BACKGROUND AND AIMS:Whether HBsAg seroclearance provides further clinical benefit over complete viral suppression in nucleos(t)ide analogue (NA)-treated patients with chronic hepatitis B with cirrhosis remained unclear. We aimed to compare the risk of HCC and hepatic decompensation in treated patients with cirrhosis with complete viral suppression versus HBsAg seroclearance. APPROACH AND RESULTS:All adult patients with chronic hepatitis B and cirrhosis receiving entecavir/tenofovir between January 2005 and September 2020 were identified. Patients with HCC before or within the first 6 months of baseline, other cancers or liver transplantation before baseline, liver transplantation before HBsAg loss, and without complete viral suppression were excluded. One-year landmark analyses were performed; patients with clinical outcomes or follow-up <1 year were excluded. Of 5149 patients (mean age 60.1±12.6 y, 66.3% male) included in the 1-year landmark analysis, 456/4988 (9.1%) and 5/161 (3.1%) of patients with complete viral suppression alone and HBsAg seroclearance developed HCC, respectively, at a median (25th-75th percentile) follow-up of 4.1 (2.5-5.0) years; 334/4777 (7.0%) and 10/153 (6.5%) patients with complete viral suppression and HBsAg loss developed hepatic events. HBsAg seroclearance was associated with a lower risk of HCC (adjusted subdistribution HR: 0.37, 95% CI 0.15-0.91, p =0.030) but not hepatic events (adjusted subdistribution HR: 1.01, 95% CI: 0.52-1.95) than complete viral suppression. Similar results on HCC were observed in a 2-year landmark analysis (adjusted subdistribution HR: 0.37 [0.14-1.04]). CONCLUSIONS:HBsAg seroclearance is associated with a lower risk of HCC but not first/further hepatic decompensation in NA-treated patients with chronic hepatitis B and cirrhosis with complete viral suppression.

BACKGROUND & AIMS:The risk of hepatocellular carcinoma (HCC) decreases after hepatitis B surface antigen (HBsAg) seroclearance. We examined HCC incidence in patients with chronic hepatitis B (CHB) who cleared HBsAg compared with the general population. METHODS:All adults with CHB who cleared HBsAg between 2000 and 2022 were identified using a territory-wide database in Hong Kong. Annual HCC incidences were estimated and compared with the general population. Age- and sex-specific population statistics were retrieved from the Hong Kong Cancer Registry and Census and Statistics Department. RESULTS:Of 13,379 patients with HBsAg seroclearance (mean age, 59.7 ± 13.7 years; 59.8% men, 14.6% cirrhosis), HCC developed in 274 (2.0%) at a median of 5.6 years (25th-75th percentile, 3.1-9.8 years). Annual HCC incidence was 0.43% (95% confidence interval [CI], 0.22%-0.73%) and 0.62% (95% CI, 0.50%-0.76%) among patients with cirrhosis aged <50 years and ≥50 years at HBsAg seroclearance, respectively. In patients without cirrhosis who cleared HBsAg before age 50, the annual HCC incidence was 0.03% (95% CI, 0.01%-0.06%), comparable to 0.03% in general population. Annual HCC incidence of male patients without cirrhosis aged <40 and 40 to 49 years at HBsAg was 0.02% (95% CI, 0.002%-0.08%) and 0.09% (95% CI, 0.03%-0.19%), respectively. No HCC cases occurred during 15 years/ of follow-up among 1317 female patients without cirrhosis aged <50 years at HBsAg loss; the annual HCC incidence was 0.06% (95% CI, 0.02%-0.13%) among those aged 50 to 59 years. CONCLUSIONS:Patients with CHB who clear HBsAg at younger ages, particularly men <40 years and women <50 years without cirrhosis or additional risk factors, have very low HCC risk and may not require routine surveillance.

BACKGROUND:The role of alanine aminotransferase (ALT) dynamics during nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) is unclear. We aimed to evaluate the correlation between ALT dynamics and liver-related events (LRE), and explore the optimal threshold of ALT during NA treatment. METHODS:We enrolled 18,129 NA-treated patients, comprising 3104 patients from the Search-B study (NCT02167503) and 15,025 patients from a real-world cohort in Hong Kong. Latent-class mixed model (LCMM) was adopted to identify trajectory patterns of ALT during treatment. ALT value at the 95th percentile of the trajectory group with the lowest LRE risk was obtained as the optimal threshold. RESULTS:During a median follow-up of 53.3 months, 1164 patients developed LRE with a 7-year cumulative incidence of 9.9%. In the Search-B cohort, LCMM recognised 3 trajectory groups with progressively increasing ALT levels, which were positively associated with LRE risk. Subsequently, the optimal thresholds for ALT were obtained as 23 U/L for men and 16 U/L for women. The 7-year cumulative incidence of LRE was 5.5% for ALT ≤ 23 or 16 U/L, significantly lower than that for ALT > 23 or 16 U/L but ≤ 40 U/L (10.8%; aHR = 2.0, p < 0.001), and ALT > 40 U/L (15.1%; aHR = 3.4, p < 0.001). Similarly, in the Hong Kong cohort, ALT > 23 or 16 U/L but < 40 U/L and ALT > 40 U/L also increased the LRE risk, with aHRs of 2.0 (p = 0.003) and 6.1 (p < 0.001), respectively. CONCLUSION:On-treatment ALT levels were significantly correlated with the prognosis of CHB. ALT ≤ 23 U/L for men and ≤ 16 U/L for women were identified as the optimal thresholds during NA treatment, suggesting that CHB patients should strive for a lower ALT level beyond the traditional normal range.

1Medical Data Analytics Centre 2Department of Medicine and Therapeutics 3State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China 4Department of Internal Medicine, Union Hospital, Hong Kong SAR, China Abbreviations: HBV, hepatitis B virus; NA, nucleos(t)ide analogues; WHO, World Health Organization. Correspondence Grace Lai-Hung Wong, Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong. Email: [email protected]

ABSTRACTPurposeRecent research (Li et al. 2021) suggests an upregulated expression and activation of H1 receptors on macrophages in the tumor microenvironment, and concomitant H1‐antihistamine use is associated with improved overall survival in patients with lung and skin cancers receiving immunotherapy. Therefore, we retrospectively evaluated the impacts of H1‐antihistamine use in cancer patients during immunotherapy.MethodsAll patients who had received at least one dose of immune checkpoint inhibitors (ICIs) from July 1, 2014 to October 31, 2019 were identified from Hong Kong's territory‐wide database, with this date defined as the baseline. A 1‐month landmark analysis was conducted with follow–for up to 6 months, including an exposure period of 1 month before and after the baseline date. Patients were grouped according to the types of primary cancer and the percentages of daily H1‐antihistamine usage within the exposure period. The primary outcome was overall survival.ResultsA total of 1740 (65.1% male, mean age 61.9 years) were included in the landmark analysis, of which 529 (30.4%) and 307 (17.6%) had primary lung and liver malignancies. The multivariable Cox regression model estimated statistically significant improvement in overall survival of intermediate use in patients with primary lung malignancies (adjusted hazard ratio [aHR] 0.223, 95% confidence interval [CI] 0.052–0.958, p = 0.044), but not with primary liver maligancies. Similar frequency‐dependent effects were identified in Kaplan–Meier analysis.ConclusionThe benefits of adjunctive use of H1‐antihistamines may be generation‐ and tumor‐dependent. Further clinical and mechanistic studies are required to confirm the findings.

BACKGROUND:Current and past hepatitis B virus (HBV) infection remains the leading cause of liver cancer in endemic areas. AIM:To examine the risk of HBV reactivation (HBVr) in patients receiving immune checkpoint inhibitors (ICI) for liver cancer. METHODS:Patients with current or past HBV infection receiving systemic treatments for liver cancer from March 2015 to March 2023 were identified using a territory-wide electronic database in Hong Kong. The primary outcome was HBVr in ICI compared to tyrosine kinase inhibitor (TKI) use, defined according to the American Association for the Study of Liver Diseases criteria. The secondary outcome was HBVr in different types of ICI. RESULTS:One thousand five hundred and ninty-six patients with current or past HBV infection (222 first received ICI; 1374 first received TKI) were included. 205 patients (12.8%) had past HBV infection, and 93.2% of the cohort were on HBV antiviral prophylaxis at baseline. At a median of 10.7 months (IQR: 3.7-12.0), 25 (1.6%) patients had HBVr, among whom 5 were exposed to ICI. The 12-month cumulative incidence (95% CI) of HBVr of the 1596 patients was 1.7% (1.1%-2.4%). The proportion of patients experiencing HBVr with and without antiviral prophylaxis was 1.4% and 3.7%, respectively. In multivariable analysis, ICI use was not associated with a higher risk of HBVr than TKI use, and the use of different ICI did not impact the risk of HBVr. CONCLUSION:With adequate antiviral prophylaxis, the absolute risk of HBVr is low in advanced HBV-related liver cancer patients receiving ICI, regardless of current or past HBV infection.

BACKGROUND AND AIMS:Linkage of hepatitis B virus (HBV)-infected individuals to medical care is a major hurdle in the HBV elimination care cascade. This study aimed to investigate the rate and factors influencing specialist referral of HBV cases identified in health check programs. METHODS:This was a retrospective study among consecutive individuals undergoing health check programs with hepatitis B surface antigen (HBsAg) tested in a hospital from 2014 to 2023. Clinical data were captured from the hospital electronic database. Letter of referral after health check was recorded. RESULTS:A total of 28 940 individuals underwent health check with HBsAg tested. Six hundred and seventy-three HBsAg-positive individuals were eligible for analysis. Overall, 322 (47.8%) individuals received referral to hepatology specialist. There was a trend of increasing referral with time over the 10 years; trend slope (95% confidence interval): 5.0% (3.5%-6.4%) per year; p < 0.001. HBV DNA was tested in 207 (30.8%) individuals. On multivariable analysis, with reference to individuals with no HBV DNA tested, HBV DNA ≥ 2000 IU/mL was the strongest independent factor associated with referral (adjusted odds ratio 21.42; 95% confidence interval 8.79-52.24; p < 0.001). Detectable HBV DNA < 2000 IU/mL had a modest association with referral (adjusted odds ratio 1.84; 95% confidence interval 1.08-3.11; p = 0.024). CONCLUSIONS:Elevated HBV DNA is an important factor associated with specialist referral among HBsAg-positive individuals identified at health check programs. These findings suggest that implementing reflex HBV DNA testing could be a key strategy to improve specialist referral and facilitate linkage to care.

BACKGROUND & AIMS:The presence of metabolic comorbidities is associated with a higher risk of liver-related events in chronic hepatitis B (CHB) patients. However, the association between presence of metabolic comorbidities and the severity of biopsy-proven liver fibrosis is yet unknown. METHODS:Data from CHB patients from 2 tertiary clinics and 8 clinical trials was analyzed. We studied the association between presence of metabolic comorbidities with severity of liver fibrosis in untreated patients, and with fibrosis regression or progression in biopsies taken after initiation of antiviral therapy. RESULTS:We analyzed biopsies from 3179 untreated CHB patients. Median age was 37 years, 57.6% were hepatitis B e antigen positive, with median hepatitis B virus DNA of 7.30 logIU/mL. Overweight (29.4% vs 19.0%; P < .001), hypertension (40.7% vs 23.2%; P < .001), diabetes (42.2% vs 23.6%; P < .001), and dyslipidemia (42.9 vs 23.6%; P < .001) were associated with a higher risk of advanced fibrosis, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in multivariable analysis (1 comorbidity: adjusted odds ratio [aOR], 1.115; ≥2 comorbidities: aOR, 1.627; P = .006). Regression to nonadvanced fibrosis, after treatment initiation, was more often observed in patients without metabolic comorbidities (43.1%), compared with patients with 1 (31.6%) or ≥2 comorbidities (17.0%) (P = .005). Findings were consistent in multivariable analysis (1 comorbidity: aOR, 0.792; ≥2 comorbidities: aOR, 0.260; P = .025). The risk of progression to advanced fibrosis was highest in patients with ≥2 comorbidities (14.3% vs 4.6%; P = .001). CONCLUSIONS:Presence of metabolic comorbidities in untreated CHB patients is associated with more severe liver fibrosis and, after initiation of antiviral therapy, with less fibrosis regression and a higher risk of fibrosis progression.

BACKGROUND AND AIMS:The outcomes and benefits of antiviral therapy in patients with indeterminate phase HBeAg-negative chronic hepatitis B are not well described in treatment guidelines. We examined HCC risk among these patients. APPROACH AND RESULTS:We identified all non-cirrhotic treatment-naïve patients with HBeAg-negative chronic hepatitis B who received ≥1 test for HBV DNA and HBeAg. HBeAg-negative indeterminate phase included abnormal ALT (≥40 IU/L) and low HBV DNA (<2000 IU/mL), or normal ALT (<40 IU/L) and high HBV DNA (≥2000 IU/mL). Cox model evaluated the relationship between HBV phase and HCC risk, with antiviral therapy as a time-dependent variable. In 17,287 patients (mean age 54.1 y, 50% male), 4071 (24%) transitioned to HBeAg-negative chronic hepatitis, 8722 (50%) remained in the indeterminate phase, and 4494 (26%) moved to HBeAg-negative chronic infection over a median follow-up of 55.1 (IQR: 21.3-105.4) months. Patients in the indeterminate phase had a significantly higher HCC risk than those in chronic infection (adjusted hazard ratio: 1.587, 95% CI: 1.262-1.995). Among patients in the indeterminate phase, those with normal ALT and high HBV DNA had a higher HCC risk than those with abnormal ALT and low HBV DNA (adjusted hazard ratio: 1.377, 95% CI: 1.007-1.883, p =0.045). The 5-year cumulative HCC incidence showed no significant difference between treated and untreated patients in either group. CONCLUSIONS:In patients with indeterminate phase HBeAg-negative chronic hepatitis B, those with normal ALT and high HBV DNA showed a higher HCC risk than those with abnormal ALT and low HBV DNA, with no difference between treated and untreated patients in either group. Close monitoring with timely antiviral treatment may suffice to mitigate HCC risk in untreated patients.

Background & Aims: The outcomes and benefits of antiviral therapy in patients with indeterminate phase HBeAg-negative chronic hepatitis B (CHB) are not well described in treatment guidelines. We examined hepatocellular carcinoma (HCC) risk among these patients. Approach & Results: We identified all non-cirrhotic treatment-na & iuml;ve patients with HBeAg-negative CHB who received >= 1 test for hepatitis B virus (HBV) DNA and HBeAg. HBeAg-negative indeterminate phase included abnormal alanine aminotransferase (ALT >= 40 IU/L) and low HBV DNA (<2,000 IU/mL), or normal ALT (<40 IU/L) and high HBV DNA (>= 2,000 IU/mL). Cox model evaluated relationship between HBV phase and HCC risk, with antiviral therapy as time-dependent variable. In 17,287 patients (mean age 54.1 years, 50% male), 4,071 (24%) transitioned to HBeAg-negative chronic hepatitis, 8,722 (50%) remained in the indeterminate phase, and 4,494 (26%) moved to HBeAg-negative chronic infection over a median follow-up of 55.1 [interquartile range 21.3-105.4] months. Patients in the indeterminate phase had a significantly higher HCC risk than those in chronic infection (adjusted hazard ratio [aHR] 1.587, 95% CI 1.262-1.995). Among patients in the indeterminate phase, those with normal ALT and high HBV DNA had a higher HCC risk than those with abnormal ALT and low HBV DNA (aHR 1.377, 95% CI 1.007-1.883, p=0.045). The 5-year cumulative HCC incidence showed no significant difference between treated and untreated patients in either group. Conclusions: In patients with indeterminate phase HBeAg-negative CHB, those with normal ALT and high HBV DNA showed a higher HCC risk than those with abnormal ALT and low HBV DNA, with no difference between treated and untreated patients in either group. Close monitoring with timely antiviral treatment may suffice to mitigate HCC risk in untreated patients.

INTRODUCTION: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS: This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS: Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION: Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.

BACKGROUND & AIMS: The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy, and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs). METHODS: MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in 2 prospective cohorts from Hong Kong (HK) (N = 2732) and Europe (N = 2384). Model performance was assessed according to Harrell's C -index and time -dependent receiver operating characteristic (ROC) curve. RESULTS: We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's Cindex of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval, 0.85-0.92) and 0.91 (95% confidence interval, 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years was double dagger 0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and 7 hepatitis B-related risk scores. Using dual cutoffs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low -risk group and 2.54%-4.64% for high -risk group in the HK and Europe validation cohorts. CONCLUSIONS: The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.

AbstractHepatocellular carcinoma (HCC) is often detected at advanced stages among patients with hepatitis B virus (HBV), underscoring the urgency for more precise surveillance tests. Here, we compare the clinical performance of the novel - GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], protein-induced by vitamin K absence-II [PIVKA-II]) and GALAD (gender [biological sex], age, AFP, Lens-culinaris AFP [AFP-L3]), PIVKA-II) algorithms to assess the utility of AFP-L3 for distinguishing HCC from benign chronic liver disease (CLD) in Chinese patients with predominantly chronic HBV infection. Eligible adults were enrolled, and biomarkers were measured using Elecsys (Cobas) or µTASWAKO assays. In total, 411 participants provided serum samples (HCC, n = 176 [early-stage, n = 110]; CLD, n = 136; specificity n = 101). HBV was the underlying disease etiology for most participants (HCC, 95%; benign CLD, 72%). For GAAD (Cobas), GALAD (Cobas), and GALAD (µTASWAKO), AUCs were 93.1% (95% CI: 90.0–96.2), 93.2% (90.0–96.3), and 92.7% (88.4–96.9) for early-stage, and 95.6% (93.6–97.6), 95.6% (93.6–97.7), and 95.8% (93.2–98.3) for all-stage HCC, versus CLD, respectively. Interestingly, both GAAD and GALAD algorithms demonstrated comparable diagnostic performance regardless of disease etiology (HBV vs. non-HBV), presence of cirrhosis, geographic region, and within pan-tumor specificity panels (p < 0.001), indicating AFP-L3 may have a negligible role in HCC surveillance.

Background To develop innovative risk models for predicting liver-related events including hepatic decompensation and hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods The training cohort included adult patients with MASLD from a territory-wide database in Hong Kong between January 2000 and July 2021. Five modern domain adaptation (DA) methods on fully connected neural networks were evaluated using the area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with the FIB-4 index, NAFLD outcomes score (NOS), and a Fine-Gray model. The validation cohort comprised adult patients with type 2 diabetes (T2D) and probable MASLD, identified using previously developed NAFLD ridge score. We excluded patients with liver-related events before MASLD diagnosis or follow-up <6 months. This study was supported by the Health and Medical Research Fund (Reference number: 19202141). Results Among 25,166 patients with MASLD in the training cohort (mean age 56.9 years, 54.3% females, 0.7% cirrhosis), 272 (1.1%) developed liver-related events during 133,816 person-years (PYs). During 4,386,544 PYs among 411,395 patients in the validation cohort (mean age 61.8 years, 49.3% females, 0.4% cirrhosis), 5,984 (1.5%) developed liver-related events. Among the five DA methods, maximum classifier discrepancy (MCD) (AUROC [95% CI] 0.822 [0.814-0.829]) and confidence regularised self-training (CRST) (0.825 [0.817-0.832]) performed best in validation (IDDF2024-ABS-0124 Figure 1). The AUROC of the Fine-Gray model decreased from 0.804 in training to 0.681 in validation, demonstrating the advantage of DA in preserving model accuracy in a less definite MASLD population. Similarly, the AUROC of NOS and FIB-4 dropped to 0.649 and 0.645 in validation. Among the 19 factors, including common laboratory tests, comorbidities, and demographics in MCD and CRST, the eight leading factors were cirrhosis, diabetes, platelets, aspartate aminotransferase, gamma-glutamyl transferase, international normalised ratio, dyslipidaemia, and albumin. MCD labelled 78.6% of patients with T2D and MASLD as low risk, achieving a 99.2% negative predictive value for excluding liver-related events in 15 years. Conclusions Our novel models, integrating common clinical parameters, effectively identify low-risk individuals for liver-related events among patients with MASLD and patients with T2D and probable MASLD.