Noninvasive tests for liver fibrosis in 2024: are there different scales for different diseases?

Liver fibrosis is the common pathway from various chronic liver diseases and its progression leads to cirrhosis which carries a significant risk for the development of portal hypertension-related complications and hepatocellular carcinoma. It is crucial to identify and halt the worsening of liver fibrosis given its important prognostic implication. Liver biopsy is the gold standard for assessing the degree of liver fibrosis but is limited due to its invasiveness and impracticality for serial monitoring. Many noninvasive tests have been developed over the years trying to assess liver fibrosis in a practical and accurate way. The tests are mainly laboratory- or imaging-based, or in combination. Laboratory-based tests can be derived from simply routine blood tests to patented laboratory parameters. Imaging modalities include ultrasound and magnetic resonance elastography, in which vibration-controlled transient elastography is the most widely validated and adopted whereas magnetic resonance elastography has been proven the most accurate liver fibrosis assessment tool. Nonetheless, noninvasive tests do not always apply to all liver diseases, nor does a common cut-off value of a test mean the same degree of liver fibrosis in different scenarios. In this review, we discuss the diagnostic and prognostic performance, as well as the confounders and limitations, of different noninvasive tests on liver fibrosis assessment in various liver diseases.

Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B.

BACKGROUND & AIMS: The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB). METHODS: Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching. RESULTS: A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1-58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56-1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11-2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%-3.4%) vs. 2.6% (1.9%-3.5%), 6.4% (5.0%-8.2%) vs. 4.7% (3.8%-6.0%), and 10.2% (8.3%-12.6%) vs. 6.8% (5.4%-8.5%), respectively. CONCLUSIONS: The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities. IMPACT AND IMPLICATIONS: Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.

MAFLD fibrosis score: Using routine measures to identify advanced fibrosis in metabolic-associated fatty liver disease.

BACKGROUND: Early screening may prevent fibrosis progression in metabolic-associated fatty liver disease (MAFLD). AIMS: We developed and validated MAFLD fibrosis score (MFS) for identifying advanced fibrosis (≥F3) among MAFLD patients. METHODS: This cross-sectional, multicentre study consecutively recruited MAFLD patients receiving tertiary care (Malaysia as training cohort [n = 276] and Hong Kong and Wenzhou as validation cohort [n = 431]). Patients completed liver biopsy, vibration-controlled transient elastography (VCTE), and clinical and laboratory assessment within 1 week. We used machine learning to select 'highly important' predictors of advanced fibrosis, followed by backward stepwise regression to construct MFS formula. RESULTS: MFS was composed of seven variables: age, body mass index, international normalised ratio, aspartate aminotransferase, gamma-glutamyl transpeptidase, platelet count, and history of type 2 diabetes. MFS demonstrated an area under the receiver-operating characteristic curve of 0.848 [95% CI 0.800-898] and 0.823 [0.760-0.886] in training and validation cohorts, significantly higher than aminotransferase-to-platelet ratio index (0.684 [0.603-0.765], 0.663 [0.588-0.738]), Fibrosis-4 index (0.793 [0.735-0.854], 0.737 [0.660-0.814]), and non-alcoholic fatty liver disease fibrosis score (0.785 [0.731-0.844], 0.750 [0.674-0.827]) (DeLong's test p < 0.05). MFS could include 92.3% of patients using dual cut-offs of 14 and 15, with a correct prediction rate of 90.4%, resulting in a larger number of patients with correct diagnosis compared to other scores. A two-step MFS-VCTE screening algorithm demonstrated positive and negative predictive values and overall diagnostic accuracy of 93.4%, 89.5%, and 93.2%, respectively, with only 4.0% of patients classified into grey zone. CONCLUSION: MFS outperforms conventional non-invasive scores in predicting advanced fibrosis, contributing to screening in MAFLD patients.

Risk and predictors of hepatic decompensation in grey zone patients by the Baveno VII criteria: A competing risk analysis.

BACKGROUND: Baveno VII was proposed for non-invasive identification of clinically significant portal hypertension. However, a substantial proportion of patients is classified in the grey zone (i.e., liver stiffness 15-24.9 kPa and/or platelet count <150 × 109 /L). AIMS: To evaluate the risk and predictors of hepatic decompensation in patients in the grey zone, and to determine the prognostic role of spleen stiffness measurement. METHODS: We included prospective cohorts (from Hong Kong, Korea and France) of patients who had undergone transient elastography examination for chronic liver disease. We estimated risk of hepatic decompensation using competing risk regression with hepatocellular carcinoma and non-liver-related death as competing events. RESULTS: We identified 2763 patients with compensated advanced chronic liver disease (cACLD). There were 1243 (44.9%) and 536 (19.4%) patients in the Baveno VII grey zone and high-risk groups, respectively. The cumulative incidence of decompensation at 5 years was significantly different among low-risk (0.6% [95% CI: 0.2%-1.3%]), grey zone 4.2% (95% CI: 3.1%-5.4%) and high-risk groups (11.4% [95% CI: 8.7%-14.6%]). By competing risk analysis, aetiology of liver disease (alcohol-related liver disease), albumin-bilirubin score and alkaline phosphatase level were independently associated with decompensation among patients in the grey zone. The combination of Baveno VII and spleen stiffness significantly reduced patients classified into grey zone (12.8% in cACLD patients), while maintaining high discrimination of decompensation in low- and high-risk groups. CONCLUSIONS: Patients in grey zone of Baveno VII criteria remain at high risk of hepatic decompensation. Clinical risk factors and spleen stiffness can further stratify the risk in such patients.

Baveno VII criteria for recompensation predict transplant-free survival in patients with hepatitis B-related decompensated cirrhosis.

Background & Aims: The latest Baveno VII consensus has provided guidance for identifying patients who have truly recompensated from those with hepatic decompensation. This study aimed to evaluate patients' transplant-free survival in three different stages of cirrhosis. Methods: All patients with chronic HBV infection and liver cirrhosis treated with oral nucleos(t)ide analogues from March 2006 to December 2022 were identified from a territory-wide database in Hong Kong. Patients with follow-up duration of <1 year were excluded. Participants were classified into three mutually exclusive groups: (1) no decompensated events (i.e. compensated group); (2) decompensated events occurred (i.e. decompensated group); or (3) decompensated events occurred followed by recompensation according to Baveno VII criteria (i.e. recompensated group). A time-dependent Cox proportional hazard model was adopted for evaluation. The follow-up period was 5 years. Results: A total of 4,701 patients with cirrhosis and HBV who were treated with entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) were identified. During a median follow-up of 5 years (interquartile range 3.7, 5 years), 3,327 (70.8%), 1,347 (29.2%), and 265 (5.6%) patients had compensated, decompensated, and recompensated cirrhosis, respectively, at least once before the end of the study. In the time-dependent multivariable model, the recompensated group had similar transplant-free survival compared with the compensated group (adjusted hazard ratio 1.16; 95% CI 0.72-1.86; p = 0.536). The 5-year transplant-free survival rate was 89.3% for the compensated group, whereas it was 76.0% for the recompensated group, reflecting a minimal difference between the two groups. Conclusions: The clinical significance of recompensation of cirrhosis in improving patient outcomes for individuals with CHB infection was highlighted in this study. Early identification and treatment with nucleos(t)ide analogues might promote hepatic recompensation and thus reduce mortality in patients with CHB. Impact and implications: The latest Baveno VII consensus introduces the new concept of hepatic recompensation, which refers to the reversal of the structural and functional changes of cirrhosis after removal, cure, or suppression of the aetiology of cirrhosis. It is essential to investigate the transplant-free survival rates of patients who are able to achieve hepatic recompensation, as this has significant implications for the medical resources required to manage liver failure and transplantation. This study features the clinical significance of hepatic recompensation by comparing patient outcomes of those who achieve it to those who do not. The early identification and use of antiviral treatment with nucleos(t)ide analogues is a pivotal strategy to promote hepatic recompensation, which has the potential to significantly reduce mortality rates in patients with chronic HBV infection and ultimately aid in the elimination of hepatitis.

Clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomised controlled trial.

OBJECTIVE: We aimed to test the hypothesis that automated fibrosis score calculation and electronic reminder messages could increase the detection of advanced liver disease in patients with type 2 diabetes. DESIGN: In this pragmatic randomised controlled trial at five general medical or diabetes clinics in Hong Kong and Malaysia, we randomly assigned patients in a 1:1 ratio to the intervention group with Fibrosis-4 index and aspartate aminotransferase-to-platelet ratio index automatically calculated based on routine blood tests, followed by electronic reminder messages to alert clinicians of abnormal results, or the control group with usual care. The primary outcome was the proportion of patients with increased fibrosis scores who received appropriate care (referred for hepatology care or specific fibrosis assessment) within 1 year. RESULTS: Between May 2020 and Oct 2021, 1379 patients were screened, of whom 533 and 528 were assigned to the intervention and control groups, respectively. A total of 55 out of 165 (33.3%) patients with increased fibrosis scores in the intervention group received appropriate care, compared with 4 of 131 (3.1%) patients in the control group (difference 30.2% (95% CI 22.4% to 38%); p<0.001). Overall, 11 out of 533 (2.1%) patients in the intervention group and 1 out of 528 (0.2%) patients in the control group were confirmed to have advanced liver disease (difference 1.9% (95% CI 0.61% to 3.5%); p=0.006). CONCLUSION: Automated fibrosis score calculation and electronic reminders can increase referral of patients with type 2 diabetes and abnormal fibrosis scores at non-hepatology settings. TRIAL REGISTRATION NUMBER: NCT04241575.

Incidence of hepatocellular carcinoma and mortality in chronic viral hepatitis in an Asian population with and without HIV infection.

BACKGROUND: It is uncertain whether people with HIV infection have a higher incidence of hepatocellular carcinoma (HCC) than the general population. AIMS: To compare the incidence of HCC between people infected with HBV and/or HCV with and without HIV METHODS: We performed a retrospective population-based cohort study, involving people with HBV and/or HCV infection from 2001 to 2018. The primary endpoint was incidence of HCC; secondary endpoint was all-cause mortality. We performed Cox proportional hazard regression models to estimate the hazard ratios (HR) of HIV for the primary and secondary endpoints. RESULTS: We identified 1374 people infected with HIV and 39,908 people without HIV with HBV and/or HCV infection. Among those with HIV, 654 (47.6%) had HBV, 649 (47.2%) HCV and 71 (5.2%) HBV-HCV-co-infection; they were younger, and had a higher prevalence of HCV and a lower prevalence of cirrhosis. The incidence rate estimates of HCC were, respectively, 1.5 (95% CI: 0.8-2.5) and 7.6 (95% CI 7.3-8.0) per 1000 person-years for those with and without HIV infection. Using multivariate Cox proportional hazard regression models, among people with HBV, HIV was associated with lower risk of HCC (adjusted HR: 0.376, 95% CI: 0.201-0.704, p = 0.01) and death (adjusted HR: 0.692, 95% CI: 0.552-0.867, p = 0.007). Risks of HCC were similar for HCV and HBV-HCV co-infection for people with and without HIV. CONCLUSIONS: Among individuals with HBV infection, the Incidence of HCC was lower in those with HIV. For HCV infection, incidence of HCC was similar between those with and without HIV.

Baveno VII criteria identify varices needing treatment in patients with hepatocellular carcinoma of different Barcelona Clinic Liver Cancer stages.

BACKGROUND: Baveno VII criteria for predicting varices needing treatment (VNT) have not been tested in hepatocellular carcinoma (HCC) population. We evaluated Baveno VII consensus for VNT in HCC patients of different stages according to Barcelona Clinic Liver Cancer (BCLC) stages undergoing curative hepatectomy. METHODS: This was a prospective cohort study of patients with HCC. Patients underwent transient elastography examination before HCC treatment and received at least one upper endoscopic examination afterwards. Patients were prospectively followed for clinical events including VNT. RESULTS: Six hundred and seventy-three patients (83.1% male, median age 62 years) with HCC of BCLC stage 0 (10%), A (57%), B (17%) and C (15%) were recruited and followed for 47 months. The median (range) LSM was 10.5 (6.9-20.4) kPa; 74% had LSM ≤ 20 kPa and 58% had platelet count ≥150 × 10/L, respectively. VNT occurred in 51 (7.6%) patients. In patients who fulfilled Baveno VII criteria, that is, LSM ≤ 20 kPa and platelet count above 150 × 10/L, only 11 (1.6%) patients had VNT. In all BCLC stages of HCC, the proportion of patients with VNT was below 5%, which support the validity and applicability of Baveno VII criteria in all BCLC stages of HCC. CONCLUSIONS: The Baveno VII criteria are valid and applicable in HCC patients undergoing curative hepatectomy for selecting patients to undergo screening endoscopy for VNT. The validity was consistent across different BCLC stages of HCC.

Baveno VII Criteria Is an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and Hepatic Events in Patients with Advanced Hepatocellular Carcinoma.

The Baveno VII criteria are used in patients with liver cirrhosis to predict high-risk varices in patients with liver cirrhosis. Yet its use in patients with advanced hepatocellular carcinoma (HCC) has not been validated. HCC alone is accompanied with a higher variceal bleeding risk due to its association with liver cirrhosis and portal vein thrombosis. The use of systemic therapy in advanced HCC has been thought to further augment this risk. Upper endoscopy is commonly used to evaluate for the presence of varices before initiation of treatment with systemic therapy. Yet it is associated with procedural risks, waiting time and limited availability in some localities which may delay the commencement of systemic therapy. Our study successfully validated the Baveno VI criteria with a 3.5% varices needing treatment (VNT) missed rate, also with acceptable <5% VNT missed rates when considering alternative liver stiffness (LSM) and platelet cut-offs. The Baveno VII clinically significant portal hypertension rule-out criteria (LSM < 15 kPa and platelet >150 × 109/L) also revealed a low frequency (2%) of hepatic events, whilst the rule-in criteria (LSM > 25 kPa) was predictive of a higher proportion of hepatic events (14%). Therefore, our study has successfully validated the Baveno VII criteria as a non-invasive stratification of the risk of variceal bleeding and hepatic decompensation in the HCC population.

Duration of type 2 diabetes and liver-related events in nonalcoholic fatty liver disease: A landmark analysis.

BACKGROUND AND AIMS: We aimed to determine the impact of the duration of type 2 diabetes (T2D) on the risk of liver-related events and all-cause mortality in patients with NAFLD. APPROACH AND RESULTS: We conducted a territory-wide cohort study of adult patients with NAFLD diagnosed between January 1, 2000, and July 31, 2021, in Hong Kong. T2D was defined by the use of any antidiabetic agents, laboratory tests, and/or diagnosis codes. The primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications. To conduct a more granular assessment of the duration of T2D, we employed landmark analysis in four different ages of interest (biological age of 40, 50, 60, and 70 years). By multivariable analysis with adjustment of non-liver-related deaths, compared with patients without diabetes at age 60 (incidence rate of liver-related events: 0.70 per 1,000 person-years), the adjusted subdistribution HR (SHR) of liver-related events was 2.51 (95% CI: 1.32-4.77; incidence rate: 2.26 per 1,000 person-years) in patients with T2D duration < 5 years, 3.16 (95% CI: 1.59-6.31; incidence rate: 2.54 per 1,000 person-years) in those with T2D duration of 6-10 years, and 6.20 (95% CI: 2.62-14.65; incidence rate: 4.17 per 1000 person-years) in those with T2D duration more than 10 years. A similar association between the duration of T2D and all-cause mortality was also observed. CONCLUSIONS: Longer duration of T2D is significantly associated with a higher risk of liver-related events and all-cause mortality in patients with NAFLD.

Diabetes Mellitus Impacts on the Performance of Hepatocellular Carcinoma Risk Scores in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: We examined whether changing clinical characteristics and presence of diabetes mellitus (DM) impact the performance of hepatocellular carcinoma (HCC) risk scores. METHODS: Adult patients with chronic hepatitis B (CHB) on ≥6 months of entecavir/tenofovir treatment between January 2005 and March 2020 were identified using a territory-wide electronic database in Hong Kong. DM was defined by antidiabetic agents, hemoglobin A1c ≥6.5%, fasting glucose ≥7 mmol/L, and/or diagnosis codes. PAGE-B, modified PAGE-B (mPAGE-B), and aMAP scores were assessed by area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with CAMD and REAL-B scores with DM as a component. RESULTS: Of 48,706 patients, 2792, 11,563, 15,471, and 18,880 started entecavir/tenofovir treatment between 2005-2008, 2009-2012, 2013-2016, and 2017-2020, respectively; DM prevalence rose from 15.5% in 2005-2008 to 24.3% in 2017-2020. AUROCs were comparable across the 4 periods in the 5 HCC risk scores (AUROCs ranged between 0.75 and 0.81). At a median follow-up of 4.4 years, 1512 non-diabetic (4.0%) and 645 (6.2%) diabetic patients developed HCC. AUROCs of all 5 scores were lower in diabetic patients than in non-diabetic patients (AUROCs ranged between 0.67-0.71 vs 0.78-0.82; all P < .001). REAL-B score achieved an AUROC of 0.71 in diabetic and 0.82 in non-diabetic patients. Both diabetic and non-diabetic patients in the low-risk group by REAL-B score had a low HCC incidence below the threshold of cost-effective HCC surveillance, ie, 0.2% annually. CONCLUSIONS: REAL-B score is accurate and preferred in entecavir/tenofovir-treated CHB patients because of the increasing prevalence of DM.

Trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease and type 2 diabetes between 2000 and 2020: A territory-wide study.

BACKGROUND & AIMS: We aimed to determine the trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) in 2000-2020. METHODS: We conducted a territory-wide cohort study of adult patients with NAFLD and T2D diagnosed between 1 January 2000 and 31 July 2021 in Hong Kong. T2D was defined by use of any anti-diabetic agents, laboratory tests and/or diagnosis codes. RESULTS: This study included 16,084 patients with NAFLD and T2D (mean age, 54.8 ± 12.0 years; 7124 male [44.3%]). The percentage of patients achieving individualised haemoglobin A1c (HbA1c ) targets increased from 44.5% (95% confidence interval [CI], 42.9-46.1) to 64.8% (95% CI, 64.1-65.5), and percentage of patients achieving individualised low-density lipoprotein-cholesterol (LDL-C) targets increased from 23.3% (95% CI, 21.9-24.7) to 54.3% (95% CI, 53.5-55.1) from 2000-2005 to 2016-2020, whereas percentage of patients achieving blood pressure control (<140/90 mm Hg) remained static at 53.1-57.2%. Combination therapy for diabetes increased, especially among those with poor glycaemic control, but there was no increase in combination therapy for hypertension. Fewer cirrhotic patients achieved blood pressure control and individualised LDL-C targets, but they were more likely to achieve individualised HbA1c targets than non-cirrhotics. Metformin and statins were underused in cirrhotic patients. Younger patients (18-44 years) were less likely to achieve individualised HbA1c targets than middle-aged (45-64 years) and older ones (≥65 years). CONCLUSIONS: From 2000 to 2020, glycaemic and lipid control improved significantly, whereas blood pressure control remained static among patients with NAFLD and T2D.

Age and the relative importance of liver-related deaths in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: It is unclear if the leading causes of death in patients with NAFLD differ by age. We aimed to investigate if the relative importance of liver-related deaths is lower and overshadowed by cardiovascular and cancer-related deaths in the elderly population. APPROACH AND RESULTS: We conducted a territory-wide retrospective cohort study of adult patients with NAFLD between 2000 and 2021 in Hong Kong. The outcomes of interest were all-cause and cause-specific mortality. Age groups at death were studied at 10-year intervals. During 662,471 person-years of follow-up of 30,943 patients with NAFLD, there were 2097 deaths. The top three causes of death were pneumonia, extrahepatic cancer, and cardiovascular diseases. Liver disease was the sixth leading cause of death in patients aged 70-79 and 80-89 years, accounting for 5.1% and 5.9% of deaths, respectively, but only accounted for 3% or fewer of the deaths in the other age groups. Nonetheless, liver disease was the leading cause of death in patients with NAFLD-related cirrhosis, accounting for 36.8% of all deaths. The incidence of liver-related death was higher in men younger than age 70 but higher in women afterwards. The incidence of liver-related death in women increased from 0.62 to 7.14 per 10,000 person-years from age 60-69 to 70-79 years. CONCLUSION: The relative importance of liver-related death increases with age in patients with NAFLD, especially among women. In patients with cirrhosis, liver disease is the leading cause of death.

Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss.

BACKGROUND & AIMS: We examined the long-term incidence of hepatocellular carcinoma (HCC) and hepatic decompensation among chronic hepatitis B (CHB) patients who have achieved hepatitis B surface antigen (HBsAg) seroclearance. METHODS: All adult CHB-monoinfected patients who cleared HBsAg between January 2000 and December 2020 were identified using a territory-wide database in Hong Kong. Patients who underwent liver transplantation and/or developed HCC before HBsAg seroclearance or less than 6 months follow-up were excluded. The primary and secondary endpoints were HCC and hepatic decompensation respectively. RESULTS: We identified 9,769 patients with CHB who achieved HBsAg seroclearance (mean age 57 years, 60.0% male, 13.2% cirrhosis); most had compensated liver function at HBsAg loss. At a median (25th-75th percentile) follow-up of 4.6 (2.2-8.4) years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and have cirrhosis, and had higher alanine aminotransferase and lower platelets at the time of HBsAg loss than patients without HCC. The cumulative incidence of HCC remained steady 0-7 and 8-12 years after HBsAg loss (p = 0.898) (crude annual incidence drop: -0.04%, 95% CI -0.13% to 0.04%, p = 0.265). Moreover, 124/9,640 (1.3%) patients developed hepatic decompensation. The growth in cumulative incidence of hepatic decompensation decelerated 8-12 years after HBsAg loss (p = 0.009) (crude annual incidence drop: -0.23%, 95% CI -0.40% to -0.06%, p = 0.012). In multivariable analysis, HBsAg loss for over 7 years was associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.55, 95% CI 0.31-0.97, p = 0.039) but not HCC (aSHR 1.35, 95% CI 0.83-2.19, p = 0.230). CONCLUSION: HCC risk persists in patients after HBsAg loss, whereas the risk of hepatic decompensation decreases over time. IMPACT AND IMPLICATIONS: Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) after 12 years of HBsAg seroclearance, especially among those with cirrhosis. The risk of developing hepatic decompensation decreases over time after HBsAg seroclearance. In clinical practice, although patients with CHB who cleared HBsAg have a more favourable clinical outcome than those who remain chronically infected, long-term HCC surveillance would still be necessary for patients with cirrhosis and other high-risk subgroups after HBsAg seroclearance.