Man-fung Yuen - Academia.edu (original) (raw)

Papers by Man-fung Yuen

Research paper thumbnail of Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection

Research paper thumbnail of Deeper virologic suppression with the addition of vebicorvir, a first-generation hepatitis B core inhibitor, to entecavir correlates with reduced inflammation and fibrosis-4 index in treatment naïve patients with HBeAg positive chronic hepatitis B

Research paper thumbnail of Viral nucleic acids suppression activity of RO7049389 plus NUC with/without Peg-IFN in virologically-suppressed and naive chronic hepatitis B patients: 48-week treatment and post-treatment follow-up

Research paper thumbnail of 328: Real-World Treatment Outcome with Protease Inhibitor (Pi) vs Non-Pi Direct Acting Antivirals (Daas) in Decompensated HCV Cirrhosis: A Real-C Study

Research paper thumbnail of Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy

Research paper thumbnail of Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection

Journal of Hepatology

BACKGROUND AND AIMS Hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitors (NrtI)... more BACKGROUND AND AIMS Hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitors (NrtI) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase 2 trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically-suppressed patients on NrtI. METHODS Noncirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B "e" antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS Of 73 patients enrolled, 47 and 26 were HBeAg positive and negative. In HBeAg positive and negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline receiving VBR+NrtI achieved DNA target not detected at Week 24 compared to PBO+NrtI. In HBeAg positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was evident by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. LAY SUMMARY Core inhibitors represent a novel approach to treating chronic HBV infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated. CLINICAL TRIALS NUMBER NCT03576066.

Research paper thumbnail of Stanniocalcin 1 is a serum biomarker and potential therapeutic target for HBV ‐associated liver fibrosis

The Journal of Pathology, 2022

Stanniocalcin 1 (STC1), a secreted protein, is upregulated in human cancers including hepatocellu... more Stanniocalcin 1 (STC1), a secreted protein, is upregulated in human cancers including hepatocellular carcinoma (HCC). While most HCCs develop from chronic liver disease which involves progressive parenchymal injury and fibrosis, the role of STC1 in this pre-neoplastic stage remains poorly understood. In this study, we investigated the clinical relevance and functional significance of secreted STC1 in liver fibrosis. To this end, STC1 level was determined in the serum samples of chronic hepatitis B patients and correlated with the degree of liver fibrosis. Diagnostic performance of STC1 was analysed by area under receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value. The results were compared with other well-characterised serum biomarkers for liver fibrosis, aspartate transaminase to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). The functional role of STC1 was interrogated by in vitro experiments using cell line models. Expression of fibrogenic markers was quantified by RT-qPCR and western blotting. Our results showed that serum STC1 level in chronic hepatitis B patients was positively correlated with the degree of liver fibrosis and showed a stepwise increase in accordance with the severity of fibrosis. The AUROCs for detecting significant fibrosis (>9.0 kPa) and cirrhosis (>12.0 kPa) was 0.911 and 0.880, respectively. STC1 demonstrated a superior specificity and positive predictive value when compared to APRI and FIB-4. Consistent with this, STC1 was elevated in the liver tissues and sera of CCl4 -treated mice showing marked liver fibrosis. In vitro, STC1 was secreted by the human hepatic stellate cell line LX2. Human recombinant STC1 (rhSTC1) induced expression of fibrogenic markers in LX2 cells. The pro-fibrogenic phenotype conferred by rhSTC1 or TGF-β1 in LX2 cells could be attenuated using anti-STC1 antibody. Taken together, STC1 is a specific serum biomarker for HBV-associated liver fibrosis. STC1 functionally promotes liver fibrogenesis and is a potential actionable target. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-positive chronic hepatitis B infection in a long-term extension study

Journal of Hepatology, 2020

Conclusion: Two monthly doses of VIR-2218 at 20-200 mg were well tolerated in CHB patients. Subst... more Conclusion: Two monthly doses of VIR-2218 at 20-200 mg were well tolerated in CHB patients. Substantial reductions in HBsAg were observed in both HBeAg-and HBeAg+ patients and across all dose levels. Differential patterns of decline suggest that early responses (<8 weeks) in HBsAg may not predict the final magnitude of decline. Evaluation of VIR-2218 in CHB patients is ongoing. AS069 RO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy Man

Research paper thumbnail of Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment

Gut, 2021

ObjectiveWe examined the serological, virological (in serum and liver) and histological profiles ... more ObjectiveWe examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.DesignThe present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4–9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.ResultsAll patients had 28.9–30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of −1.7 and −3.5 log IU/mL >30 months after MD. ...

Research paper thumbnail of ALT Levels for Asians With Metabolic Diseases: A Meta‐analysis of 86 Studies With Individual Patient Data Validation

Hepatology Communications, 2020

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healt... more The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta‐analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound‐detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random‐effects mixed model and upper threshold (95th‐percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper th...

Research paper thumbnail of FRI-151-Characterization of regulatory T cells and the role of PD-1 and TNF-alpha in spontaneous hepatitis B surface antigen seroclearance in chronic hepatitis B

Journal of Hepatology, 2019

PEG-IFN-alpha (GS-US-174-0149).Next-generation sequencing was performed on 54 samples from 46 pat... more PEG-IFN-alpha (GS-US-174-0149).Next-generation sequencing was performed on 54 samples from 46 patients with high quality mRNA libraries, which included 8 pairs of longitudinal biopsies baseline and 96 weeks post-antiviral treatment. A multimodal bioinformatics pipeline was used to analyze both host and viral transcriptomes including viral transcript quantification, detection of HBV integration events, and cell-type enrichment analysis using the xCell algorithm. Results: Using gene set enrichment analysis we found two unique immune signatures in baseline samples: 1) high CD4+ memory T cells, high CD8+ TCM, high Th2, high PD-L1, and 2) low CD4+ memory T cells, low CD8+ TCM, high Th1, low PD-L1. Preliminary correlations found a trend toward ALT levels (p = 0.052), however, a complete analysis of baseline and disease factors is ongoing. Additionally, a subset analysis of the paired liver biopsy samples revealed an enhancement of the latter immune signature. Our deep sequencing approach also enabled detection of viral transcripts. In HBeAg positive patients, we see coverage across the entire HBV genome, suggestive of transcription from cccDNA (Figure 1). However, in HBeAg negative patients, we observe loss of coverage in the core region and downstream of DR1, suggestive of transcription largely from HBV integration (Figure 1). This suggests that the contribution of viral transcripts from cccDNA is dramatically reduced in HBeAg negative patients, thereby revealing the contribution of viral transcripts from HBV DNA integration. We also observed this pattern of HBV transcription in patients following who lost HBeAg following antiviral treatment. Conclusion: Here, we report the first transcriptome characterization of intrahepatic immune and viral signatures in CHB patients without HCC. RNA-seq analysis of longitudinal biopsies will allow for an understanding of how the immune microenvironment and viral transcripts are affected by treatment which will provide insight into necessary steps needed for a functional cure.

Research paper thumbnail of THU-236-Integration of HBV DNA near cancer-related genes in HBsAg-negative hepatocellular carcinoma patients

Journal of Hepatology, 2019

Research paper thumbnail of LBO-06-Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients

Journal of Hepatology, 2019

strongest median decline of HEV RNA was observed between baseline and week 2 (1.1 log10). However... more strongest median decline of HEV RNA was observed between baseline and week 2 (1.1 log10). However, no patient reached the primary end point and only two patients maintained a >1log10 reduction of HEV RNA at week 24. Importantly, ALT level showed a significant decline from 4.6 upper limit of normal (ULN) to 2.2 ULN at week 12 and 2.7 ULN at week 24. Treatment with SOF was well tolerated. Creatinine clearance was stable during therapy; all patients stayed above GFR 30 ml/min. Six serious adverse events were reported in three patients but only one (elevated lipase) was considered to be related to SOF. Sadly, this patient experienced a sepsis and died 4 weeks after SOF was stopped. Conclusion: Sofosbuvir shows moderate antiviral efficacy but does not lead to cure of cHEV. HEV RNA decline was associated with ALT improvements. SOF should be further investigated in combination with RBV for the treatment of cHEV in immunocompromised patients. LBO-05 Bezafibrate improves the effect of obeticholic acid on cholestasis in patients with primary biliary cholangitis

Research paper thumbnail of Oral nucleos(t)ide Analogs Alone After Liver Transplantation in Chronic Hepatitis B with Preexisting rt204 Mutation

Transplantation, Oct 21, 2017

There is currently limited data regarding the use of oral antiviral therapy alone without HBIG fo... more There is currently limited data regarding the use of oral antiviral therapy alone without HBIG for CHB patients with preexisting LAM-resistance (LAM-R) undergoing liver transplantation. This is a cohort study determining the effectiveness and long-term outcome in this group of patients. Fifty-seven consecutive CHB patients with preexisting rt204 LAM-R mutations or virological load refractory to LAM undergoing liver transplantation were included, with a median follow-up of 73 months. Fifty-five (96.5%) patients received a regimen that included the use of nucleotide analogs. The cumulative rate of HBsAg seroclearance at 1, 5, and 10 years was 82%, 88%, and 91% respectively. At the time of transplantation, 39 (72%) patients had detectable HBV DNA, with a median of 4.5 log copies/mL. The cumulative rate of HBV undetectability was 91% at 1 year, increasing to 100% by 5 years. After 1 year of liver transplantation, over 90% of patients had undetectable HBV DNA, and from 8 years onwards, 1...

Research paper thumbnail of Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re‐evaluation of HBsAg seroclearance

Liver International, 2015

Background & AimsSerologic profiles after hepatitis B surface antigen (HBsAg) seroclearance in ch... more Background & AimsSerologic profiles after hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B (CHB) have not been well‐studied.MethodsWe employed a highly sensitive HBsAg (hs‐HBsAg) assay (lower detection limit 0.5 mIU/ml), 100 times more sensitive than conventional HBsAg measurements. CHB patients achieving HBsAg seroclearance defined by conventional assays were followed up for serum hs‐HBsAg, HBV DNA and antibody to HBsAg (anti‐HBs) levels at 0 months, 6–12 months and 3–5 years after HBsAg seroclearance. Factors associated with hs‐HBsAg detectability were determined.ResultsOne hundred and nine patients were recruited; 94 (86.2%) were followed up to years 3–5; and 25 patients (22.9%) were on nucleoside analogue therapy for a median duration of 6.0 (range 1.5–12.7) years before HBsAg seroclearance. Detectable hs‐HBsAg was noted in 88 (80.7%), 60 (55.0%) and 20 (21.3%) patients at 0 months, 6–12 months and 3–5 years respectively. At years 3–5, genotype B patients...

Research paper thumbnail of Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity

Oncogene, 2006

Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from ... more Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from several chronic liver diseases, most of which culminate in cirrhosis. As the most common causes, other than alcoholic cirrhosis, are chronic hepatitis B and C infections, its prevalence worldwide is linked to the prevalence of these two viruses. Thus, the highest rates are in southeast Asia and sub-Saharan Africa, the world's most populous nations, where hepatitis B virus infection is endemic. In most western countries, hepatitis C virus infection is the predominant cause, and hepatitis B-related liver cancer occurs largely among immigrants from countries of high hepatitis B endemicity. In most western countries, the incidence and mortality from HCC is increasing as a consequence of the chronic sequelae of the 'epidemic' of hepatitis C of the 1960-1980s. In the US, modeling of this infection predicts a continued rise in liver cancer over the next decade. Surveillance by the National Cancer Institute and the Centers for Disease Control confirms the increasing incidence of and mortality from HCC to the year 2000, although subsequent analyses suggest a slowing or possibly decline in the rate of increase. Whether this trend will continue requires further evaluation.

Research paper thumbnail of Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study

Gut, Jan 15, 2014

The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HB... more The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated. Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥2 years with undetectable HBV DNA levels on ≥3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6-12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000 IU/mL). 184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11 000 (range 2115 to >1.98×10(8)) IU/mL. 42 (25.8%) patients had elevated alanine aminotra...

Research paper thumbnail of P175 Association of Methylated Histones and Dna Methylases with Hepatitis B Virus Covalently Closed Circular Dna and Their Association with Hepatitis B Virus Replication

Journal of Hepatology, 2014

Poster Presentation - Session 7A: Viral Hepatitis: Hepatitis B & D - ExperimentalLink_to_subs... more Poster Presentation - Session 7A: Viral Hepatitis: Hepatitis B & D - ExperimentalLink_to_subscribed_fulltex

Research paper thumbnail of P568 Virological and Clinico-Pathological Factors in Predicting Recurrence of Hepatitis B Related Hepatocellular Carcinoma After Surgical Resection

Journal of Hepatology, 2014

POSTERS defined eIF3 subunit (eIF3m) has not characterized. Recently, reported that eIF3m express... more POSTERS defined eIF3 subunit (eIF3m) has not characterized. Recently, reported that eIF3m expression affects cell proliferation and cell cycle progression in colon cancer and one of tumorigenesis-related genes, macrophage migration inhibitory factor (MIF) is affected by eIF3m. We investigated expressions of eIF3m and MIF in human HCCs via immunohistochemistry and their relations with clinicopathological parameters. Methods: Surgically resected HCCs from 114 patients were selected. Immunohistochemistry for anti-eIF3m and anti-MIF processed, using auto-immunostainer. Results: One hundred HCCs (87.7%) expressed eIF3m, low grade 20.2%, intermediate 45.6% and high 21.9%. eIF3m expressed predominantly at peripheries and invasive fronts of tumor nests. Higher expression significantly associated with high preoperative AFP, poor differentiation and septal formation (P = <0.0001, 0.0001, 0.0055). Fatty change, mononuclear cell infiltration, vascular invasion and progression tended to be associated with higher expression. MIF expressed in 103 of 114 HCCs (90.4%), low grade 43.0% and high 47.4%. High expression was significantly associated with high preoperative AFP and encapsulation (P = 0.0123, 0.0142). Vascular invasion tended to be associated with high expression. Significant positive correlation was found between eIF3m and MIF expressions (P = 0.0048). Higher MIF expression tended to be related with high recur probability. eIF3m or MIF expression was not an independent predictive factor for recur throughout multivariate analysis. Conclusions: eIF3m expression suggested to have a pivotal role in HCC progression and invasion with downstream regulation of MIF expression. MIF expression may be an important factor for prediction of HCC recur.

Research paper thumbnail of Future Prevention and Treatment of Chronic Hepatitis B Infection

Journal of Clinical Gastroenterology, 2012

The authors declare they have participated in the preparation of the manuscript and have seen and... more The authors declare they have participated in the preparation of the manuscript and have seen and approved the final version. Disclosure statement WK Seto is a clinical investigator for trials under LG Life Science and Bristol-Myers Squibb. J Fung is an invited speaker for Bristol-Myers Squibb. MF Yuen is a clinical investigator for trials under LG Life Science, FibroGen and Bristol-Myers Squibb, and is an invited speaker for Bristol-Myers Squibb. CL Lai is a clinical investigator for trials under LG Life Science and FibroGen, and is an invited speaker for Bristol-Myers Squibb.

Research paper thumbnail of Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection

Research paper thumbnail of Deeper virologic suppression with the addition of vebicorvir, a first-generation hepatitis B core inhibitor, to entecavir correlates with reduced inflammation and fibrosis-4 index in treatment naïve patients with HBeAg positive chronic hepatitis B

Research paper thumbnail of Viral nucleic acids suppression activity of RO7049389 plus NUC with/without Peg-IFN in virologically-suppressed and naive chronic hepatitis B patients: 48-week treatment and post-treatment follow-up

Research paper thumbnail of 328: Real-World Treatment Outcome with Protease Inhibitor (Pi) vs Non-Pi Direct Acting Antivirals (Daas) in Decompensated HCV Cirrhosis: A Real-C Study

Research paper thumbnail of Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy

Research paper thumbnail of Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection

Journal of Hepatology

BACKGROUND AND AIMS Hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitors (NrtI)... more BACKGROUND AND AIMS Hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitors (NrtI) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase 2 trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically-suppressed patients on NrtI. METHODS Noncirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B "e" antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS Of 73 patients enrolled, 47 and 26 were HBeAg positive and negative. In HBeAg positive and negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline receiving VBR+NrtI achieved DNA target not detected at Week 24 compared to PBO+NrtI. In HBeAg positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was evident by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. LAY SUMMARY Core inhibitors represent a novel approach to treating chronic HBV infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated. CLINICAL TRIALS NUMBER NCT03576066.

Research paper thumbnail of Stanniocalcin 1 is a serum biomarker and potential therapeutic target for HBV ‐associated liver fibrosis

The Journal of Pathology, 2022

Stanniocalcin 1 (STC1), a secreted protein, is upregulated in human cancers including hepatocellu... more Stanniocalcin 1 (STC1), a secreted protein, is upregulated in human cancers including hepatocellular carcinoma (HCC). While most HCCs develop from chronic liver disease which involves progressive parenchymal injury and fibrosis, the role of STC1 in this pre-neoplastic stage remains poorly understood. In this study, we investigated the clinical relevance and functional significance of secreted STC1 in liver fibrosis. To this end, STC1 level was determined in the serum samples of chronic hepatitis B patients and correlated with the degree of liver fibrosis. Diagnostic performance of STC1 was analysed by area under receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value. The results were compared with other well-characterised serum biomarkers for liver fibrosis, aspartate transaminase to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). The functional role of STC1 was interrogated by in vitro experiments using cell line models. Expression of fibrogenic markers was quantified by RT-qPCR and western blotting. Our results showed that serum STC1 level in chronic hepatitis B patients was positively correlated with the degree of liver fibrosis and showed a stepwise increase in accordance with the severity of fibrosis. The AUROCs for detecting significant fibrosis (>9.0 kPa) and cirrhosis (>12.0 kPa) was 0.911 and 0.880, respectively. STC1 demonstrated a superior specificity and positive predictive value when compared to APRI and FIB-4. Consistent with this, STC1 was elevated in the liver tissues and sera of CCl4 -treated mice showing marked liver fibrosis. In vitro, STC1 was secreted by the human hepatic stellate cell line LX2. Human recombinant STC1 (rhSTC1) induced expression of fibrogenic markers in LX2 cells. The pro-fibrogenic phenotype conferred by rhSTC1 or TGF-β1 in LX2 cells could be attenuated using anti-STC1 antibody. Taken together, STC1 is a specific serum biomarker for HBV-associated liver fibrosis. STC1 functionally promotes liver fibrogenesis and is a potential actionable target. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-positive chronic hepatitis B infection in a long-term extension study

Journal of Hepatology, 2020

Conclusion: Two monthly doses of VIR-2218 at 20-200 mg were well tolerated in CHB patients. Subst... more Conclusion: Two monthly doses of VIR-2218 at 20-200 mg were well tolerated in CHB patients. Substantial reductions in HBsAg were observed in both HBeAg-and HBeAg+ patients and across all dose levels. Differential patterns of decline suggest that early responses (<8 weeks) in HBsAg may not predict the final magnitude of decline. Evaluation of VIR-2218 in CHB patients is ongoing. AS069 RO7062931 antisense oligonucleotide phase 1 study demonstrates target engagement in patients with chronic hepatitis B on established nucleos(t)ide therapy Man

Research paper thumbnail of Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment

Gut, 2021

ObjectiveWe examined the serological, virological (in serum and liver) and histological profiles ... more ObjectiveWe examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.DesignThe present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4–9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.ResultsAll patients had 28.9–30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of −1.7 and −3.5 log IU/mL >30 months after MD. ...

Research paper thumbnail of ALT Levels for Asians With Metabolic Diseases: A Meta‐analysis of 86 Studies With Individual Patient Data Validation

Hepatology Communications, 2020

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healt... more The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta‐analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound‐detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random‐effects mixed model and upper threshold (95th‐percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper th...

Research paper thumbnail of FRI-151-Characterization of regulatory T cells and the role of PD-1 and TNF-alpha in spontaneous hepatitis B surface antigen seroclearance in chronic hepatitis B

Journal of Hepatology, 2019

PEG-IFN-alpha (GS-US-174-0149).Next-generation sequencing was performed on 54 samples from 46 pat... more PEG-IFN-alpha (GS-US-174-0149).Next-generation sequencing was performed on 54 samples from 46 patients with high quality mRNA libraries, which included 8 pairs of longitudinal biopsies baseline and 96 weeks post-antiviral treatment. A multimodal bioinformatics pipeline was used to analyze both host and viral transcriptomes including viral transcript quantification, detection of HBV integration events, and cell-type enrichment analysis using the xCell algorithm. Results: Using gene set enrichment analysis we found two unique immune signatures in baseline samples: 1) high CD4+ memory T cells, high CD8+ TCM, high Th2, high PD-L1, and 2) low CD4+ memory T cells, low CD8+ TCM, high Th1, low PD-L1. Preliminary correlations found a trend toward ALT levels (p = 0.052), however, a complete analysis of baseline and disease factors is ongoing. Additionally, a subset analysis of the paired liver biopsy samples revealed an enhancement of the latter immune signature. Our deep sequencing approach also enabled detection of viral transcripts. In HBeAg positive patients, we see coverage across the entire HBV genome, suggestive of transcription from cccDNA (Figure 1). However, in HBeAg negative patients, we observe loss of coverage in the core region and downstream of DR1, suggestive of transcription largely from HBV integration (Figure 1). This suggests that the contribution of viral transcripts from cccDNA is dramatically reduced in HBeAg negative patients, thereby revealing the contribution of viral transcripts from HBV DNA integration. We also observed this pattern of HBV transcription in patients following who lost HBeAg following antiviral treatment. Conclusion: Here, we report the first transcriptome characterization of intrahepatic immune and viral signatures in CHB patients without HCC. RNA-seq analysis of longitudinal biopsies will allow for an understanding of how the immune microenvironment and viral transcripts are affected by treatment which will provide insight into necessary steps needed for a functional cure.

Research paper thumbnail of THU-236-Integration of HBV DNA near cancer-related genes in HBsAg-negative hepatocellular carcinoma patients

Journal of Hepatology, 2019

Research paper thumbnail of LBO-06-Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients

Journal of Hepatology, 2019

strongest median decline of HEV RNA was observed between baseline and week 2 (1.1 log10). However... more strongest median decline of HEV RNA was observed between baseline and week 2 (1.1 log10). However, no patient reached the primary end point and only two patients maintained a >1log10 reduction of HEV RNA at week 24. Importantly, ALT level showed a significant decline from 4.6 upper limit of normal (ULN) to 2.2 ULN at week 12 and 2.7 ULN at week 24. Treatment with SOF was well tolerated. Creatinine clearance was stable during therapy; all patients stayed above GFR 30 ml/min. Six serious adverse events were reported in three patients but only one (elevated lipase) was considered to be related to SOF. Sadly, this patient experienced a sepsis and died 4 weeks after SOF was stopped. Conclusion: Sofosbuvir shows moderate antiviral efficacy but does not lead to cure of cHEV. HEV RNA decline was associated with ALT improvements. SOF should be further investigated in combination with RBV for the treatment of cHEV in immunocompromised patients. LBO-05 Bezafibrate improves the effect of obeticholic acid on cholestasis in patients with primary biliary cholangitis

Research paper thumbnail of Oral nucleos(t)ide Analogs Alone After Liver Transplantation in Chronic Hepatitis B with Preexisting rt204 Mutation

Transplantation, Oct 21, 2017

There is currently limited data regarding the use of oral antiviral therapy alone without HBIG fo... more There is currently limited data regarding the use of oral antiviral therapy alone without HBIG for CHB patients with preexisting LAM-resistance (LAM-R) undergoing liver transplantation. This is a cohort study determining the effectiveness and long-term outcome in this group of patients. Fifty-seven consecutive CHB patients with preexisting rt204 LAM-R mutations or virological load refractory to LAM undergoing liver transplantation were included, with a median follow-up of 73 months. Fifty-five (96.5%) patients received a regimen that included the use of nucleotide analogs. The cumulative rate of HBsAg seroclearance at 1, 5, and 10 years was 82%, 88%, and 91% respectively. At the time of transplantation, 39 (72%) patients had detectable HBV DNA, with a median of 4.5 log copies/mL. The cumulative rate of HBV undetectability was 91% at 1 year, increasing to 100% by 5 years. After 1 year of liver transplantation, over 90% of patients had undetectable HBV DNA, and from 8 years onwards, 1...

Research paper thumbnail of Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re‐evaluation of HBsAg seroclearance

Liver International, 2015

Background & AimsSerologic profiles after hepatitis B surface antigen (HBsAg) seroclearance in ch... more Background & AimsSerologic profiles after hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B (CHB) have not been well‐studied.MethodsWe employed a highly sensitive HBsAg (hs‐HBsAg) assay (lower detection limit 0.5 mIU/ml), 100 times more sensitive than conventional HBsAg measurements. CHB patients achieving HBsAg seroclearance defined by conventional assays were followed up for serum hs‐HBsAg, HBV DNA and antibody to HBsAg (anti‐HBs) levels at 0 months, 6–12 months and 3–5 years after HBsAg seroclearance. Factors associated with hs‐HBsAg detectability were determined.ResultsOne hundred and nine patients were recruited; 94 (86.2%) were followed up to years 3–5; and 25 patients (22.9%) were on nucleoside analogue therapy for a median duration of 6.0 (range 1.5–12.7) years before HBsAg seroclearance. Detectable hs‐HBsAg was noted in 88 (80.7%), 60 (55.0%) and 20 (21.3%) patients at 0 months, 6–12 months and 3–5 years respectively. At years 3–5, genotype B patients...

Research paper thumbnail of Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity

Oncogene, 2006

Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from ... more Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from several chronic liver diseases, most of which culminate in cirrhosis. As the most common causes, other than alcoholic cirrhosis, are chronic hepatitis B and C infections, its prevalence worldwide is linked to the prevalence of these two viruses. Thus, the highest rates are in southeast Asia and sub-Saharan Africa, the world's most populous nations, where hepatitis B virus infection is endemic. In most western countries, hepatitis C virus infection is the predominant cause, and hepatitis B-related liver cancer occurs largely among immigrants from countries of high hepatitis B endemicity. In most western countries, the incidence and mortality from HCC is increasing as a consequence of the chronic sequelae of the 'epidemic' of hepatitis C of the 1960-1980s. In the US, modeling of this infection predicts a continued rise in liver cancer over the next decade. Surveillance by the National Cancer Institute and the Centers for Disease Control confirms the increasing incidence of and mortality from HCC to the year 2000, although subsequent analyses suggest a slowing or possibly decline in the rate of increase. Whether this trend will continue requires further evaluation.

Research paper thumbnail of Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study

Gut, Jan 15, 2014

The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HB... more The off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg) levels in predicting off-treatment durability has not been well investigated. Following Asia-Pacific Association for the Study of the Liver guidelines, entecavir was stopped in Asian HBeAg negative patients treated for ≥2 years with undetectable HBV DNA levels on ≥3 separate occasions 6 months apart before treatment cessation. HBsAg and HBV DNA levels were prospectively monitored every 6-12 weeks for 48 weeks. Entecavir was restarted if there was virologic relapse (defined as HBV DNA >2000 IU/mL). 184 patients (mean age 53.9 years, 67.9% male) were recruited. The cumulative rate of virologic relapse at 24 and 48 weeks was 74.2% and 91.4%, respectively. The median HBV DNA level at virologic relapse was 11 000 (range 2115 to >1.98×10(8)) IU/mL. 42 (25.8%) patients had elevated alanine aminotra...

Research paper thumbnail of P175 Association of Methylated Histones and Dna Methylases with Hepatitis B Virus Covalently Closed Circular Dna and Their Association with Hepatitis B Virus Replication

Journal of Hepatology, 2014

Poster Presentation - Session 7A: Viral Hepatitis: Hepatitis B & D - ExperimentalLink_to_subs... more Poster Presentation - Session 7A: Viral Hepatitis: Hepatitis B & D - ExperimentalLink_to_subscribed_fulltex

Research paper thumbnail of P568 Virological and Clinico-Pathological Factors in Predicting Recurrence of Hepatitis B Related Hepatocellular Carcinoma After Surgical Resection

Journal of Hepatology, 2014

POSTERS defined eIF3 subunit (eIF3m) has not characterized. Recently, reported that eIF3m express... more POSTERS defined eIF3 subunit (eIF3m) has not characterized. Recently, reported that eIF3m expression affects cell proliferation and cell cycle progression in colon cancer and one of tumorigenesis-related genes, macrophage migration inhibitory factor (MIF) is affected by eIF3m. We investigated expressions of eIF3m and MIF in human HCCs via immunohistochemistry and their relations with clinicopathological parameters. Methods: Surgically resected HCCs from 114 patients were selected. Immunohistochemistry for anti-eIF3m and anti-MIF processed, using auto-immunostainer. Results: One hundred HCCs (87.7%) expressed eIF3m, low grade 20.2%, intermediate 45.6% and high 21.9%. eIF3m expressed predominantly at peripheries and invasive fronts of tumor nests. Higher expression significantly associated with high preoperative AFP, poor differentiation and septal formation (P = <0.0001, 0.0001, 0.0055). Fatty change, mononuclear cell infiltration, vascular invasion and progression tended to be associated with higher expression. MIF expressed in 103 of 114 HCCs (90.4%), low grade 43.0% and high 47.4%. High expression was significantly associated with high preoperative AFP and encapsulation (P = 0.0123, 0.0142). Vascular invasion tended to be associated with high expression. Significant positive correlation was found between eIF3m and MIF expressions (P = 0.0048). Higher MIF expression tended to be related with high recur probability. eIF3m or MIF expression was not an independent predictive factor for recur throughout multivariate analysis. Conclusions: eIF3m expression suggested to have a pivotal role in HCC progression and invasion with downstream regulation of MIF expression. MIF expression may be an important factor for prediction of HCC recur.

Research paper thumbnail of Future Prevention and Treatment of Chronic Hepatitis B Infection

Journal of Clinical Gastroenterology, 2012

The authors declare they have participated in the preparation of the manuscript and have seen and... more The authors declare they have participated in the preparation of the manuscript and have seen and approved the final version. Disclosure statement WK Seto is a clinical investigator for trials under LG Life Science and Bristol-Myers Squibb. J Fung is an invited speaker for Bristol-Myers Squibb. MF Yuen is a clinical investigator for trials under LG Life Science, FibroGen and Bristol-Myers Squibb, and is an invited speaker for Bristol-Myers Squibb. CL Lai is a clinical investigator for trials under LG Life Science and FibroGen, and is an invited speaker for Bristol-Myers Squibb.