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Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) account for an increasing proportion of liver disease in the Asia-Pacific region. Many areas in the region are experiencing epidemics of metabolic syndrome among rapidly ageing populations. Aims To estimate using modelling the growth in NAFLD populations, including cases with significant fibrosis that are most likely to experience advanced liver disease and related mortality. Methods A disease progression model was used to summarise and project fibrosis progression among the NAFLD populations of Hong Kong, Singapore, South Korea and Taiwan. For each area, changes in the adult prevalence of obesity was used to extrapolate long-term trends in NAFLD incidence. Results In the areas studied, prevalent NAFLD cases were projected to increase 6%-20% during 2019-2030, while prevalent NASH cases increase 20%-35%. Incident cases of hepatocellular carcinoma are projected to increase by 65%-85%, while incident decompensated cirrhosis cases increase 65%-100% by 2030. Likewise, NAFLD-related mortality is projected to increase between 65% and 100% from 2019 to 2030. NAFLD disease burden is expected to increase alongside rising trends in metabolic syndrome and obesity among populations in the region. This leads to more cases of advanced liver disease and associated mortality. Conclusions Preventing the growth of diabetic and obese populations will be a key factor in reducing ongoing increases in NAFLD-related disease burden in the Asia-Pacific region.

Background: Individuals may still develop gastric cancer even after Helicobacter pylori eradication. We aimed to investigate statin effect on gastric cancer development in H. pylori–eradicated subjects. Methods: All adult subjects who were prescribed clarithromycin-based triple therapy between 2003 and 2012 were identified in this retrospective cohort study utilizing a territory-wide electronic healthcare database. Patients were observed from index date of H. pylori therapy, and censored at gastric cancer diagnosis, death, or December 2015 (study end date). Statin use was defined as ≥180-day use after index date. Exclusion criteria included gastric cancer diagnosed within the first year after index date, previous gastric cancer or gastrectomy, and H. pylori treatment failure. Subdistribution hazard ratio (SHR) of gastric cancer with statins was calculated by competing risk regression with propensity score (PS) analysis matching 19 variables (age, sex, comorbidities, and other drug usage, including proton pump inhibitors, nonsteroidal anti-inflammatory drugs, aspirin, cyclooxygenase-2 inhibitors, and metformin). Results: During a median follow-up of 7.6 years (interquartile range = 5.1–10.3), 169 (0.27%) of 63,605 patients developed gastric cancer at an incidence rate of 3.5 per 10,000 person-years. Among 22,870 PS-matched subjects, statins were associated with a lower gastric cancer risk (SHR = 0.34; 95% confidence interval, 0.19–0.61), in a duration– and dose–response manner (Ptrend < 0.05). Conclusions: Statins were associated with a lower gastric cancer risk in a duration– and dose–response manner among H. pylori–eradicated patients. Impact: This study provides evidence on the additional benefits of statins as chemopreventive agents against gastric cancer among H. pylori–eradicated patients.

Patients with occult hepatitis B infection (OBI) have undetectable hepatitis B surface antigen (HBsAg) by conventional assays but detectable hepatitis B virus (HBV) DNA in blood/liver. We evaluated the key performance characteristics of a sensitive HBsAg assay (Architect HBsAg Next qualitative assay, referred to as NEXT) with respect to HBsAg detection. Assay precision, sample carryover, and seroconversion sensitivity of NEXT were evaluated. HBsAg was measured by NEXT in 1,138 individuals, including 1,038 patients who attended liver clinics in a tertiary hospital (200 HBV DNA-positive blood donors whose HBsAg was undetectable by conventional assays, 38 patients receiving immunosuppressive therapy, and 800 chronic hepatitis B patients with HBsAg seroclearance) and 100 HBsAg-negative subjects recruited from a community project. The within-run and within-laboratory coefficients of variation were 5 to 8, >8 to 11, and >11 years after HBsAg seroclearance, respectively. Seven out of 100 HBsAg-negative community-identified subjects were tested positive by NEXT. Compared with conventional HBsAg assays, NEXT demonstrated a higher sensitivity and conferred an increment of 5 to 7% detection rate in patients with OBI, thereby helping in identifying HBV carriers and prevention of OBI-associated HBV transmission and reactivation.

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Real-world studies examining reduction in risk of hepatocellular carcinoma (HCC) in patients receiving antivirals are limited by the small size of the studies, or by data insufficiency and heterogeneity with short follow-up duration. We aimed to examine the real-world long-term outcome of patients receiving entecavir treatment on HCC incidence and HBsAg seroclearance. The incidence of HCC in 1225 entecavir-treated patients between 2002 and 2015 was compared with the HCC incidence estimated using the REACH-B, GAG-HCC and CU-HCC scores. Standardized incidence ratios (SIR) were calculated. The impact of entecavir treatment on HBsAg seroclearance was also explored. The median follow-up of the cohort was 6.6 years, with 66 cases of HCC development. Using the REACH-B model, the reduction of HCC risk was significant from year 6 onwards with SIR of 0.68 (95% CI 0.535-0.866) at year 10. In subgroup patients without cirrhosis, consistent risk reduction was observed from the fifth year and the SIR reached 0.51 (95% CI 0.271-0.704) by year 10. Benefit in cirrhotic patients was demonstrated when using the GAG-HCC and CU-HCC score, with the SIR at year 10 being 0.38 (95% CI 0.259-0.544) and 0.46 (95% CI 0.314-0.659), respectively. The cumulative rate of HBsAg seroclearance was 5.2%. HBsAg level at third year of treatment and baseline-to-3-year percentage reduction was predictive of subsequent HBsAg seroclearance. In conclusion, long-term entecavir therapy was associated with significant reduction in the risk of HCC in the real world. However, HBsAg seroclearance rate remained low. Additional therapy may be considered in patients with adverse predictive factors for subsequent HBsAg seroclearance.

Non-alcoholic fatty liver disease (NAFLD), the world’s most common chronic liver disease, is increasingly linked to gut dysbiosis. Paneth cells secrete antimicrobial peptides that regulate the gut microbiome, but their role in the pathogenesis of NAFLD remains unclear. Here, we determine the changes in NAFLD development and gut microbial composition and function via the injection of dithizone that can pharmacologically deplete the granules of Paneth cells. Eight-week-old C57BL/6J male mice (n = 31) were given a high-fat diet (HFD) or standard control diet for 12 weeks. Dithizone (10 mg/kg) was intravenously injected every 3 weeks during the period of diet feeding. Metagenomic DNA was extracted from fecal samples for PacBio Single-Molecule Real-Time sequencing to identify changes in microbial composition and predicted function. We observed dithizone-treated HFD mice, when compared to non-treated HFD mice, to have significant reductions in hepatic triglyceride content (28.98 vs. 53.52 mg/g, p = 0.0419); plasma insulin level (2.18 vs. 6.63 ng/ml, p = 0.0079); and relative mRNA levels of fatty acid synthase (0.52 vs. 1.57, p = 0.0428) and stearoyl-CoA desaturase-1 (0.43 vs. 1.20, p = 0.0121). Bacterial taxonomic profiling found dithizone-treated HFD mice, when compared to non-treated HFD mice, had a lower Firmicutes/Bacteroidetes ratio (2.53 vs. 5.26, p = 0.0541); a higher relative abundance of Bacteroides ASV21 and ASV42 (1.04 vs. 0.22%, p = 0.0277 and 0.96 vs. 0.09%, p = 0.0213); and a reduction in microbes belonging to Firmicutes (all p < 0.05). Bacteroides species correlated positively with predicted microbial functions such as L-methionine (r = 0.54, p = 0.0019) and tetrahydrofolate (r = 0.52, p = 0.0029) biosynthesis. Collectively, dithizone treatment was associated with alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in Bacteroides, suggesting microbiome-targeted therapies may have a role in the treatment of NAFLD.

Background This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B. Methods Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction. Results All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 × 109 per liver and hepatocyte clone size of 2.41 × 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 × 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 × 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 × 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 × 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively). Conclusions NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.

Chronic hepatitis B virus (HBV) infection can cause oxidative stress and induce cell death. The mechanisms by which cells overcome oxidative stress to survive remain largely unknown. Here, we used human sera, liver tissues and cell lines to study how HBV modulates cellular pathways to counteract oxidative stress-induced cell death. We found high-mobility group AT-hook 2 (HMGA2), an architectural transcription factor is upregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Elevated serum HMGA2 is significantly associated with viral load in HBV carriers, and HBV-related HCC. We showed that HBV X protein (HBx) encoded by HBV-induced cell growth via HMGA2 activation. The growth-promoting effect is abolished when HMGA2 is suppressed. Ectopic HBx expression induced DNA damage and oxidative stress. HMGA2 silencing reduced oxidative stress in HBx-expressing cells. Cytoprotective stanniocalcin 2 (STC2) protein is a downstream target of HMGA2. Consistent with the findings in HMGA2, STC2 mRNA and protein expression are upregulated in HCC tissues. Elevated serum STC2 is also associated with viral load in HBV carriers, and HCC. STC2 is transcriptionally upregulated by HBx and HMGA2 to elicit cytoprotection against apoptosis. STC2 knockdown disrupted Bax/Bcl-2 balance that increased cytochrome c release, caspase 3/7 activity and apoptosis, and thus abolished the growth-promoting effect of HMGA2. Clinical relevance of HBx/HMGA2/STC2 signaling is evidenced by the significant correlation of serum HMGA2/STC2 in active HBV infection and HCC. These findings reveal a novel HBx regulatory HMGA2/STC2 pathway in counteracting reactive oxygen species-induced cell death. HMGA2 and STC2 may be therapeutic targets for prevention of hepatocarcinogenesis in chronic HBV infection.

The nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are preferred treatment options for patients with chronic hepatitis B infection (CHB). However, resistance to ETV has been reported, especially with prior exposure to other NAs, and long-term TDF treatment has been associated with decline in renal function and loss of bone mineral density in some patients. Consequently, TAF may be preferable to ETV, TDF or other NAs in specific circumstances such as in patients with risk of bone or renal complications, elderly patients or those with previous NA experience.To provide a summary of the available efficacy and safety data following switch to TAF from other NAs in patients with CHB in clinical studies and real-world settings.Literature searches were performed on PubMed and abstracts from three major international liver congresses between 2019 and 2021. Studies that included efficacy and/or safety data for patients with CHB switching from any NA to TAF were selected.Thirty-six papers and abstracts were included in this narrative review. Switching from TDF to TAF maintained or improved virological and biochemical responses with improved bone and renal safety. Switching from ETV or other NAs to TAF maintained or improved virological and biochemical responses and varying results for bone and renal safety.Switching to TAF appears to maintain or improve virological, biochemical and bone- and renal-related safety outcomes. These data support the concept of switching to TAF in some patients with CHB based on their individual circumstances.

Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host’s immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host’s immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB.

Treating patients with chronic hepatitis B (CHB) infection with long-term oral antiviral therapy or pegylated interferon is the current standard of care (SOC). However, functional cure, defined as sustained hepatitis B surface antigen (HBsAg) seroclearance that is associated with favorable clinical outcomes, is a rarely achieved treatment endpoint with the SOC. Remarkable advances in CHB therapy have been made in the recent years. This review was aimed to describe the different new treatment agents that are in the clinical phase of development. These include two main groups of agents that either target the viral replication cycle or enhance host immune control on the hepatitis B virus (HBV). The former group includes viral entry inhibitor, RNA gene silencers, core protein inhibitors, nucleic acid polymer, and monoclonal antibodies. The latter group includes toll-like receptor agonists, RIG-1/NOD2 agonist, therapeutic vaccines, and apoptosis inducer. While some agents show promise in reduction of HBsAg levels and even HBsAg seroclearance, others are relatively modest in term of additional virological control effected by their different modes of action against HBV. These agents are in general well tolerated. Many upcoming new drugs against HBV are expected to enter phase II clinical trials. New challenge ahead would be the choice and duration of combination therapy to achieve a satisfactory rate of HBsAg seroclearance.

BACKGROUND Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible growth arrest cell cycle, apoptosis, and cell survival. GAS2 protein is universally expressed in most normal tissues, particularly in the liver, but is depleted in some tumor tissues. However, the functional mechanisms of GAS2 in hepatocellular carcinoma (HCC) are not fully defined. AIM To investigate the function and mechanism of GAS2 in HCC. METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting. Cell proliferation was analyzed by counting, MTS, and colony formation assays. Cell cycle analysis was performed by flow cytometry. Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting. RESULTS GAS2 protein expression was lower in HCC than in normal tissues. Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53, while knockdown of GAS2 promoted the proliferation of hepatocytes (P < 0.05). Furthermore, GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells, particularly the elevation of sub G1 (P < 0.01). Apoptosis induced by GAS2 was dependent on p53, which was increased by etoposide addition. The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated, but became diminished upon downregulation of GAS2. In the clinic specimen, GAS2 was downregulated in more than 60% of HCCs. The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues (P < 0.05). CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis, possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

OBJECTIVE Whether diabetes mellitus (DM) increases risk of gastric cancer (GC) remains controversial because of inadequate adjustments for important risk factors, including Helicobacter pylori (HP) infection status, concomitant medication use, and cancer site. We investigated whether type 2 DM increased risk of GC in patients after they received treatment for HP infection. RESEARCH DESIGN AND METHODS This was a territory-wide cohort study of patients aged ≥45 years who had received clarithromycin-based triple therapy for HP infection between 2003 and 2012 in Hong Kong. Data were retrieved from a public electronic health database. Observation started from receipt of therapy for HP infection to GC diagnosis, death, or the end of the study (December 2015). Exclusion criteria included type 1 DM, GC diagnosed within the 1st year of HP therapy, prior GC or gastrectomy, and retreatment for HP infection. The adjusted hazard ratio (aHR) of GC with type 2 DM was calculated by using a Cox model that adjusted for 20 covariates (age, sex, comorbidities, and medications) through propensity score regression. RESULTS During a median follow-up of 7.1 years (interquartile range 4.8–9.3 years), 153 of 46,460 patients (0.33%) developed GC at a median age of 72.4 years. Type 2 DM was associated with an increased risk of GC (aHR 1.73 [95% CI 1.08–2.79]). Stratified analysis showed an increase in risk for cardia cancer only (aHR 3.40 [95% CI 1.45–7.97]) and in those with suboptimal DM control (time-weighted mean HbA1c ≥6.0% [42 mmol/mol]; aHR 1.68 [95% CI 1.07–2.63]). CONCLUSIONS Type 2 DM is associated with an increased risk of GC among patients in whom HP was eradicated, in particular gastric cardia cancer and in those with suboptimal DM control.

Background and aim Population-based studies on post-colonoscopy colorectal cancer (CRC) from Asia are sparse. We aimed to determine the characteristics and predictive factors and survival of post-colonoscopy CRC in Hong Kong. Methods This is a territory-wide retrospective cohort study. Patients aged ≥ 40 years with colonoscopies performed between 2005 and 2013 without history of CRCs, inflammatory bowel disease, and prior colectomy were included. Post-colonoscopy colorectal cancer for an interval of 3 years (PCCRC-3y) was defined as CRC diagnosed between 6 and 36 months after index colonoscopy, whereas CRC diagnosed within 6 months of index colonoscopy was regarded as "detected CRC." We used multivariable logistic regression to derive adjusted odds ratio (aOR) of PCCRC-3y and Cox model for adjusted hazard ratio (aHR) of cancer-specific mortality after CRC diagnosis. Results Of the 197 902 eligible patients, 10 005 (92.1%) were detected CRC and 854 (7.9%) PCCRC-3y. The median age at PCCRC-3y diagnosis was 75.9 years (interquartile range: 65.5-83.8)-a delay of 1.2 years (interquartile range: 0.8-1.9) from index colonoscopy-and 60.1% were male. Predictive factors for PCCRC-3y included older age (aOR: 1.07), male sex (aOR: 1.45), history of colonic polyps (aOR: 1.31), polypectomy/biopsy at index colonoscopy (aOR: 3.97), surgical endoscopists (aOR: 1.53), and a higher center annual endoscopy volume. Independent predictive factors for cancer-specific mortality after CRC diagnosis included PCCRC-3y (aHR: 1.32), proximal cancer location (aHR: 1.80), and certain patient factors. Conclusion The PCCRC-3y rate was 7.9% in Hong Kong, with a high proportion (> 80%) of distal cancers and a higher cancer-specific mortality compared with detected CRC.

The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long-term dynamic changes of liver fibrosis are limited. This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10-year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow-up LSM. Fibrosis stages were classified according to EASL-ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)-negative patients (224 untreated, 235 treated with nucleos(t)ide analogues [NAs]) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval [CI]: 1.032-4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128-16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271-26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = -0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis-related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB-related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time-dependent decline in liver stiffness.

It is unknown how concomitant hepatic steatosis affects disease progression in chronic hepatitis B (CHB). Adipokines such as fibroblast growth factor 21 (FGF21) and adipocyte fatty acid-binding protein (AFABP) have been associated with non-alcoholic fatty liver disease. We determined the significance of these metabolic markers in CHB-related liver injury.We recruited CHB patients on antiviral treatment for transient elastography assessment to determine liver stiffness (advanced fibrosis/cirrhosis, F3/F4, defined by EASL-ALEH criteria) and controlled attenuation parameter (hepatic steatosis, defined as ≥ 248 dB/m). Plasma FGF-21, AFABP and adiponectin levels were measured.A total of 415 patients [mean age 59.6 years, 71.6% male, median treatment duration 6.2 years] were recruited. Patients with F3/F4 (N = 151) had lower FGF-21 (11.7 vs 13.6 pg/mL, P = 0.055), higher AFABP (126.8 vs 84.1 pg/mL, P 0.001) and HOMA-IR (7.1 vs 5.1, P = 0.004) levels compared to those without F3/F4 (N = 264). Multivariate analysis showed that FGF-21 level was associated with hepatic steatosis (OR 1.005, 95% CI 1.001-1.009) and F3/F4 (OR 0.993, 95% CI 0.989-0.998), while AFABP level (OR 1.001, 95% CI 1-1.002), body mass index (BMI) (OR 1.107, 95% CI 1.037-1.182) and presence of diabetes mellitus (OR 2.059, 95% CI 1.206-3.516) were associated with F3/F4. With the combined presence of BMI ≥ 25 kg/mLow FGF-21 and high AFABP levels were associated with advanced fibrosis/cirrhosis in CHB patients on antiviral treatment. Plasma AFABP, together with other metabolic risk factors, may aid identification of patients lacking fibrosis improvement during antiviral treatment.

Background and aim Hepatocellular carcinoma (HCC) can still develop in chronic hepatitis B (CHB) patients receiving antiviral treatment. Serum Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel marker for liver fibrosis. We investigated its role on incidence of HCC in entecavir (ETV)-treated CHB patients. Methods We identified HCC cases diagnosed at ≥ 1 year of ETV treatment. CHB patients without HCC (matched for age, gender, baseline hepatitis B virus-DNA, and duration of ETV treatment) were identified in approximately 1:2 ratio (HCC: non-HCC) for comparison. Serum samples were retrieved at baseline (initiation of ETV), 3, and 5 years of ETV for serum M2BPGi measurement (expressed in cut-off index [COI]). Results One hundred HCC cases were matched with 185 CHB patients without HCC (median age 56.7 years, 78.9% male, baseline hepatitis B virus-DNA 5.6 logIU/mL, and median follow-up 7.1 years). Median time from ETV initiation to incident HCC was 3.9 years. Serum M2BPGi levels were significantly higher in HCC cases compared with controls at baseline and year 3 (1.25 vs 0.98 [P = 0.004], 0.89 vs 0.74 [P = 0.018] COI, respectively). Multivariate analysis showed that baseline M2BPGi was the only independent factor associated with incident HCC (odds ratio 1.241, 95% confidence interval 1.039-1.482, P = 0.017). Using a cut-off value of 1.15 COI, the sensitivity, specificity, positive predictive value, and negative predictive value of baseline serum M2BPGi in cirrhotic patients to predict incident HCC were 90%, 53.8%, 69.6%, and 82.1%, respectively. Conclusions Baseline and 3-year serum M2BPGi may be useful to identify high risk patients on antiviral treatment for subsequent HCC development.

BACKGROUND Liver cirrhosis is a major risk factor for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB). Serum Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel serological marker for fibrosis. The role of M2BPGi in prediction of HCC is unknown. AIM To examine the role of serum M2BPGi in predicting HCC development in hepatitis B e antigen (HBeAg)-negative patients. METHODS Treatment-naive CHB patients with documented spontaneous HBeAg seroconversion were recruited. Serum M2BPGi was measured at baseline (within 3 years from HBeAg seroconversion), at 5 years and 10 years after HBeAg seroconversion and expressed as cut-off index (COI). Multivariate cox regression was performed to identify predictors for HCC development. ROC analysis was used to determine the cut-off value of M2BPGi. RESULTS Among 207 patients (57% male, median age at HBeAg seroconversion 40 years old) with median follow-up of 13.1 (11.8-15.5) years, the cumulative incidence of HCC at 15 years was 7%. Median M2BPGi levels were significantly higher in patients with HCC compared to those without HCC (baseline: 1.39 COI vs 0.38 COI, P < 0.001; 5-year: 1.45 COI vs 0.47 COI, P < 0.001; 10-year: 1.20 COI vs 0.55 COI, P = 0.001). Multivariate analysis revealed age at HBeAg seroconversion [odds ratio (OR) = 1.196, 95% confidence interval (CI): 1.034-1.382, P = 0.016] and baseline M2BPGi (OR = 4.666, 95%CI: 1.296-16.802, P = 0.018) were significant factors predictive of HCC. Using a cut-off value of 0.68 COI, baseline M2BPGi yielded AUROC of 0.883 with 91.7% sensitivity and 80.8% specificity. CONCLUSION High serum M2BPGi within 3 years after HBeAg seroconversion was a strong predictor for subsequent HCC development in treatment-naive HBeAg-negative CHB patients.

Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel serum diagnostic marker for liver fibrosis in various liver diseases. We aimed to evaluate its role in assessment of liver fibrosis in chronic hepatitis B infection (CHB) with reference to liver stiffness measurement (LSM). CHB patients with LSM by transient elastography technology and retrievable serum samples were recruited. Ten-year re-assessments of LSM and M2BPGi were repeated in a patient subgroup. 240 CHB patients (M:F = 116:124; median age 47.5 years) were recruited. The median M2BPGi values for F0/F1/F2, F3 and F4 progressively increased with more advanced stages of liver fibrosis: 0.39, 0.46 and 0.82 COI, respectively (p

Long-term nucleos(t)ide analogue therapy in chronic hepatitis B virus (HBV) infection is effective in suppressing viral replication and reducing liver-related complications. However, HBV-related liver events can still occur in different patient sub-groups. There is emerging evidence that, similar to chronic hepatitis C virus infection, metabolic risk factors may play a role in the disease process of chronic HBV. While the mechanistic nature of metabolic-HBV interactions remains uncertain, studies in different HBV-infected populations have demonstrated that hepatic steatosis, increased body-mass index, diabetes, or a combination of different metabolic risk factors are associated with an increased risk of hepatocellular carcinoma and cirrhosis. The impact of metabolic risk factors is especially prominent in patients with quiescent virological activity, including on-treatment patients with effective viral suppression. As the proportion of on-treatment chronic HBV patients increases worldwide, longitudinal studies determining the relative risks of different metabolic parameters with respect to clinical outcomes are needed. Future studies should also determine if metabolic-directed interventions can improve disease outcomes in chronic HBV.

Chronic hepatitis B (CHB) infection causes considerable morbidity and mortality and hence should be a target for global elimination. In recent years, advances have been made in understanding the disease pathophysiology and the relationship to clinical outcome. Novel treatment targets are actively being sought in the hope of improving the treatment outlook. Areas covered: We discussed the cascade of cure of CHB with respect to the degree of persistence of viral genome and proteins. Several novel antiviral agents either targeting the virus or the host are in different clinical phases of development. Serum hepatitis B core-related antigen and HBV RNA are novel markers, which might have a role in the prediction of specific clinical outcomes such as development of hepatocellular carcinoma or virological relapse after cessation of antiviral therapy. These markers may also be used to monitor treatment response in the drug trials. Expert commentary: Global elimination of CHB is challenged by extremely low awareness of illness and poor access to care. CHB and its related complications can be reduced by birth dose vaccine, antiviral therapy, and alleviated by complication screening. Treatment options for CHB will expand in the next decade and early functional cure is not an impractical goal.

e16176 Background: Dual-tracer positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose and 11C-acetate is increasingly used in the management of hepatocellular carcinoma (HCC). However, considering the high cost of dual-tracer PET/CT, there is a need to assess its value by considering both the efficacy and cost. Methods: In this retrospective cohort study, 223 dual-tracer PET/CT scans were performed in 206 patients between 2014 and 2020 for tumor staging for radiologically or histologically confirmed HCC. New lesion detection rate, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and changes in treatment allocation based on dual-tracer PET/CT were evaluated. Validation was performed on a cohort of staging patients from another institution (n = 48). A cost-benefit analysis model was built for the incurred costs and the impact of dual-tracer PET/CT findings on treatment strategy over conventional imaging was studied. Results: Of the 223 patients that underwent dual-tracer PET/CT for staging, new lesions were detected in 33 (14.8%) patients, resulting in BCLC upstaging in 26 (11.6%) and treatment modification in 16 (7.2%) cases. The external staging cohort showed similar findings where dual-tracer PET/CT resulted in 12.5% (6/48) BCLC upstaging and 10.4% (5/48) treatment modifications (concordance-index: 0.85; 95% CI: 0.82-0.88). In subgroup analysis of 200 patients performed for pre-treatment metastatic screening, dual-tracer PET/CT detected extra-hepatic metastasis in 11, 10, and 16 patients, respectively, and led to treatment modifications in all of these patients. Sixteen locoregional therapies (8%) were avoided (8 resections, 3 transplantations, and 5 TACEs), with an estimated cost saving of US$161,665 (US$808 / patient) from the use of dual-tracer PET/CT. Sensitivity analyses suggested that dual-tracer PET/CT is consistently more cost-saving than conventional imaging, irrespective of the changes in the cost of imaging, procedures, and the duration of hospital stay (range: US$112,945-210,385). The cost of PET/CT had the greatest influence on the cost savings. Conclusions: Comparing to conventional imaging, dual-tracer PET/CT improves tumor staging, alters treatment allocation and is cost-saving in patients undergoing pre-treatment metastatic screening. Our results demonstrated that the use of dual-tracer PET/CT provides additional value and improves patient care.

Background: Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein. Results: A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6–44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0–16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08–2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17–2.28). Conclusions: Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI.

We aimed to describe long-term clinical outcomes in chronic hepatitis B (CHB) patients after HBsAg seroclearance, and identify factors that modify disease outcomes.CHB patients with HBsAg seroclearance occurring between 1986 and 2017 were recruited. Primary outcome was cirrhosis/hepatocellular carcinoma (HCC), and secondary outcomes were hepatic decompensation, liver-related death/transplantation, and all-cause mortality. Multivariable Cox model included demographics, prior antivirals, comorbidities, drugs (statins, metformin, proton-pump inhibitors, non-selective beta-blockers), and laboratory parameters (platelet, liver function test, prothrombin time, alpha-fetoprotein [AFP], anti-HBs). Statin users were propensity score matched (PSM) with non-users (1:2 ratio) for survival analysis of all outcomes.Of 913 patients with HBsAg seroclearance (male: 613 [67.1%]; median age: 53.4 years [18.5-87.0]), 129 (14.1%) were statin users. During median follow-up of 7.7 years (up to 29.1 years), 64/833 (7.7%) developed cirrhosis, 25/905 (2.8%) developed HCC, 3/913 (0.3%) underwent transplantation, and 76/913 (8.3%) died. Statins were associated with lower cirrhosis/HCC risk (adjusted hazard ratio [aHR]: 0.44; 95% CI 0.20-0.96; aHR for every 1-year increase in use: 0.85; 95% CI 0.75-0.97). Statin users had no hepatic decompensation or liver-related death/transplantation (vs 18/778 [2.3%] and 18/784 [2.3%] cases in statin non-users, respectively). Statins were also associated with lower all-cause mortality risk (aHR: 0.21; 95% CI 0.08-0.53). PSM yields consistent results for beneficial effects of statins (log-rank p 0.05 for all outcomes). Other factors for cirrhosis/HCC included increasing age (aHR: 1.06), diabetes (aHR: 2.03), higher creatinine (aHR: 1.008), GGT 50U/L (aHR: 3.25), and AFP 9 ng/mL (aHR: 10.14).Patients with HBsAg seroclearance have favorable long-term survival. However, liver-related adverse outcomes still develop, necessitating further investigations on beneficial effects of statins.

OBJECTIVE Preclinical studies have suggested that thrombospondin-2 (TSP2) is implicated in liver fibrosis. However, the clinical relevance of TSP2 in nonalcoholic fatty liver disease (NAFLD) remains undefined. Here, we investigated the cross-sectional and longitudinal associations of circulating TSP2 levels with advanced fibrosis (F3 or greater [≥FE] fibrosis) in NAFLD. RESEARCH DESIGN AND METHODS Serum TSP2 levels were measured in 820 patients with type 2 diabetes and NAFLD. All participants received vibration-controlled transient elastography (VCTE) at baseline to evaluate their hepatic steatosis and fibrosis using controlled attenuation parameter (CAP) and liver stiffness (LS) measurements, respectively. Among those without advanced fibrosis at baseline, reassessment VCTE was performed to determine whether ≥F3 fibrosis had developed over time. Multivariable logistic regression analysis was used to evaluate the cross-sectional and longitudinal associations of serum TSP2 level with ≥F3 fibrosis. RESULTS Baseline serum TSP2 level was independently associated with the presence of ≥F3 fibrosis (odds ratio [OR] 5.13, P < 0.001). The inclusion of serum TSP2 level significantly improved the identification of ≥F3 fibrosis by clinical risk factors. Over a median follow-up of 1.5 years, 8.8% developed ≥F3 fibrosis. Baseline serum TSP2 level was significantly associated with incident ≥F3 fibrosis (OR 2.82, P = 0.005), independent of other significant clinical risk factors of fibrosis progression, including BMI, platelet count, and CAP at baseline. CONCLUSIONS Circulating TSP2 level was associated with both the presence and the development of advanced fibrosis and might be a potentially useful prognostic biomarker for the development and progression of liver fibrosis in patients with type 2 diabetes and NAFLD.

Additional file 1: Supplementary material.

Background: With the largest hepatitis B virus (HBV) infected population worldwide, universal HBV screening in China may significantly contribute to the World Health Organization (WHO) 2030 goals in eliminating viral hepatitis. We evaluated the cost-effectiveness of universal HBV screening in China and identified optimal screening strategies. Methods: We conducted a cost-effectiveness analysis using a Markov cohort model based on four HBV serological screening methods in China. We simulated these universal screening in 15 different adult age groups with different initiation time (year 2021, 2026 and 2031). We performed probabilistic and one-way deterministic sensitivity analyses to assess the robustness of our findings. Results: With a willingness-to-pay level of 3x Chinese gross domestic product (GDP) per capita (US$30,828), HBsAg/HBsAb/HBeAg/HBeAb/HBcAb (five-test) screening among 18-70 years was the most cost-effective strategy in 2021 (incremental cost-effectiveness ratio [ICER] US$18,295/quality-adjusted life-year [QALY] gained). This remained the most cost-effective strategy, even when the willingness-to-pay threshold reduced to US$17,778; other strategies became more cost-effective at lower willingness-to-pay levels. This strategy would potentially prevent 3.46 million liver-related deaths over the lifetime of the cohort. It remained the most cost-effective even when the implementation was delayed to 2026 and 2031, but with greater ICERs (US$20,183/QALY and US$23,123/QALY, respectively). The screening will no longer be cost-effective in younger age groups in delayed scenarios. Conclusion: Five-test universal screening among 18-70 years implemented in 2021 is the optimal HBV screening strategy in China. Delaying strategy implementation reduces overall cost-effectiveness. Early screening initiation will aid global efforts in achieving viral hepatitis elimination. Funding: LZ is supported by the National Natural Science Foundation of China (grant number 8191101420); Outstanding Young Scholars Funding (3111500001); Xi'an Jiaotong University Basic Research and Profession Grant (xtr022019003); and Xi'an Jiaotong University Young Talent Support Program (YX6J004). WKS is supported by the Outstanding Young Researcher Award, the University of Hong Kong. JJO is supported by the Australian National Health and Medical Research Council Emerging Leadership Fellowship (GNT11953955). This project is funded by The University of Hong Kong Common Core Course. Declaration of Interest: PC is a staff member of the World Health Organization; the author alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions or policies of the World Health Organization. MFY is an advisory board member and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals; and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation and Sysmex Corporation. WKS received speaker's fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker's fees from AbbVie, and is an advisory board member, received speaker's fees and researching funding from Gilead Sciences. The remaining authors have no conflict of interests.

Background/Purpose Use of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV. Methods In a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA Results In 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA Conclusions In WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.

Background: Integration of HBV DNA into human genome and hepatocyte clonal expansion are implicated in hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) infection. This study investigated the effect of nucleos(t)ide analogues (NUC) treatment on HBV DNA integration and hepatocyte clonal expansion. Methods: Twenty-eight patients receiving NUCs (11 lamivudine, seven telbivudine, ten entecavir) were included. All had liver biopsies at baseline and year 1, and seven had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse PCR, a semiquantitative, end-point PCR-based method which specifically detected viral-host integration junctions. Findings: All patients had detectable HBV DNA integration at baseline, with median integration frequency of 1·01×109 per liver and hepatocyte clone size of 2·21×10 5 . Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After one year of treatment, HBV DNA integration was still detectable in all patients, with a median of 5·74×108 integration per liver (0·22 log reduction; p=0·011) and hepatocyte clone size of 1·22×105 (0·45 log reduction; p=0·026). HBV DNA integration remained detectable in the seven patients at year 10 of treatment, with a median integration frequency of 4·84×107 integration per liver (0·93 log reduction from baseline) and hepatocyte clone size of 1·89×104 (1·02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (p=0·066 and 0·018, respectively). Interpretation: NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings also supported an early treatment of CHB to prevent HCC. Funding: None to declare. Declaration of Interest: D Wong received speaker’s fees from Abbott Laboratories and travel support from Gilead Sciences and Chong Lap. CL Lai received speaker’s fees from Gilead Sciences, GlaxoSmithKline and AbbVie. WK Seto received speaker’s fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. MF Yuen serves as advisor/consultant for AbbVie, Assembly Biosciences, Aligos Therapeutics, Arbutus Biopharma, Bristol Myer Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Hoffmann-La Roche and Springbank Pharmaceuticals, Vir Biotechnology and receives grant/research support from Assembly Biosciences, Aligos Therapeutics, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Immunocore, Merck Sharp and Dohme, Hoffmann-La Roche, Springbank Pharmaceuticals and Sysmex Corporation. The remaining authors have no conflict of interests. Ethical Approval: This study was approved by the Institution Review Board of The University of Hong Kong and Hospital Authority Hong Kong West Cluster (UW 19-842).

We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development. This is a case–control study of 104 patients [52 HCC and 52 non-HCC (matched with age, gender, cirrhosis and treatment duration)] on ≥ 3 years entecavir (ETV) with unquantifiable HBV DNA by Cobas Taqman assay v2.0 (Roche Diagnostics; lower limit of quantification [LLOQ] 20 IU/mL). Serial sera within 1, 1–2, and > 2 years prior to HCC diagnosis or last follow-up (LFU) were measured for HBV DNA and pre-genomic (pg) RNA using a highly sensitive semi-quantitative PCR assay with lower limit of detection of 10 IU/mL and LLOQ of 51.5 IU/mL, respectively. Among the 104 patients (80.8% male, median age 61.2 years old, 38.5% cirrhosis, median duration of ETV 45.5 months), 38.5% and 9.6% HCC patients had undetectable serum DNA and pgRNA, respectively, compared to 65.4% and 36.5% in non-HCC patients; P = 0.005 & 0.001, respectively, at the time of HCC diagnosis/LFU. Detectable HBV DNA and pgRNA were associated with a higher 2-year risk of HCC development (HR 2.79, 95% CI 1.424–5.468 & HR 4.544, 95% CI 1.07–19.289, respectively). No significant differences were observed for qHBsAg levels between HCC and non-HCC patients. More than 50% CHB patients on ETV with HBV DNA

Background & Aims: Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). Methods: This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)–negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. Results: Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7–16.8; P < .001) and among patients with HBsAg levels 30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. Conclusions: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with

Background Liver stiffness (LS) assessed by transient elastography is associated with adverse events in patients with heart failure. However, the predictive value of LS for adverse outcome is uncertain in patients undergoing tricuspid annuloplasty (TA). This study sought to evaluate the prognostic value and reversibility of LS in patients undergoing TA during left-sided valve surgery. Methods and results A total of 158 patients who underwent TA were prospectively evaluated. Patients were divided into three groups according to tertile of LS. Adverse outcome was defined as heart failure that required hospital admission or all-cause mortality following TA. The median LS was 13.9 (inter-quartile range 8.1–22.3) kPa and independently correlated positively with tricuspid regurgitation (TR) severity, inferior vena cava diameter and negatively with tricuspid annular plane systolic excursion. During a median follow-up of 31 months, 49 adverse events occurred. Multivariable Cox regression analysis revealed that LS was an independent predictor of adverse events. Significant improvement in LS at 1-year post-TA (13.1–7.8 kPa, P Conclusions This study demonstrated that LS is predictive of adverse outcome and is reversible in patients undergoing TA without TR recurrence at 1 year. These findings suggest that assessing LS, an integrative correlate of right heart condition, may aid the pre-operative risk assessment of candidate for heart surgery including TA.

Background Potent antivirals can reduce HCC incidence in CHB. TDF and TAF are first-line treatments, and in Phase 3 studies through 3 years, TAF has shown antiviral efficacy similar to TDF, higher rates of ALT normalization, and no resistance. We evaluated HCC incidence in patients participating in these ongoing studies. Methods HBeAg-positive (n=1039) and -negative (n=593) patients with HBV DNA 20,000 IU/mL and ALT >60 U/L (males) or >38 U/L (females) were randomized (2:1) to TAF 25 mg QD or TDF 300 mg QD for up to 3 years, followed by open-label TAF through Year 8. Patients with hepatic decompensation, co-infection with HCV/HDV/HIV, or evidence of HCC were excluded. HCC was assessed at 6 monthly intervals by hepatic ultrasonography beginning after Week 96 and by local standards of care. The standardized incidence ratio (SIR) for HCC was calculated for observed cases relative to predicted cases using the REACH-B model. Results 1632 patients were followed for up to 4 years; HCC was seen in 16 patients (0.98%; 7 TAF; 9 TDF); median time to onset was 568 days. At baseline HCC patients were older (median age 53 vs 40 y; p Conclusions In CHB patients treated with TAF or TDF for up to 4 years, HCC incidence was reduced, particularly in noncirrhotic patients. Additional follow up is needed to further characterize the impact of longer-term treatment on HCC risk reduction.

Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p p p p

Background: In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to iden tify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to fa cilitate AF risk stratification, especially for use in diabetes clinics where TE is not readily available. Methods: Seven hundred sixty-six adults with type 2 diabetes and NAFLD were recruited and randomly divided into a training set (n=534) for the development of diabetes fibrosis score (DFS), and a testing set (n=232) for internal validation. DFS identified pa tients with AF on TE, defined as liver stiffness (LS) ≥9.6 kPa, based on a clinical model comprising significant determinants of LS with the lowest Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NFS, FIB-4, and APRI), using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive and nega tive predictive values (NPV). Results: DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albumin uria, five routine measurements in standard diabetes care. Derived low and high DFS cut-offs were 0.1 and 0.3, with 90% sensitivity and 90% specificity, respectively. Both cut-offs provided better NPVs of >90% than conventional fibrosis scores. The AUROC of DFS for AF on TE was also higher (P

Background Hepatitis C virus (HCV) is a growing public health problem with a large disease burden worldwide. In China many people living with HCV are unaware of their hepatitis status and not connected to care and treatment. Crowdsourcing is a technique that invites the public to create health promotion materials and has been found to increase HIV testing uptake, including in China. This trial aims to evaluate crowdsourcing as a strategy to improve HCV awareness, testing and linkage-to-care in China. Methods A randomized controlled, two-armed trial (RCT) is being conducted in Shenzhen with 1006 participants recruited from primary care sectors of The University of Hong Kong-Shenzhen Hospital. Eligible participants are ≥30 years old; a resident in Shenzhen for at least one month after recruitment; no screening for HCV within the past 12 months and not known to have chronic HCV; and, having a WeChat social media account. Allocation is 1:1. Both groups will be administered a baseline and a follow-up survey (4-week post-enrollment). The intervention group will receive crowdsourcing materials to promote HCV testing once a week for two weeks and feedback will be collected thereafter, while the control group will receive no promotional materials. Feedback collected will be judged by a panel and selected to be implemented to improve the intervention continuously. Those identified positive for HCV antibodies will be referred to gastroenterologists for confirmation and treatment. The primary outcome will be confirmed HCV testing uptake, and secondary outcomes include HCV confirmatory testing and initiation of HCV treatment with follow-ups with specialist providers. Data will be collected on Survey Star@ via mobile devices. Discussion This will be the first study to evaluate the impact of crowdsourcing to improve viral hepatitis testing and linkage-to-care in the health facilities. This RCT will contribute to the existing literature on interventions to improve viral hepatitis testing in primary care setting, and inform future strategies to improve HCV care training for primary care providers in China. Trial registration Chinese Clinical Trial Registry. ChiCTR1900025771. Registered September 7th, 2019, http://www.chictr.org.cn/showprojen.aspx?proj=42788

Objective: In NAFLD, non-invasive serum-based fibrosis scores are often recommended as first-line assessment tools, followed by transient elastography to identify patients at high risk of liver fibrosis for consideration of liver biopsy. However, some studies had reported lower accuracy of these scores in diabetes. Therefore, we conducted this cross-sectional study to develop a non-invasive fibrosis score specifically for type 2 diabetes to improve risk stratification. Research Design and Methods: A total of 815 adults with type 2 diabetes and NAFLD was recruited from the diabetes clinic in Hong Kong. A random sample of 643 individuals were included in the training set, and the remaining 172 in the testing set. All participants had transient elastography for assessment of liver fibrosis. Diabetes Fibrosis Score (DFS) was developed to identify patients with advanced fibrosis (AF) on transient elastography, defined as liver stiffness (LS) >9.5kPa, using significant determinants of LS with variables selected based on Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NAFLD fibrosis score [NFS], Fib-4 and APRI), based on their area under the receiver operating characteristic (AUROC) curve, sensitivity (Sn), specificity (Sp), positive (PPV) and negative predictive values (NPV). Results: The variables included in DFS consisted of body mass index, platelet, alanine and aspartate aminotransferase levels. The AUROC of DFS for AF on transient elastography was 0.822, while those of NFS, APRI and Fib-4 were 0.629, 0.643 and 0.788, respectively. In the testing set, the AUROC of DFS was 0.852, with 76.7% Sn, 82.3% Sp, PPV 48.2% and NPV 94.3%. Conclusions: Compared to conventional non-invasive fibrosis scores, DFS more accurately identified, amongst patients comorbid with type 2 diabetes and NAFLD, those who should undergo transient elastography to evaluate their risk of liver fibrosis. Disclosure C. Lee: None. W. Seto: None. K. Ieong: None. D.T.W. Lui: None. H. Fong: None. H. Wan: None. W. Chow: None. Y. Woo: None. M. Yuen: None. K.S. Lam: Advisory Panel; Self; Merck Sharp & Dohme Corp.

BACKGROUND Regulatory T cells (Tregs) possess hepatitis B virus (HBV)-specific immunoregulatory effects in chronic HBV infection. The role of Tregs in spontaneous seroclearance of hepatitis B surface antigen (HBsAg) remains to be determined. METHODS We recruited treatment-naive chronic HBV patients achieving spontaneous HBsAg seroclearance (experimental group) and matched HBsAg-positive controls. Peripheral blood mononuclear cells were isolated using the Ficoll-Paque density gradient centrifugation method. The frequency of Tregs and inhibitory phenotypes and immunoregulatory cytokines of Tregs were detected by flow cytometry. RESULTS Twenty-seven patients with HBsAg seroclearance (mean age: 52.40±6.00 y, 55.6% male) and 27 matched controls were recruited. Median HBsAg and HBV DNA levels in the control group were 2.80 (1.24 to 3.43) and 3.16 (1.68 to 3.85) log IU/mL, respectively. Mean frequencies of Tregs and expressions of FoxP3+ Tregs were comparable in both groups (both P>0.05). The mean expression of programmed death 1 (PD-1) and glucocorticoid-induced TNFR family-related gene (GITR) in total CD4+ T cells were significantly downregulated in the experimental group when compared with the control group (10.62% vs. 13.85%, P=0.003; 16.20% vs. 27.02%, P=0.002, respectively). When compared with the control group, PD-1+CD4+ Tregs expression in the experimental group was significantly downregulated (13.85% vs. 10.62%, P=0.003). A similar phenomenon was noted for GITR+CD8+ Tregs (20.16% vs. 14.08%, P=0.049). Intracellular cytokine productions showed no significant differences (all P>0.05). CONCLUSIONS The reduced expression of PD-1 and GITR might attenuate the immunosuppressive capability of Tregs. Decreased expression on CD4+ T cells might represent an enhanced antiviral function, playing a role in initiating the "functional cure" of chronic HBV infection.

BACKGROUND & AIMS Lifestyle modification is the cornerstone for the management of non-alcoholic fatty liver disease (NAFLD). We aim to understand lifestyle habits of NAFLD patients, compare across Asian regions and identify area of deficiency. METHODS In the multi-centre controlled attenuation parameter (CAP)-Asia study, we collected clinical data and lifestyle habit data of NAFLD patients from Singapore, mainland China, Hong Kong, Taiwan and Malaysia. Physical activity was assessed using the International Physical Activity Questionnaire. RESULTS A total of 555 patients were included in the final analysis (mean age 54.5 ± 11.2 years, 54.1% men and median liver stiffness 6.7 kPa). More patients from mainland China (27.4%) and Taipei (25.0%) were smokers. Modest drinking was more common in Taiwan (25.0%) and Hong Kong (18.2%); only 1.3% had binge drinking. Majority of patients drank coffee (64.0%) and tea (80.2%), with varying amounts and durations in different regions. Soft drinks consumption was most common in Singapore (62.2%) and Malaysia (57.7%). Only 29.7% of patients met the Physical Activity Guidelines Recommendations, with no major differences across regions. Patients with liver stiffness

Concomitant non-alcoholic fatty liver disease is common in patients with chronic hepatitis B (CHB) infection, although its impact on liver-related outcomes remains controversial. We aimed to study the effect of hepatic steatosis on the risk of fibrosis progression and the likelihood of HBsAg seroclearance.Treatment-naïve patients with CHB, normal alanine aminotransferase and low viraemia (serum HBV DNA2,000 IU/ml) were prospectively recruited for baseline and 3-year transient elastography assessment. Fibrosis staging was defined according to the EASL-ALEH guidelines, with fibrosis progression defined as ≥1 stage increment of fibrosis. Hepatic steatosis and severe hepatic steatosis were defined as controlled attenuation parameter (CAP) ≥248 dB/m and ≥280 dB/m, respectively.A total of 330 patients (median age 50.5 years, 41.2% male, median HBV DNA 189 IU/ml) were recruited. Twenty-two patients (6.7%) achieved HBsAg seroclearance during follow-up, and the presence of hepatic steatosis was associated with a significantly higher chance of HBsAg seroclearance (hazard ratio 3.246; 95% CI 1.278-8.243; p = 0.013). At baseline, 48.8% and 28.8% of patients had steatosis and severe steatosis, respectively, while 4.2% had F3/F4 fibrosis at baseline, increasing to 8.7% at 3 years. The rate of liver fibrosis progression in patients with persistent severe steatosis was higher than in those without steatosis (41.3% vs. 23%; p = 0.05). Persistent severe hepatic steatosis was independently associated with fibrosis progression (odds ratio 2.379; 95% CI 1.231-4.597; p = 0.01).CAP measurements have predictive value in patients with virologically quiescent CHB. The presence of hepatic steatosis was associated with a higher risk of fibrosis progression but, paradoxically, a 3-fold increase in HBsAg seroclearance rate.Co-existing fatty liver disease in patients with chronic viral hepatitis B infection leads to worsening liver fibrosis, but also increases the chance of cure from hepatitis B virus. Routine bedside assessment of liver fat content is important for risk assessment in treatment-naïve patients with chronic hepatitis B.