Publications by authors named "Man-Fung Yuen"

349 Publications

Prognostic value and reversibility of liver stiffness in patients undergoing tricuspid annuloplasty.

Eur Heart J Cardiovasc Imaging 2021 Apr 7. Epub 2021 Apr 7.

Division of Cardiology, Department of Medicine, The University of Hong Kong Shen Zhen Hospital, Shen Zhen, China.

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 < 0.01) was noted only in patients who had no adverse events, not in those who experienced heart failure (17.1-14.2 kPa, P = 0.87) and seems to be linked to an absence of TR recurrence.

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.
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http://dx.doi.org/10.1093/ehjci/jeab059DOI Listing
April 2021

RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies.

Viruses 2021 Mar 30;13(4). Epub 2021 Mar 30.

Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA.

Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection.
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http://dx.doi.org/10.3390/v13040581DOI Listing
March 2021

Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy.

J Gastroenterol 2021 Mar 27. Epub 2021 Mar 27.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 4/F, Professorial Block, Pokfulam Road 102, Pok Fu Lam, Hong Kong.

Background: We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development.

Methods: 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.

Results: 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.

Conclusions: More than 50% CHB patients on ETV with HBV DNA < LLOQ by standard assay had persistent viraemia as determined by a more sensitive assay. Detectable HBV DNA or pgRNA by more sensitive assays was associated with HCC development. More potent viral suppression is required to further reduce the risk of HCC.
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http://dx.doi.org/10.1007/s00535-021-01780-5DOI Listing
March 2021

First-line oral antiviral therapies showed similar efficacies in suppression of serum HBcrAg in chronic hepatitis B patients.

BMC Gastroenterol 2021 Mar 17;21(1):123. Epub 2021 Mar 17.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102,, Pok Fu Lam, Hong Kong.

Background: Serum hepatitis B core-related antigen (HBcrAg) is a potential surrogate marker for intra-hepatic covalently-closed circular DNA in chronic hepatitis B (CHB). We aimed to study the profiles of serum HBcrAg in CHB patients treated with first-line nucleos(t)ide analogues (NA): entecavir (ETV), tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).

Method: Serum HBcrAg was measured in 120 treatment-naïve CHB patients receiving one of the 3 NAs (ETV: TDF: TAF = 60: 26: 34) using the Lumipulse G HBcrAg assay in a Lumipulse G1200 analyzer (Fujirebio Inc, Toyko, Japan). Serum HBcrAg levels were measured at week 0, week 48 and week 96 of NA therapy.

Results: Among the 120 patients, 67 (55.8%) were hepatitis B e antigen (HBeAg) positive. Both tenofovir and ETV led to significantly lower serum HBcrAg at week 48 and week 96 compared to week 0. There were no significant differences for the magnitude of median HBcrAg decline at week 96 between tenofovir and ETV in HBeAg-positive (2.28 vs. 1.65 log U/mL, p > 0.05) and HBeAg-negative (0.83 vs. 0.54 log U/mL, p > 0.05) patients. TDF and TAF produced no significant differences in the magnitude of median HBcrAg decline at week 96 (HBeAg-positive: 2.63 vs. 1.83, respectively; HBeAg-negative: 1.04 vs. 0.40, respectively; both p > 0.05).

Conclusion: Magnitude of reduction of HBcrAg levels after 2-year first-line treatment did not differ statistically among the current first-line NAs, although HBcrAg reduction was numerically greater in tenofovir-treated group. More long-term studies are essential to determine whether tenofovir exerts a more pronounced effect on HBcrAg.
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http://dx.doi.org/10.1186/s12876-021-01711-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968194PMC
March 2021

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

Gut 2021 Mar 12. Epub 2021 Mar 12.

Arrowhead Pharmaceuticals, Pasadena, California, USA.

Objective: We 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.

Design: The 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.

Results: All 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. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with 10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.

Conclusions: MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.

Trial Registration Number: NCT02065336.
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http://dx.doi.org/10.1136/gutjnl-2020-323445DOI Listing
March 2021

Development of a Non-Invasive Liver Fibrosis Score Based on Transient Elastography for Risk Stratification in Patients with Type 2 Diabetes.

Endocrinol Metab (Seoul) 2021 Feb 24;36(1):134-145. Epub 2021 Feb 24.

Department of Medicine, University of Hong Kong, Hong Kong, China.

Background: In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to identify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to facilitate 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 patients 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 negative predictive values (NPV).

Results: DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albuminuria, 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<0.01) than the conventional fibrosis scores, being 0.85 and 0.81 in the training and testing sets, respectively.

Conclusion: Compared to conventional fibrosis scores, DFS, with a high NPV, more accurately identified diabetes patients at-risk of AF, who need further evaluation by hepatologists.
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http://dx.doi.org/10.3803/EnM.2020.887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937838PMC
February 2021

Reply.

Clin Gastroenterol Hepatol 2021 Feb;19(2):408-409

Department of Medicine, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1016/j.cgh.2020.03.058DOI Listing
February 2021

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

Hepatol Int 2021 Feb 4;15(1):71-81. Epub 2021 Jan 4.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, 780 Welch Road, CJ250K, Palo Alto, CA, 94304, USA.

Background: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.

Methods: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.

Results: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.

Conclusion: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.
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http://dx.doi.org/10.1007/s12072-020-10113-2DOI Listing
February 2021

Reply to "Can the ratio of serum HBV RNA to DNA reflect the reverse transcription efficiency of viral pgRNA?"

Hepatology 2020 Dec 23. Epub 2020 Dec 23.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.

We thank Li et al for their interest regarding our article reporting the profile of serum HBV RNA in patients with chronic hepatitis B infection. In our study, we used a relatively established assay that detects amplicons in the HBV X and core targets to measure serum HBV RNA, which is full-length pre-genomic RNA. We acknowledged that the assay could not detect all RNA materials that are present in the serum, e.g. spliced HBV variants, X gene RNA and smaller fragments.
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http://dx.doi.org/10.1002/hep.31689DOI Listing
December 2020

HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort.

Hepatol Int 2020 Dec 4;14(6):1023-1033. Epub 2020 Dec 4.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 780 Welch Road, Palo Alto, CA, 94304, USA.

Background: Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients.

Methods: To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups.

Results: In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p < 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p < 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005).

Conclusions: Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.
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http://dx.doi.org/10.1007/s12072-020-10105-2DOI Listing
December 2020

Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1.

Adv Sci (Weinh) 2020 Nov 19;7(21):2002157. Epub 2020 Aug 19.

Department of Pathology, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong.

In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell-derived extracellular vesicles (EVs) promotes pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV-NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti-TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell-derived EVs in mice. In the clinical perspective, analysis of serum EV-NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre-metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.
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http://dx.doi.org/10.1002/advs.202002157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640351PMC
November 2020

ALT Levels for Asians With Metabolic Diseases: A Meta-analysis of 86 Studies With Individual Patient Data Validation.

Hepatol Commun 2020 Nov 9;4(11):1624-1636. Epub 2020 Sep 9.

Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA.

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 threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.
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http://dx.doi.org/10.1002/hep4.1593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603525PMC
November 2020

HBV RNA profiles in chronic hepatitis B patients under different disease phases and anti-viral therapy.

Hepatology 2020 Nov 6. Epub 2020 Nov 6.

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.

Background And Aims: Large-scale comprehensive studies on hepatitis B virus (HBV) RNA in chronic hepatitis B are lacking. We aimed to study HBV RNA profile and its correlation with other viral markers in CHB treatment-naïve patients and patients receiving nucleos(t)ide analogues (NA).

Approach & Results: Novel biomarkers including HBV RNA and hepatitis B core-related antigen (HBcrAg) were measured in 388 patients. Of these, 246 were treatment-naïve and were categorized into HBeAg-positive chronic infection (n=41), HBeAg-positive chronic hepatitis (n=81), HBeAg-negative chronic infection (n=39), HBeAg-negative chronic hepatitis (n=66), and HBsAg seroclearance (n=19). These biomarkers were also measured in 142 NA-treated patients receiving tenofovir or entecavir at baseline, week 48 and 96. The pattern of serum HBV RNA levels mirrored HBV DNA (1-2 logs higher than HBV RNA) and HBcrAg in treatment-naïve patients. HBV RNA correlated best with HBcrAg (r=0.84), and to a lesser extent with HBV DNA (r=0.737) (both p<0.001). In patients with HBsAg seroclearance, 15.8% and 15.8% had detectable serum HBV RNA and HBcrAg, respectively. NA treatment reduced serum HBV RNA by 1.46 logs and 1.77 logs at week 48 and week 96, respectively. At week 96 of NA therapy, only 19.1% tenofovir-treated and 25.7% entecavir-treated patients had unquantifiable HBV RNA (p>0.05). In treated-patients with undetectable HBV DNA, 77.5% and 30% had quantifiable HBV RNA and HBcrAg respectively.

Conclusions: HBV RNA showed distinct and corresponding profile in HBV patients in different disease phases. HBV RNA and HBcrAg could be used to monitor residual transcriptional activities in patients with HBsAg seroclearance. NA led to reduction of serum HBV RNA. Monitoring of viral activities can still be achieved in patients with undetectable HBV DNA by serum HBV RNA.
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http://dx.doi.org/10.1002/hep.31616DOI Listing
November 2020

Phenotypic Changes of PD-1 and GITR in T Cells Are Associated With Hepatitis B Surface Antigen Seroclearance.

J Clin Gastroenterol 2020 Oct 28. Epub 2020 Oct 28.

Department of Medicine, The University of Hong Kong.

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-1CD4 Tregs expression in the experimental group was significantly downregulated (13.85% vs. 10.62%, P=0.003). A similar phenomenon was noted for GITRCD8 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.
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http://dx.doi.org/10.1097/MCG.0000000000001461DOI Listing
October 2020

Incidence, Factors, and Patient-Level Data for Spontaneous HBsAg Seroclearance: A Cohort Study of 11,264 Patients.

Clin Transl Gastroenterol 2020 09;11(9):e00196

Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA.

Introduction: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics.

Methods: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed.

Results: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state.

Discussion: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).
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http://dx.doi.org/10.14309/ctg.0000000000000196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494149PMC
September 2020

LOXL4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis.

Hepatology 2020 Oct 17. Epub 2020 Oct 17.

School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR of China.

Background & Aims: Lysyl oxidase-like 4 (LOXL4) is an amine oxidase that primarily involved in extracellular matrix remodeling and is highly expressed in hepatocellular carcinoma tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis.

Approach & Results: Here we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline-deficient, L-amino acid-defined (CDAA) diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated PD-L1 expression, which further suppressed the function of CD8 T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T cell transfer or PD-L1 neutralization. Labelled-free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on IFN-mediated STATs-dependent PD-L1 activation. Hydrogen peroxide scavenge or copper chelation on macrophages abolished the IFN-mediated PD-L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68 cells were positively correlated with that of PD-L1 level. High expression of LOXL4 in CD68 cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of HCC patients.

Conclusions: LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.
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http://dx.doi.org/10.1002/hep.31600DOI Listing
October 2020

Entecavir vs Tenofovir in Hepatocellular Carcinoma Prevention in Chronic Hepatitis B Infection: A Systematic Review and Meta-Analysis.

Clin Transl Gastroenterol 2020 10;11(10):e00236

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.

Introduction: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line therapies for chronic hepatitis B (CHB) infection. Although both drugs reduce hepatocellular carcinoma (HCC) risk, their comparative effectiveness remains controversial. We aimed to determine whether TDF is superior to ETV in preventing HCC.

Methods: PubMed, Embase, and Cochrane Library from inception until June 9, 2020, were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Key terms included entecavir, tenofovir, and hepatocellular carcinoma. The adjusted hazard ratios (HRs) were pooled using a random effects model. Heterogeneity among studies was assessed by the Cochran Q test and I.

Results: Thirteen observational studies (4 of which were conference abstracts) were included with 85,008 patients with CHB (ETV: 56,346; TDF: 28,662). TDF was associated with a lower HCC risk (adjusted HR [aHR]: 0.81; 95% confidence interval [CI]: 0.67-0.99). This beneficial effect was present in cirrhotic patients (aHR: 0.73; 95% CI: 0.62-0.85) and retrospective cohort studies using electronic data sets (aHR: 0.63; 95% CI: 0.51-0.78). However, this beneficial effect did not reach statistical significance for noncirrhotic patients (aHR: 0.83, 95% CI: 0.51-1.35) and retrospective/prospective cohort studies using clinical records (aHR: 0.97; 95% CI: 0.80-1.18).

Discussion: TDF was associated with a lower HCC risk compared with ETV among patients with CHB, particularly cirrhotic patients. Further prospective large-scale studies with longer follow-up periods were required to identify specific subgroups that will benefit most from TDF.
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http://dx.doi.org/10.14309/ctg.0000000000000236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544163PMC
October 2020

Letter regarding "A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement".

J Hepatol 2020 12 17;73(6):1573-1574. Epub 2020 Sep 17.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.07.008DOI Listing
December 2020

East Asia expert opinion on treatment initiation for chronic hepatitis B.

Aliment Pharmacol Ther 2020 11 20;52(10):1540-1550. Epub 2020 Sep 20.

Hong Kong, SAR, China.

Background: Globally, chronic hepatitis B (CHB) is a major public health concern. Timely and effective management can prevent disease progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC). Currently, there is no consensus on the clinical management of CHB in East Asia.

Aim: To establish an East Asia expert opinion on treatment initiation for CHB based on alanine aminotransferase (ALT) level, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, cirrhosis and HCC risk scores.

Methods: A meeting was held online with a panel of 10 experts from East Asia to discuss ALT, HBV DNA, cirrhosis and HCC risk scores. Indications for CHB treatment in the latest international guidelines were reviewed. Consensus was summarised to provide recommendations on the initiation of treatment for CHB.

Results: Anti-viral therapy is recommended for CHB patients with (a) HBV DNA ≥ 2000 IU/mL and ALT ≥ 1× upper limit of normal (ULN); (b) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and ≥ F2 fibrosis and/or ≥ A2 necroinflammation occurs; (c) cirrhosis and detectable HBV DNA; or (d) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and a family history of cirrhosis or HCC, extrahepatic manifestations or age > 40 years. Patients with cirrhosis and/or HCC should be treated regardless of ALT levels if HBV DNA level is detectable. Initiating anti-viral therapy or close monitoring at 3-month intervals is recommended for CHB patients with at least two HCC risk factors.

Conclusions: These expert recommendations will contribute to a new standard of daily clinical practice in East Asia.
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http://dx.doi.org/10.1111/apt.16097DOI Listing
November 2020

Use of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus infection and severe renal impairment.

Clin Mol Hepatol 2020 10 28;26(4):554-561. Epub 2020 Aug 28.

Division of Gastroenterology and Hepatology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.

Background/aims: Data on treatment efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) for chronic hepatitis C virus (HCV) infection in Asian patients with severe renal impairment are limited. This study aimed to study the treatment and side effects of GLE/PIB in these patients infected with non-1 genotype (GT) HCV.

Methods: We prospectively recruited patients with Child's A cirrhosis and eGFR <30 mL/min/1.73 m2 in Hong Kong and Taiwan during 2017-2018 to receive GLE/PIB treatment.

Results: Twenty-one patients (GT2, n=7; GT3, n=6; and GT6, n=8) received GLE/PIB for 11.2±1.8 weeks. All except one were treatment-naïve. GLE/PIB was initiated in 16 patients while on dialysis (seven on peritoneal dialysis [PD] and nine on hemodialysis) and in five patients before dialysis. One patient died of PD-related peritonitis during treatment and two were lost to follow up. The SVR12 rate in the remaining 18 patients was 100%. All patients achieved undetectable levels at 4-, 12-, 24- and 48-week after treatment. Patients with deranged alanine aminotransferase showed normalization after 4 weeks and the response was sustained for 48 weeks. No significant adverse event was observed.

Conclusion: GLE/PIB treatment was associated with high efficacy and tolerability in HCV-infected patients with severe renal impairment.
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http://dx.doi.org/10.3350/cmh.2020.0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641551PMC
October 2020

Modulation of gut microbiota mediates berberine-induced expansion of immuno-suppressive cells to against alcoholic liver disease.

Clin Transl Med 2020 Aug 13;10(4):e112. Epub 2020 Aug 13.

School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China.

Background: Berberine is an isoquinoline alkaloid compound derived from many herbs, which has been used extensively to improve liver function. But action mechanism of its hepatoprotection in alcoholic liver disease (ALD) is far from being clear.

Aim: To investigate the underlying mechanism of berberine's therapeutic effect on ALD associated with gut microbiota-immune system axis.

Method: An animal model fed with ethanol that mimics drinking pattern ideally in ALD patients was established. Liver function was evaluated by biochemical test and histological examination. Immune cells were detected by flow cytometry and feces samples were collected for 16S rRNA gene amplicon sequencing.

Results: We first reported the promising beneficial effect of berberine on ameliorating acute-on-chronic alcoholic hepatic damage and explored the underlying mechanism involving gut microbiota-immune system axis. Notably, berberine activated a population with immune suppressive function, defined as granulocytic- myeloid-derived suppressor cell (G-MDSC)-like population, in the liver of mice with alleviating alcohol-induced hepatic injury. Berberine remarkably enhanced the increase of G-MDSC-like cells in blood and liver and decreased cytotoxic T cells correspondingly. Suppression of G-MDSC-like population significantly attenuated the protective effect of berberine against alcohol. Berberine activated IL6/STAT3 signaling in in vitro culture of G-MSDCs-like population, while inhibition of STAT3 activity attenuated the activation of this population by berberine. Moreover, berberine changed the overall gut microbial community, primarily increased the abundance of Akkermansia muciniphila. Of note, depletion of gut microbiota abolished the inducing effect of berberine on G-MDSC-like population, and attenuated its hepatoprotective effect against alcohol in mice, suggesting intestinal flora might be involved in mediating the expansion of this protective population.

Conclusion: Collectively, this study delivered insight into the role of immunosuppressive response in ALD, and facilitated the understanding of the pharmacological effects and action mechanisms of berberine.
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http://dx.doi.org/10.1002/ctm2.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438809PMC
August 2020

Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation.

Gut 2021 Apr 5;70(4):775-783. Epub 2020 Aug 5.

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Background: Treatment cessation in chronic HBV infection may be durable in certain patient subgroups before hepatitis B surface antigen (HBsAg) seroclearance. The role of serum HBV RNA in determining treatment cessation suitability has not been well-investigated.

Methods: Nucleos(t)ide analogue (NUC) treatment was discontinued in non-cirrhotic patients with chronic HBV with serum HBsAg <200 IU/mL and fulfilling internationally recommended criteria for treatment cessation. Patients were monitored till 48 weeks with baseline and serial measurements of serum HBsAg, HBV RNA and hepatitis B core-related antigen. NUCs were resumed when HBV DNA reaches >2000 IU/mL regardless of alanine aminotransferase (ALT) levels.

Results: 114 entecavir-treated patients (median age 58.4 years, median serum HBsAg 54.4 IU/mL) with median treatment duration of 6.7 years were recruited. The 48-week cumulative rate of HBV DNA >2000 IU/mL was 58.1%. End-of-treatment serum HBV RNA and off-treatment serial HBV RNA were both independently associated with HBV DNA >2000 IU/mL (HR 2.959, 95% CI 1.776 to 4.926, p<0.001; HR 2.278, 95% CI 1.151 to 4.525, p=0.018, respectively). Patients with HBV RNA ≥44.6 U/mL had a cumulative 48-week rate of 93.2%, while combining HBV RNA undetectability and HBsAg <10 IU/mL had a cumulative 48-week rate of 9.1%. 24 patients (38.7%) developed off-treatment ALT elevation, highest peak ALT was 1515 U/L. 8 patients (median serum HBsAg 2.6 IU/mL) developed HBsAg seroclearance.

Conclusion: Serum HBV RNA measurement is essential for deciding on entecavir cessation in patients with chronic HBV, especially with low HBsAg levels. Patients can be stratified on their risk of off-treatment relapse based on both viral determinants.

Trial Registration Number: NCT02738554.
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http://dx.doi.org/10.1136/gutjnl-2020-321116DOI Listing
April 2021

Trends in Liver Transplantation for Chronic Hepatitis B in an Era of Highly Potent Antiviral Therapies.

Liver Transpl 2021 01 20;27(1):134-139. Epub 2020 Aug 20.

The Liver Transplant Center, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong.

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http://dx.doi.org/10.1002/lt.25846DOI Listing
January 2021

Hepatocellular carcinoma: recent advances and emerging medical therapies.

F1000Res 2020 17;9. Epub 2020 Jun 17.

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.

Hepatocellular carcinoma remains a deadly disease with poor prognosis in patients with unresectable cancer. Trans-arterial chemoembolization is the primary locoregional therapy for intermediate-stage hepatocellular carcinoma, with an estimated median overall survival of less than two years. For almost a decade, sorafenib has been the only standard systemic treatment for metastatic disease or tumors which progress or are considered unsuitable for locoregional therapy. Major breakthroughs have been made over the past few years in the management of hepatocellular carcinoma, especially in medical therapies for advanced disease. In this article, recent advances in intra-arterial therapy, multi-kinase inhibitors, and immunotherapy will be reviewed.
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http://dx.doi.org/10.12688/f1000research.24543.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308880PMC
October 2020

A double-blind randomized phase 2 controlled trial of intradermal hepatitis B vaccination with a topical Toll-like receptor 7 agonist imiquimod, in patients on dialysis.

Clin Infect Dis 2020 Jun 18. Epub 2020 Jun 18.

Carol Yu's Centre for Infection and Division of Infectious Diseases, the University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.

Background: Patients on dialysis are hyporesponsive to the current hepatitis B virus vaccines (HBVv). We conducted a phase-2 trial examining four-doses of intradermal (ID) HBVv Sci-B-Vac™, with topical TLR7 agonist imiquimod pretreatment in dialysis patients.

Methods: In this double-blind, randomized-controlled trial, we enrolled and prospectively followed adult patients on dialysis between January 2016 and September 2018. Eligible patients were randomly allocated (1:1:1) into one treatment: topical imiquimod-cream followed by intradermal HBVv (IMQ_ID), and two control groups: topical aqueous-cream (placebo) followed by ID HBVv (AQ_ID) or topical aqueous-cream followed by intramuscular (IM) HBVv (AQ_IM). The primary end-point was the seroprotection rate (anti-HBs≥10mIU/mL) at 52 weeks after the first dose of HBVv.

Results: Ninety-four patients on dialysis were enrolled, among which 57.4% were previous non-responders. The primary outcome of seroprotection rate was significantly better at week 52 for the treatment group (IMQ_ID) with 96.9% seroprotection rate, comparing compared to 74.2% and 48.4% for the AQ_ID and AQ_IM groups, respectively (p<0.0001). The GMC was also significantly higher at week 52 for the IMQ_ID group of 1135 mIU/mL (95% CI, 579.4-2218.2 mIU/mL), compared to 86.9 mIU/mL (95% CI, 18.5-409.3 mIU/mL) and 7.2 mIU/mL (2.0-26.5mIU/mL) for the AQ_ID and AQ_IM groups, respectively (p<0.0001). IMQ_ID vaccination [OR, 3.70 (95% CI, 1.16-11.81;p=0.027) was the only factor independently associated with higher seroprotection rate at 52 weeks. Adverse reaction was infrequent.

Conclusions: Pretreatment with topical imiquimod (TLR7 agonist) before ID HBVv Sci-B-Vac™ was safe with favorable seroprotection and as such potentially improved prevention against HBV infection in dialysis patients.
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http://dx.doi.org/10.1093/cid/ciaa804DOI Listing
June 2020

Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B.

J Hepatol 2020 10 3;73(4):800-806. Epub 2020 Jun 3.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong; Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address:

Background & Aims: 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.

Methods: Treatment-naïve patients with CHB, normal alanine aminotransferase and low viraemia (serum HBV DNA <2,000 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.

Results: 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).

Conclusions: 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.

Lay Summary: 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.
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http://dx.doi.org/10.1016/j.jhep.2020.05.040DOI Listing
October 2020

Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance.

J Hepatol 2020 10 3;73(4):952-964. Epub 2020 Jun 3.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong. Electronic address:

Occult hepatitis B infection (OBI) refers to a condition where replication-competent HBV DNA is present in the liver, with or without HBV DNA in the blood, in individuals with serum HBsAg negativity assessed by currently available assays. The episomal covalently closed circular DNA (cccDNA) in OBI is in a low replicative state. Viral gene expression is mediated by epigenetic control of HBV transcription, including the HBV CpG island methylation pathway and post-translational modification of cccDNA-bound histone, with a different pattern from patients with chronic HBV infection. The prevalence of OBI varies tremendously across patient populations owing to numerous factors, such as geographic location, assay characteristics, host immune response, coinfection with other viruses, and vaccination status. Apart from the risk of viral reactivation upon immunosuppression and the risk of transmission of HBV, OBI has been implicated in hepatocellular carcinoma (HCC) development in patients with chronic HCV infection, those with cryptogenic or known liver disease, and in patients with HBsAg seroclearance after chronic HBV infection. An increasing number of prospective studies and meta-analyses have reported a higher incidence of HCC in patients with HCV and OBI, as well as more advanced tumour histological grades and earlier age of HCC diagnosis, compared with patients without OBI. The proposed pathogenetic mechanisms of OBI-related HCC include the influence of HBV DNA integration on the hepatocyte cell cycle, the production of pro-oncogenic proteins (HBx protein and mutated surface proteins), and persistent low-grade necroinflammation (contributing to the development of fibrosis and cirrhosis). There remain uncertainties about exactly how, and in what order, these mechanisms drive the development of tumours in patients with OBI.
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http://dx.doi.org/10.1016/j.jhep.2020.05.042DOI Listing
October 2020

Rebound of HBV DNA after cessation of nucleos/tide analogues in chronic hepatitis B patients with undetectable covalently closed.

JHEP Rep 2020 Jun 29;2(3):100112. Epub 2020 Mar 29.

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.

Background & Aims: Nucleos(t)ide analogues (NUCs) effectively suppress serum HBV DNA. Previously, we have identified 21 patients with undetectable covalently closed circular DNA (cccDNA) upon long-term NUC therapy. This study investigated the effect of NUC withdrawal in patients with undetectable cccDNA.

Methods: Nineteen patients on long term NUCs (median 13.4 years) were recruited: 13 were randomized to discontinue NUCs; 6 to continue taking NUCs. All had undetectable cccDNA at the time of last liver biopsy (median time 2.9 years prior to randomization). Serum HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), liver biochemistry, and serum HBV RNA were monitored.

Results: At the time of randomization, all patients had undetectable serum HBV DNA and HBV RNA. Twelve of the 13 patients had HBV DNA rebound to 100 IU/ml within 20 weeks of NUC discontinuation. The thirteenth patient had HBV DNA rebound at week 70. Three patients experienced biochemical flares after re-treatment which subsequently resolved. There was no significant association between the time of HBV DNA rebound and baseline HBsAg, HBcrAg and alanine aminotransferase, duration of treatment, and age at which treatment was stopped (all >0.05). At the time of HBV DNA rebound, HBV DNA levels correlated with HBcrAg levels ( = 0.003), but not with HBsAg levels ( = 0.262).

Conclusions: In patients with undetectable intrahepatic cccDNA, virologic rebound still occurred after NUC cessation. At the rebound of HBV DNA, the kinetics of HBsAg production were independent of those of viral DNA replication. Additional studies are required to determine the factors that may predict virologic rebound and when NUCs can be discontinued in HBsAg-positive patients with chronic hepatitis B.

Lay Summary: It has been shown that following long-term nucleos(t)ide analogue treatment for chronic hepatitis B, some patients have undetectable levels of viral DNA in their livers. We tested the results of withdrawing nucleos(t)ide analogue treatment in these patients and found that viral relapse could occur in patients with undetectable viral DNA. Further research is required to determine whether nucleos(t)ide analogue treatment can be discontinued in specific patients with chronic hepatitis B.
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http://dx.doi.org/10.1016/j.jhepr.2020.100112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242874PMC
June 2020

Entecavir Reduced Serum Hepatitis B Core-Related Antigen in Chronic Hepatitis B Patients with Hepatocellular Carcinoma.

Gut Liver 2020 09;14(5):665-668

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, China.

Serum hepatitis B core-related antigen (HBcrAg) was shown to predict the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients undergoing treatment. We investigated the longitudinal profile of HBcrAg in entecavir (ETV)-treated CHB patients with subsequent HCC development. We identified HCC cases diagnosed at ≥1 year after ETV initiation. CHB patients without HCC (matched for age, sex, cirrhosis status, baseline hepatitis B virus [HBV] DNA level, and ETV treatment duration) were identified as controls at an HCC:non-HCC ratio of 1:2. Serum samples were retrieved at baseline (ETV initiation) and at 3 and 5 years of ETV therapy for HBcrAg measurement (log IU/mL). In total, 180 patients (60 HCC patients matched with 120 CHB patients without HCC; median age, 56.5 years; 80.6% male; baseline HBV DNA, 5.9 log IU/mL; median follow-up, 6.8 years) were recruited. The median time from ETV initiation to HCC development was 3.2 years. HBcrAg levels were higher in HCC cases than in controls at all three time points: 5.69 log IU/ mL versus 5.02 log IU/mL (p=0.025), 4.23 log IU/mL versus 3.36 log IU/mL (p=0.007), and 3.86 log IU/mL versus 3.36 log IU/mL (p=0.009), respectively. ETV led to similar rates of decline in HBcrAg from baseline to 3 years in both groups (0.34 log IU/mL/year vs 0.39 log IU/mL/year, p=0.774), although the decline from 3 to 5 years was slower in the non- HCC group (0.05 log IU/mL/year) than in the HCC group (0.09 log IU/mL/year, p=0.055). ETV time-dependently reduced HBcrAg in HCC and non-HCC patients. HBcrAg interpretation should consider the antiviral treatment duration.
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http://dx.doi.org/10.5009/gnl19434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492492PMC
September 2020

Cost-Utility of All-Oral Direct-Acting Antiviral Regimens for the Treatment of Genotype 1 Chronic Hepatitis C Virus-Infected Patients in Hong Kong.

Dig Dis Sci 2021 Apr 8;66(4):1315-1326. Epub 2020 May 8.

Merck & Co., Inc., Kenilworth, NJ, USA.

Background: Direct-acting antivirals (DAAs) are entering the hepatitis C virus (HCV) treatment landscape in Hong Kong, prompting the need for cost-effectiveness evaluations of these interventions to enable optimal use of healthcare resources.

Aims: This study aimed to compare the cost-effectiveness of DAAs to standard-of-care pegylated interferon plus ribavirin (RBV) in treatment-naïve patients without significant liver fibrosis and to compare different DAAs in patients who are treatment-experienced and/or have advanced liver disease.

Methods: A Markov model was constructed to evaluate cost-effectiveness over a lifetime time horizon from the payer perspective. The target population was treatment-naïve and treatment-experienced HCV genotype 1 patients, stratified by degree of liver fibrosis. The model consists of 16 health states encompassing METAVIR fibrosis score (F0-F4), treatment success or failure, decompensated cirrhosis, hepatocellular carcinoma, liver transplant, and liver-related death. The proportions of patients achieving sustained virologic response were obtained from clinical trials. Other inputs were obtained from published and local data. The primary outcome was incremental cost-utility ratio for each DAA versus pegylated interferon + ribavirin and among different DAAs.

Results: In treatment-naïve F0-2 HCV patients, all DAAs were cost-effective in genotype 1a and daclatasvir + asunaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir were cost-effective compared to pegylated interferon + ribavirin in genotype 1b. In genotypes 1a and 1b, treatment-experienced patients, and F3-4 patients, elbasvir/grazoprevir was the least costly DAA and economically dominant over most other DAAs.

Conclusions: DAAs can be a cost-effective option for the treatment of genotype 1 HCV patients in Hong Kong, and elbasvir/grazoprevir is cost-effective.
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http://dx.doi.org/10.1007/s10620-020-06281-8DOI Listing
April 2021