the Hospital Authority Data Collaboration Lab (HADCL). Methods: This was a territory-wide, retrospective, observational, cohort study of patients with CVH in Hong Kong in 2000–2018 identified from HADCL based on viral markers, diagnosis codes, and antiviral treatment for chronic hepatitis B and/or C. The cohort was randomly split into training and validation cohorts in a 7:3 ratio. Five popular machine learning methods, namely, logistic regression, ridge regression, AdaBoost, decision tree, and random forest, were performed and compared to find the best prediction model. Results: A total of 124,006 patients with CVH with complete data were included to build the models. In the training cohort (n = 86,804; 6,821 HCC), ridge regression (area under the receiver operating characteristic curve [AUROC] 0.842), decision tree (0.952), and random forest (0.992) performed the best. In the validation cohort (n = 37,202; 2,875 HCC), ridge regression (AUROC 0.844) and random forest (0.837) maintained their accuracy, which was significantly higher than those of HCC risk scores: CU-HCC (0.672), GAG-HCC (0.745), REACH-B (0.671), PAGE-B (0.748), and REAL-B (0.712) scores. The low cut-off (0.07) of HCC ridge score (HCC-RS) achieved 90.0% sensitivity and 98.6% negative predictive value (NPV) in the validation cohort. The high cut-off (0.15) of HCC-RS achieved high specificity (90.0%) and NPV (95.6%); 31.1% of patients remained indeterminate. Conclusions: HCC-RS from the ridge regression machine learning model accurately predicted HCC in patients with CVH. These machine learning models may be developed as built-in functional keys or calculators in electronic health systems to reduce cancer mortality. Lay summary: Novel machine learning models generated accurate risk scores for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. HCC ridge score was consistently more accurate than existing HCC risk scores. These models may be incorporated into electronic medical health systems to develop appropriate cancer surveillance strategies and reduce cancer death.

Background and Aims Metformin is an oral anti‐hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)‐related cirrhosis and chronic kidney disease (CKD). Methods Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child‐Pugh class and CKD stage were included in the model as time‐dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg. Results We identified 4431 diabetic patients with CHB‐related cirrhosis between 2000 and 2017 from a territory‐wide database in Hong Kong. The risk of metabolic acidosis increased with Child‐Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child‐Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92). Conclusion In conclusion, patients with Child‐Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child‐Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis.

Introduction Aspirin may reduce the risk of chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in patients receiving antiviral treatment. We aimed to investigate the impact of aspirin on reducing HCC risk in patients treated with first-line oral nucleos(t)ide analogs (NAs; entecavir and/or tenofovir disoproxil fumarate). Methods We conducted a territorywide, retrospective cohort study in NA-treated CHB patients between 2000 and 2018 from the electronic healthcare data repository in Hong Kong. Subjects were classified into aspirin users for at least 90 days during NA treatment (aspirin group) or no aspirin or any other antiplatelet use during follow-up period (no aspirin group). Incidence rates of HCC and gastrointestinal bleeding (GIB) in 2 groups with propensity score matching with 1:3 ratio. Results Of 35,111 NA-treated CHB patients of mean age of 53.0 years and 61.6% men, sixty-nine (4.0%) and 1,488 (4.5%) developed HCC at a median (interquartile range) of 2.7 (1.4-4.8) years and 3.2 (1.8-6.0) years in the aspirin group and no aspirin group, respectively. A duration-dependent association between aspirin and the risk of HCC was observed (subhazard ratio [sHR] 3 months-2 years: 0.65; 95% confidence interval [CI] 0.47-0.92; sHR 2-5 years: 0.63; 95% CI 0.43-0.94; sHR from ≥5 years: 0.41; 95% CI 0.18-0.91). Patients who took aspirin for ≤2 years had significantly higher risk of GIB (sHR: 1.73, 95% CI 1.07-2.79) than those not receiving aspirin. The risk of GIB started declining with the longer use of aspirin and becoming insignificant for ≥5 years' use (sHR: 0.79, 95% CI 0.19-3.21). Discussion Long-term aspirin use is associated with a lower risk of HCC in a duration-dependent manner in NA-treated CHB patients without a significant increase in the risk of gastrointestinal adverse effects.

INTRODUCTION Immunotherapy has dramatically improved the survival of patients with advanced or metastatic malignancies. Recent studies suggest that immunotherapy may increase the risk of hepatitis, whereas it may also induce functional cure of chronic hepatitis B virus (HBV) infection. We evaluated the incidence of hepatitis flare, HBV reactivation, hepatitis B surface antigen (HBsAg) seroclearance or seroreversion in patients with current or past HBV infection who had received immunotherapy. METHODS This was a territory-wide observational cohort study in Hong Kong. We identified patients through electronic medical records based on the prescriptions of immune checkpoint inhibitors from July 1, 2014, to December 31, 2019. Patients who were HBsAg positive or HBsAg negative with results for antibody to hepatitis B surface or core antigen (anti-HBs or anti-HBc) were included. RESULTS A total of 990 patients (397 HBsAg-positive, 593 HBsAg-negative with 482 anti-HBc and/or anti-HBs positive, and 111 both anti-HBc and anti-HBs negative) were identified. All of HBsAg-positive and 15.9% HBsAg-negative patients were put on oral antiviral treatment. Hepatitis flare (alanine aminotransferase >2 times of the upper limit of normal) occurred in 39.3% HBsAg-positive and 30.4% HBsAg-negative patients. High baseline alanine aminotransferase and combination of immunotherapy increased the risk of hepatitis. HBV reactivation (≥2 log increase in HBV DNA from baseline) occurred in 2 HBsAg-positive patients; HBsAg seroclearance and seroreversion was observed in 1 HBsAg-positive and 1 HBsAg-negative patient, respectively (

Background & Aims Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007–2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival. Methods A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment (i.e. no NA), patients receiving NAs after their first HCC treatment (i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment (i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs). Results The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70–3.44; p, Graphical abstract, Highlights • Antiviral treatment improves survival in patients with chronic hepatitis B-related HCC. • The uptake of antiviral treatment in HCC patients was suboptimal in the past (47.3% in 2007), but dramatically improved to 98.3% in 2017. • The timing of antiviral treatment (before or after HCC occurrence) does not matter that much in terms of patient survival. • Antivirals should be started soon after HCC has been diagnosed in patients with chronic hepatitis B who are not already on them.

Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000-2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c ) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7-11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24-0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04-1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.

Background and aim Male sex is a risk factor for hepatocellular carcinoma (HCC). Diabetes mellitus (DM) is associated with a doubled risk of HCC in patients with chronic hepatitis B (CHB). We examined the relationship between serum total testosterone and HCC risk in male CHB patients with DM. Methods We performed a retrospective cohort study of male CHB patients with DM between 2000 and 2017 using a territory-wide electronic health-care database in Hong Kong. DM was defined by use of anti-diabetic medications, hemoglobin A1c ≥ 6.5%, and/or fasting glucose ≥ 7 mmol/L in two measurements or ≥ 11.1 mmol/L in one measurement. Results Of 928 male CHB patients with DM, 83 (8.9%) developed HCC at a median (interquartile range) of 10.7 (6.1-14.6) years. Higher testosterone was associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 SD increase 1.23, 95% confidence interval [CI] 1.03-1.46, P = 0.024). The upper tertile of testosterone (aHR 1.86, 95% CI 1.02-3.39, P = 0.043), but not middle tertile (aHR 0.84, 95% CI 0.41-1.69 P = 0.620), was associated with a higher risk of HCC than the lower tertile. The cumulative incidence (95% CI) of HCC at 5, 10, and 15 years was 4.4% (2.5-7.2%), 12.4% (8.7-16.7%), and 19.1% (14.2-24.5%), respectively, in patients in the upper tertile of testosterone. By subgroup analysis, the association between testosterone and HCC was stronger in patients aged ≥ 50 years and those not receiving antiviral therapy. Conclusion Higher serum testosterone is associated with a higher incidence of HCC in male CHB patients with DM.

Background The rates of hepatitis B surface antigen (HBsAg) seroclearance after stopping nucleos(t)ide analogues (NA) in European (19% in 2 years) and Asian (13% in 6 years) patients with chronic hepatitis B (CHB) vary dramatically. We evaluated the incidence of hepatitis flare and HBsAg seroclearance in hepatitis B e antigen (HBeAg)-negative Chinese CHB patients who had stopped NA. Methods This was a territory-wide retrospective study in Hong Kong. We identified HBeAg-negative CHB patients from January 2000 to December 2017 who had stopped NA treatment for more than 3 months. Hepatitis flare was defined as ALT >2×ULN. Results The 1076 patients were predominantly middle-aged men (mean age 52 years, male 74.8%) when starting NA; they stopped NA after 82 ± 35 months of treatment. At 44.3 ± 24.6 months after stopping NA, 147 (13.6%) patients had hepatitis flare, which led to resumption of NA; whereas 77 (7.2%) patients had flare but did not resume NA. Decompensation occurred in 7/914 (0.8%) patients. A total of 695 (64.6%) patients remained on NA treatment at the last visit. Eleven patients had achieved HBsAg seroclearance (6 of them had hepatitis flare and 1 of these 6 patients achieved HBsAg seroclearance after NA was restarted). Hepatic events developed in 75/695 (10.8%) patients who had NA resumed vs 43/381 (11.3%) patients who did not resume NA (P = .677). Conclusions Hepatitis flare and retreatment were common in HBeAg-negative CHB patients who stopped NA treatment; whereas HBsAg seroclearance rarely occurred. Stopping NA to achieve functional cure should not be recommended at this moment.