Immediate postpartum cessation of tenofovir did not increase risk of virological or clinical relapse in highly viremic pregnant mothers with chronic hepatitis B infection.

Background & Aims: Peripartum prophylaxis (PP) with tenofovir disoproxil fumarate (TDF) is the standard of care to prevent mother-to-child transmission of chronic hepatitis B (CHB) infection in mothers who are highly viremic. We investigated the maternal and infant outcomes in a large Chinese cohort of TDF-treated CHB pregnant participants. Methods: In this prospective study, treatment-naive mothers with CHB and highly viremic (HBV DNA ≥200,000 IU/ml) but without cirrhosis were treated with TDF at 24-28 weeks of pregnancy. In accordance with Chinese CHB guidelines, TDF was stopped at delivery or ≥4 weeks postpartum. Serum HBV DNA and alanine aminotransferase were monitored every 6-8 weeks to determine virological relapse (VR). Infants received standard neonatal immunization, and HBV serology was checked at 7-12 months of age. Results: Among 330 participants recruited (median age 30, 82.7% HBeAg+, median HBV DNA 7.82 log IU/ml), TDF was stopped at delivery in 66.4% and at ≥4 weeks in 33.6%. VR was observed in 98.3%, among which 11.6% were retreated with TDF. Timing of TDF cessation did not alter the risk of VR (99.0 vs. 96.9%), clinical relapse (19.5 vs. 14.3%), or retreatment (12.6 vs. 10.1%) (all p > 0.05). A similar proportion of patients developed alanine aminotransferase flare five times (1.1 vs. 2.1%; p = 0.464) and 10 times (0.5 vs. 0%; p = 0.669) above the upper limit of normal (ULN) in the early withdrawal and late withdrawal groups, respectively. No infants developed HBsAg-positivity. Conclusions: PP-TDF and neonatal immunization were highly effective in preventing mother-to-child transmission of HBV in mothers who are highly viremic. Timing of cessation of PP-TDF did not affect the risk of VR or retreatment. Impact and Implications: In pregnant mothers with chronic hepatitis B infection who are started on peripartum tenofovir to prevent mother-to-child-transmission (MTCT), the optimal timing for antiviral withdrawal during the postpartum period remains unknown. This prospective study demonstrates that stopping tenofovir immediately at delivery, compared with longer treatment duration of tenofovir, did not lead to an increased risk of virological relapse, retreatment, or transmission of the virus to the baby. Shortening the duration of peripartum antiviral prophylaxis from 12 weeks to immediately after delivery can be considered. The immediate withdrawal of peripartum tenofovir, combined with standard neonatal immunization schemes, is 100% effective in preventing MTCT among pregnant mothers with CHB who are highly viremic, with a high rate of vaccine response in infants.

Hepatocellular carcinoma: Advances in systemic therapies.

Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.

Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

Low Bone Mineral Density as a Risk Factor for Liver Cirrhosis: A Prospective Cohort Study.

CONTEXT: Bone metabolism interplays with liver metabolism, also known as the liver-bone axis. Osteoporosis is a common complication of cirrhosis, but whether bone mineral density (BMD) can predict cirrhosis development is unknown. OBJECTIVE: This study aims to investigate the relationship between BMD and the risk of incident cirrhosis in the Hong Kong Osteoporosis Study (HKOS). METHODS: BMD was measured at the lumbar spine, femoral neck, total hip, and trochanter of 7,752 participants by the dual-energy X-ray absorptiometer (DXA), and the incidence of cirrhosis and mortality were followed by linking to the territory-wide electronic health records database. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI. RESULTS: With a median follow-up of 18.43 years, 42 incident cirrhosis were identified. Higher BMD T-scores at the femoral neck, total hip and trochanter were significantly associated with a reduced risk of cirrhosis (femoral neck: HR 0.56, 95% CI 0.39 to 0.82; total hip: HR 0.60, 95% CI 0.44 to 0.82; trochanter: HR 0.63, 95% CI 0.46 to 0.88). Similar associations were observed in participants without risk factors of cirrhosis at the baseline and further adjusting for the baseline level of alkaline phosphatase, albumin, and alanine transaminase. Consistent relationships in multiple sensitivity analyses suggest the robustness of the results. CONCLUSION: Low BMD could be a novel risk factor and early predictor for cirrhosis, with consistent associations observed in multiple sensitivity analyses.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Virological response to nucleos(t)ide analogues treatment in chronic hepatitis B patients is associated with Bacteroides-dominant gut microbiome.

BACKGROUND: Gut dysbiosis is present in chronic hepatitis B virus (HBV) infection. In this study, we integrated microbiome and metabolome analysis to investigate the role of gut microbiome in virological response to nucleos(t)ide analogues (NAs) treatment. METHODS: Chronic HBV patients were prospectively recruited for steatosis and fibrosis assessments via liver elastography, with full-length 16S sequencing performed to identify the compositional gut microbiota differences. Fasting plasma bile acids were quantified by liquid chromatography-tandem mass spectrometry. FINDINGS: All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-Bacteroides, c-Blautia, and c-Prevotella. Patients with c-Bacteroides had a higher plasma ursodeoxycholic acids (UDCA) level and an increase in 7-alpha-hydroxysteroid dehydrogenase (secondary bile acid biotransformation) than other clusters. In NAs-treated patients (n = 84), c-Bacteroides was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-Bacteroides clusters (OR 3.49, 95% CI 1.43-8.96, p = 0.01). c-Blautia was positively associated with advanced fibrosis (OR 2.74, 95% CI 1.09-7.31, p = 0.04). No such associations were found in treatment-naïve patients. Increased Escherichia coli relative abundance (0.21% vs. 0.03%, p = 0.035) was found in on-treatment patients (median treatment duration 98.1 months) with advanced fibrosis despite HBV DNA undetectability. An enrichment in l-tryptophan biosynthesis was observed in patients with advanced fibrosis, which exhibited a positive correlation with Escherichia coli. INTERPRETATION: Collectively, unique bacterial signatures, including c-Bacteroides and c-Blautia, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment. FUNDING: This study was supported by the Guangdong Natural Science Fund (2019A1515012003).

Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease.

BACKGROUND: Chronic liver disease (CLD) was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. AIM: To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma (HCC) among patients with CLD. METHODS: A retrospective, territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong. Patients with confirmed SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)+CLD] between January 1, 2020 and October 25, 2022 were identified and matched 1:1 by propensity-score with those without (COVID-19-CLD). Each patient was followed up until death, outcome event, or November 15, 2022. Primary outcome was incidence of HCC. Secondary outcomes included all-cause mortality, adverse hepatic outcomes, and different treatment strategies to HCC (curative, non-curative treatment, and palliative care). Analyses were further stratified by acute (within 20 d) and post-acute (21 d or beyond) phases of SARS-CoV-2 infection. Incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS: Of 193589 CLD patients (> 95% non-cirrhotic) in the cohort, 55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching. Upon 249-d median follow-up, COVID-19+CLD was not associated with increased risk of incident HCC (IRR: 1.19, 95%CI: 0.99-1.42, P = 0.06), but higher risks of receiving palliative care for HCC (IRR: 1.60, 95%CI: 1.46-1.75, P < 0.001), compared to COVID-19-CLD. In both acute and post-acute phases of infection, COVID-19+CLD were associated with increased risks of all-cause mortality (acute: IRR: 7.06, 95%CI: 5.78-8.63, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.14-1.36, P < 0.001) and adverse hepatic outcomes (acute: IRR: 1.98, 95%CI: 1.79-2.18, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.13-1.35, P < 0.001), compared to COVID-19-CLD. CONCLUSION: Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC, they were more likely to receive palliative treatment than those without. The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.

Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus. APPROACH AND RESULTS: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05). CONCLUSIONS: Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).

ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Factors predicting HBsAg seroclearance after treatment cessation, irrespective of nucleos(t)ide analogue (NA) resumption, have important clinical implications. We evaluated predictors of long-term HBsAg seroclearance after entecavir cessation. METHODS: This study followed-up Chinese patients with chronic hepatitis B from two previous studies of entecavir cessation. All patients were non-cirrhotic, HBeAg-negative, with undetectable HBV DNA (<20 IU/ml) at end-of-treatment (EOT). They were monitored closely for 48 weeks with regular HBV DNA, quantitative HBsAg (qHBsAg) and alanine aminotransferase (ALT) measurements. Entecavir was resumed at HBV DNA >2,000 IU/ml, irrespective of ALT levels. After the initial 48 weeks, patients were assessed every 6 months, regardless of entecavir resumption, to monitor for HBsAg seroclearance. RESULTS: A total of 194 patients (63.4% male, mean age 49.9 years, on entecavir for a median of 47.2 months) were recruited; 94 (48.5%) and 158 (81.4%) patients had EOT qHBsAg <100 IU/ml and <1,000 IU/ml, respectively; 151 (77.8%) patients were eventually resumed on entecavir. After follow-up for a median of 70.7 (51.0-118.2) months, 28 (14.4%) patients had HBsAg seroclearance. qHBsAg levels at weeks 36 and 48 after EOT independently predicted HBsAg seroclearance (both p <0.01), whereas qHBsAg from EOT to week 24 only trended towards statistical significance. The ratio of ALT/qHBsAg at all time points from EOT to week 48 independently predicted HBsAg seroclearance (hazard ratios ranging from 1.003-1.028, all p <0.01) with excellent diagnostic performance (area under the receiver-operating characteristic curve 0.799-0.933, negative predictive value >90% at different time points), regardless of whether entecavir was resumed. CONCLUSIONS: The ALT/qHBsAg ratio after entecavir cessation predicts HBsAg seroclearance, even in patients who were resumed on treatment. Its use may mitigate the risk of severe hepatitis flares in patients managed by observation without treatment resumption. IMPACT AND IMPLICATIONS: Current predictors of HBsAg seroclearance after finite nucleos(t)ide analogue (NA) therapy have suboptimal predictive value. We demonstrated that the ALT/qHBsAg ratio may be able to reflect the balance between host control and virological activity. The ALT/qHBsAg ratio at different time points from end-of-treatment till week 48 independently and accurately predicted HBsAg seroclearance in patients who have stopped entecavir. The ALT/qHBsAg ratio may be utilized by clinicians for patient selection and retreatment decisions in finite NA therapy.

Donor Diabetes and Steatosis Affects Recipient Survival Following Liver Transplantation Based on Etiology of Liver Cirrhosis.

BACKGROUND: Liver transplantation (LT) offers patients with decompensated cirrhosis the best chance at long-term survival. With the rising prevalence of diabetes, further clarity is needed on the impact of receiving a liver allograft from a donor with diabetes on post-LT outcomes. This study aims to evaluate the impact of donor diabetes on clinical outcomes after LT. METHODS: This is a retrospective analysis of the United Network for Organ Sharing registry data of LT recipients from January 1, 2000, to December 31, 2021. Outcomes analysis was performed using Cox proportional model for all-cause mortality and graft failure. Confounding was reduced by coarsened exact matching causal inference analysis. RESULTS: Of 66 960 donors identified, 7178 (10.7%) had diabetes. Trend analysis revealed a longitudinal increase in the prevalence of donor diabetes ( P < 0.001). Importantly, donor diabetes was associated with increased all-cause mortality (hazard ratio [HR]: 1.13; 95% confidence interval [CI], 1.07-1.19; P < 0.001) and graft failure (HR: 1.16; 95% CI, 1.11-1.22; P < 0.001). Receiving donor organ with diabetes reduced graft survival in patients who received LT for nonalcoholic steatohepatitis cirrhosis (HR: 1.26; 95% CI, 1.13-1.41; P < 0.001) but not other etiologies of cirrhosis. CONCLUSIONS: Donor diabetes was associated with worse outcomes post-LT, particularly in patients receiving LT for nonalcoholic steatohepatitis cirrhosis. Future studies are needed to better understand the mechanism underlying this association to develop better risk stratification and clinical practice to improve the outcomes of the transplanted patients.

Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

Serum Tsukushi Level Is Associated With the Severity of Liver Fibrosis Independent of Type 2 Diabetes.

BACKGROUND AND AIMS: Tsukushi (TSK) is a recently identified hepatokine, and we aimed to investigate the association between systemic TSK and the severity of nonalcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes mellitus (DM). METHODS: Three hundred ninety-three DM and 289 without DM individuals were recruited for transient elastography assessment to determine liver steatosis and fibrosis. Serum TSK was measured by ELISA. The presence of NAFLD was defined as controlled attenuation parameter ≥ 248 dB/m. RESULTS: NAFLD was present in 276 (70.2%) and 129 (44.6%) subjects with and without DM respectively, and they had higher serum TSK levels than those without NAFLD [DM group: 91.0 ng/mL (61.7-133.8) vs 82.5 (60.9-118.5), P < .01 respectively; without DM group: 97.1 ng/mL (69.3-148.6) vs 80.8 (53.4-111.6) respectively, P < .01]. Univariate analysis showed that serum TSK significantly correlated with the degree of steatosis and fibrosis both in subjects with and without DM. On multivariable regression analysis, only liver stiffness and estimated glomerular filtration rate were significant determinants of TSK level, and the relationship was independent of diabetes and serum adiponectin. Out of 405 subjects with NAFLD, 49 had either advanced fibrosis or cirrhosis. The area under receiver operating characteristic curve of serum TSK to indicate advanced fibrosis or cirrhosis was 0.70 (95% CI .62-.77), which was significantly better than that of fibrosis-4 index, 0.64 (95% CI .55-.72), P < .05. CONCLUSION: Serum TSK levels were increased in subjects with NAFLD and reflected the severity of liver fibrosis.

Plasma interferon-gamma-inducible-protein 10 level as a predictive factor of spontaneous hepatitis B surface antigen seroclearance in chronic hepatitis B patients.

BACKGROUND AND AIM: Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs in patients that are chronically infected with the hepatitis B virus. As the functional cure and ultimate treatment endpoint of chronic hepatitis B (CHB), HBsAg seroclearance is an important milestone in the natural history of CHB and serves great clinical value. This study aims to identify host and viral factors associated with HBsAg seroclearance. METHODS: This is a retrospective study carried out in the Queen Mary Hospital, Hong Kong. By analyzing the plasma retrieved from the serum archive (collected during 2011-2021) of 100 CHB patients attending the hospital's liver clinic, the longitudinal cytokine profiles between the HBsAg-losers and the control groups were compared. RESULTS: Data revealed that plasma levels of IP-10 were significantly lower at 3-5 years prior to HBsAg seroclearance compared with patients who remained HBsAg positive (P < 0.05). Receiver operating characteristic curve analysis reveals that plasma IP-10 levels at multiple time points before HBsAg seroclearance return area under receivor-operating characteristic curve (AUC) greater than 0.7. Plasma IP-10 levels at 42.39 pg/mL produced an AUC = 0.723 with 74.0% sensitivity and 75.5% specificity to predict subsequent HBsAg seroclearance in the next 3-5 years. Low plasma IP-10 identified 91.4% patients with quantitative HBsAg < 100 IU/mL who would subsequently develop HBsAg seroclearance, compared with 37% with higher plasma IP-10 levels (P < 0.001). CONCLUSIONS: Low plasma levels of IP-10 are associated with subsequent HBsAg seroclearance, suggesting potential clinical utilities of measurement of IP-10 in predicting HBsAg seroclearance, especially among patients with low HBsAg.

Portable electrical impedance tomography (EIT) system stages non-alcoholic fatty liver disease for potential screening and monitoring at home.

This study demonstrates the feasibility of predicting NAFLD using multi-spectral electrical impedance tomography (EIT), group source separation, constant reference EIT and anthropometric measures. Vibration-controlled Transient Elastography (VCTE) Controlled Attenuated Parameter (CAP; n = 121) and magnetic resonance imaging-proton density fat fraction (MRI-PDFF; n = 34) achieved a sensitivity of 70.9% and specificity of 73.8% with our CAP predicting model and sensitivity of 77.8% and specificity of 80.0% with our MRI-PDFF predicting model. In summary, a portable EIT can be a cost-effective and self-administrable alternative for widespread home-based and community-based diagnostic screening and treatment monitoring of NAFLD.Clinical Relevance- Portable multi-spectral EIT system has the sensitivity and specificity to potentially unlock biomedical imaging in telemedicine for home-based and community-based screening, staging and monitoring for NAFLD.

FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways.

BACKGROUND: Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive. METHODS: CRISPR-Cas9 system was used to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using in vitro experiments. RESULTS: We found that FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. FAT4-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of FAT4-KO cells identified PAK6-mediated WNT/ß-catenin signaling to promote tumor growth. Suppression of PAK6 led to ß-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed FAT4-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on ß-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/ß-catenin signaling, suggesting the shifting of ß-catenin-dependent to ß-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival. CONCLUSIONS: Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment.

Bepirovirsen (GSK3228836) in chronic hepatitis B infection: an evaluation of phase II progress.

INTRODUCTION: Chronic hepatitis B infection is a major global health issue associated with significant liver-related morbidity and mortality. While existing treatments can suppress the virus effectively, they are incapable of inducing functional cure, as defined by hepatitis B surface antigen (HBsAg) seroclearance. Currently, numerous novel compounds are being developed, including bepirovirsen, an antisense oligonucleotide (ASO). AREAS COVERED: This review summarizes the mechanism of action, pharmacokinetics, clinical efficacy and safety data collected from phase I and II studies of bepirovirsen. The data were extracted from publications relevant to the pivotal trials of bepirovirsen, in either full manuscript or conference abstracts. EXPERTOPINION: Bepirovirsen, a 20-mer ASO, has already entered phase III clinical evaluation using the optimal dosing regimen of 300 mg subcutaneous injection weekly for 24 weeks in nucleoside analogue-treated HBeAg-negative non-cirrhotic patients with low (<3000 IU/mL) baseline HBsAg. The durability and long-term clinical outcomes among Bepirovirsen responders will need to be evaluated. The stop-to-cure approach in those reaching HBsAg < 100 IU/mL should also be explored. In the long run, Bepirovirsen has the potential to facilitate viral hepatitis elimination.

Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic hepatitis B patients - a retrospective longitudinal study.

BACKGROUND AND AIM: In chronic hepatitis B infection (CHB), seroclearance of hepatitis B surface antigen (HBsAg) is associated with favourable clinical outcomes compared to those with persistent HBsAg seropositivity, and thus considered as a desired treatment endpoint. This current study explores the possibility of serum antibody to hepatitis B core antigen (anti-HBc) as a potential predictive factor of HBsAg seroclearance. METHODS: This is a retrospective study that analyzed the plasma samples of CHB patients using the LUMIPULSE® G1200 analyzer. The longitudinal anti-HBc level between patients who subsequently achieved HBsAg seroclearance (S-losers) and those with persistent HBsAg-positivity (controls) were compared at multiple time points before the event. RESULTS: A total of 240 subjects (120 S-losers and 120 controls; age- and gender-matched) were included (mean age 56.42 ± 10.81, 65% male). Compared to controls, S-losers had significantly lower plasma anti-HBc levels prior to HBsAg seroclearance, with a significant trend of declining plasma anti-HBc 8-5 years prior to HBsAg seroclearance (p < 0.01), while such trend was not observed in controls. ROC curve analysis revealed that plasma anti-HBc at multiple time points before HBsAg seroclearance return AUC greater than 0.7. Plasma anti-HBc level at the cut-off value of 82.50 COI was 68.3% sensitive and 90% specific for HBsAg seroclearance within 1 year. Combining with quantitative HBsAg < 100 IU/mL, anti-HBc < 82.5 COI identified 88.2% patients who would develop HBsAg seroclearance within 1 year. CONCLUSION: Plasma anti-HBc level began to decline 10 years prior to HBsAg seroclearance and can serve as a potential predictor for subsequent HBsAg seroclearance.