Publications by authors named "Wai-Kay Seto"

175 Publications

Statins associate with better clinical outcomes in chronic hepatitis B patients with HBsAg seroclearance.

Hepatol Int 2021 May 14. Epub 2021 May 14.

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

Introduction: We aimed to describe long-term clinical outcomes in chronic hepatitis B (CHB) patients after HBsAg seroclearance, and identify factors that modify disease outcomes.

Methods: CHB patients with HBsAg seroclearance occurring between 1986 and 2017 were recruited. Primary outcome was cirrhosis/hepatocellular carcinoma (HCC), and secondary outcomes were hepatic decompensation, liver-related death/transplantation, and all-cause mortality. Multivariable Cox model included demographics, prior antivirals, comorbidities, drugs (statins, metformin, proton-pump inhibitors, non-selective beta-blockers), and laboratory parameters (platelet, liver function test, prothrombin time, alpha-fetoprotein [AFP], anti-HBs). Statin users were propensity score matched (PSM) with non-users (1:2 ratio) for survival analysis of all outcomes.

Results: Of 913 patients with HBsAg seroclearance (male: 613 [67.1%]; median age: 53.4 years [18.5-87.0]), 129 (14.1%) were statin users. During median follow-up of 7.7 years (up to 29.1 years), 64/833 (7.7%) developed cirrhosis, 25/905 (2.8%) developed HCC, 3/913 (0.3%) underwent transplantation, and 76/913 (8.3%) died. Statins were associated with lower cirrhosis/HCC risk (adjusted hazard ratio [aHR]: 0.44; 95% CI 0.20-0.96; aHR for every 1-year increase in use: 0.85; 95% CI 0.75-0.97). Statin users had no hepatic decompensation or liver-related death/transplantation (vs 18/778 [2.3%] and 18/784 [2.3%] cases in statin non-users, respectively). Statins were also associated with lower all-cause mortality risk (aHR: 0.21; 95% CI 0.08-0.53). PSM yields consistent results for beneficial effects of statins (log-rank p < 0.05 for all outcomes). Other factors for cirrhosis/HCC included increasing age (aHR: 1.06), diabetes (aHR: 2.03), higher creatinine (aHR: 1.008), GGT > 50U/L (aHR: 3.25), and AFP > 9 ng/mL (aHR: 10.14).

Conclusion: Patients with HBsAg seroclearance have favorable long-term survival. However, liver-related adverse outcomes still develop, necessitating further investigations on beneficial effects of statins.
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http://dx.doi.org/10.1007/s12072-021-10197-4DOI Listing
May 2021

Antiviral kinetics of tenofovir alafenamide and tenofovir disoproxil fumarate over 24 weeks in women of childbearing potential with chronic HBV.

PLoS One 2021 13;16(5):e0251552. Epub 2021 May 13.

New Zealand Liver Transplant Unit, Auckland Clinical Studies, Auckland, New Zealand.

Background/purpose: Use of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV.

Methods: In a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA <200,000 IU/mL at weeks 12 and 24 were assessed. Multivariate logistic regression was used to identify factors predictive of failure to suppress HBV DNA to the target level.

Results: In 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA <200,000 IU/mL at weeks 12 and 24, respectively. Results for TAF (n = 194) vs TDF (n = 81) treatment were similar at weeks 12 and 24 (94% vs. 90% and 97% vs. 93%), respectively. High baseline HBV DNA level, genotype D infection, and prior interferon (week 24 only) were predictive of failure to achieve the target level. Both treatments were well tolerated with TAF showing less impact on renal and bone parameters.

Conclusions: In WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118264PMC
May 2021

Tumor suppressive role of mitochondrial sirtuin 4 in induction of G2/M cell cycle arrest and apoptosis in hepatitis B virus-related hepatocellular carcinoma.

Cell Death Discov 2021 Apr 30;7(1):88. Epub 2021 Apr 30.

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

Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.
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http://dx.doi.org/10.1038/s41420-021-00470-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087836PMC
April 2021

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

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

J Gastroenterol 2021 May 27;56(5):479-488. 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
May 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

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

Chronic liver disease: Global perspectives and future challenges to delivering quality health care.

PLoS One 2021 4;16(1):e0243607. Epub 2021 Jan 4.

Department of Anaesthesiology, University of Colorado, Aurora, Colorado, United States of America.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243607PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781365PMC
April 2021

Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).

Clin Gastroenterol Hepatol 2020 Dec 10. Epub 2020 Dec 10.

Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

Background & Aims: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation.

Methods: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders.

Results: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001).

Conclusions: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.
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http://dx.doi.org/10.1016/j.cgh.2020.12.005DOI Listing
December 2020

Response to Liu et al., and Björnsson and Björnsson.

Am J Gastroenterol 2021 May;116(5):1091-1092

Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

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http://dx.doi.org/10.14309/ajg.0000000000001055DOI Listing
May 2021

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

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

Unhealthy lifestyle habits and physical inactivity among Asian patients with non-alcoholic fatty liver disease.

Liver Int 2020 11 13;40(11):2719-2731. Epub 2020 Oct 13.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Background & Aims: Lifestyle modification is the cornerstone for the management of non-alcoholic fatty liver disease (NAFLD). We aim to understand lifestyle habits of NAFLD patients, compare across Asian regions and identify area of deficiency.

Methods: In the multi-centre controlled attenuation parameter (CAP)-Asia study, we collected clinical data and lifestyle habit data of NAFLD patients from Singapore, mainland China, Hong Kong, Taiwan and Malaysia. Physical activity was assessed using the International Physical Activity Questionnaire.

Results: A total of 555 patients were included in the final analysis (mean age 54.5 ± 11.2 years, 54.1% men and median liver stiffness 6.7 kPa). More patients from mainland China (27.4%) and Taipei (25.0%) were smokers. Modest drinking was more common in Taiwan (25.0%) and Hong Kong (18.2%); only 1.3% had binge drinking. Majority of patients drank coffee (64.0%) and tea (80.2%), with varying amounts and durations in different regions. Soft drinks consumption was most common in Singapore (62.2%) and Malaysia (57.7%). Only 29.7% of patients met the Physical Activity Guidelines Recommendations, with no major differences across regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity, and sitting time was an independent factor associated with high CAP. Tea and coffee consumption were independently associated with high CAP and liver stiffness, respectively.

Conclusions: Despite some heterogeneity, unhealthy lifestyle and physical inactivity are common across Asian regions. Patients with liver stiffness <10 kPa were more likely to report any vigorous activity. Healthcare providers may use the comparative data to identify areas of deficiency.
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http://dx.doi.org/10.1111/liv.14638DOI Listing
November 2020

High prevalence and risk factors of multiple antibiotic resistance in patients who fail first-line Helicobacter pylori therapy in southern China: a municipality-wide, multicentre, prospective cohort study.

J Antimicrob Chemother 2020 11;75(11):3391-3394

Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.

Background: We aimed to study the prevalence of secondary antibiotic resistance of Helicobacter pylori in southern China and its risk factors, particularly geographical and socio-economic factors.

Methods: This was a municipality-wide, multicentre, prospective cohort study involving five major hospitals. Patients aged ≥18 years who failed first-line bismuth-based quadruple anti-H. pylori therapy between September 2016 and February 2018 were recruited. Participants underwent upper gastrointestinal endoscopy with biopsy from the antrum and body for H. pylori culture and antimicrobial susceptibility testing for six antibiotics (clarithromycin, levofloxacin, metronidazole, amoxicillin, tetracycline and furazolidone). Patients with failure of H. pylori culture were excluded. Participants completed a questionnaire profiling 22 potential risk factors of H. pylori infection and antibiotic resistance, including medical, social, household and birthplace factors.

Results: A total of 1113 patients failed first-line therapy, with successful H. pylori culture in 791 (71.1%) [male = 433 (54.7%); median age = 43 years]. Secondary resistance rates of dual antibiotics (clarithromycin + metronidazole and levofloxacin + metronidazole) and triple antibiotics (clarithromycin + levofloxacin + metronidazole) were 34.0%, 38.7% and 17.8%, respectively. Risk factors for clarithromycin + metronidazole resistance were history of ≥2 courses of H. pylori therapies [adjusted OR (aOR) = 1.71; 95% CI = 1.17-2.54], ≥3 household members (aOR = 2.00; 95% CI = 1.07-3.90) and family history of gastric cancer (aOR = 1.85; 95% CI = 1.18-2.85). Risk factors for levofloxacin + metronidazole resistance were age ≥40 years (aOR = 1.94; 95% CI = 1.37-2.75), lower gross domestic product per capita (aOR = 0.29; 95% CI = 0.10-0.80) and higher number of doctors/10 000 population (aOR = 1.59; 95% CI = 1.07-2.39). A higher human development index was of borderline significance (aOR = 2.79; 95% CI = 0.97-8.70).

Conclusions: The rates of secondary resistance of H. pylori to multiple antibiotics were high in southern China. Certain population-level risk factors were associated with levofloxacin + metronidazole resistance.
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http://dx.doi.org/10.1093/jac/dkaa315DOI Listing
November 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

ACE (Angiotensin-Converting Enzyme) Inhibitors/Angiotensin Receptor Blockers Are Associated With Lower Colorectal Cancer Risk: A Territory-Wide Study With Propensity Score Analysis.

Hypertension 2020 09 6;76(3):968-975. Epub 2020 Jul 6.

From the Department of Medicine, The University of Hong Kong, Queen Mary Hospital (K.S.C., W.K.S., W.K.L.).

Whether ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers modify colorectal cancer risk remains controversial. We aimed to determine association between their use and colorectal cancer risk after a negative baseline colonoscopy. This is a territory-wide retrospective cohort study recruiting patients aged ≥40 who had undergone colonoscopy between 2005 and 2013. Exclusion criteria included colorectal cancer detected <6 months of index colonoscopy, prior colorectal cancer, inflammatory bowel disease, and prior colectomy. The primary outcome was colorectal cancer diagnosed between 6 and 36 months after index colonoscopy. Sites of colorectal cancer were categorized as proximal (proximal to splenic flexure) and distal cancer. The adjusted hazard ratio of colorectal cancer with ACE inhibitor/angiotensin receptor blocker use (≥180-day use within 5 years before index colonoscopy) was derived by propensity score regression adjustment of 23 covariates (including patient's factors, concurrent medication use, and endoscopy center's performance). Of 187 897 eligible patients, 30 856 (16.4%) were ACE inhibitors/angiotensin receptor blocker users. Eight hundred fifty-four (0.45%) developed colorectal cancer between 6 and 36 months after index colonoscopy (proximal cancer: 147 [17.2%]). These drugs were associated with lower risk of colorectal cancer that developed <3 years after index colonoscopy (adjusted hazard ratio, 0.78 [95% CI, 0.64-0.96]), but not colorectal cancer that developed >3years (adjusted hazard ratio, 1.18 [95% CI, 0.88-1.57]); every single year increase in the drug use was associated with 5% reduction in adjusted hazard ratio risk. ACE inhibitors/angiotensin receptor blocker were associated with a lower colorectal cancer risk in a duration-response manner.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15317DOI Listing
September 2020

Crowdsourcing to promote hepatitis C testing and linkage-to-care in China: a randomized controlled trial protocol.

BMC Public Health 2020 Jul 2;20(1):1048. Epub 2020 Jul 2.

University of North Carolina Project-China, 1 Global Health Center Office, 2nd Floor of Lao Gan Building, No. 7 Lujing Road, Yuexiu District, Guangzhou City, Guangdong Province, Guangzhou, China.

Background: Hepatitis C virus (HCV) is a growing public health problem with a large disease burden worldwide. In China many people living with HCV are unaware of their hepatitis status and not connected to care and treatment. Crowdsourcing is a technique that invites the public to create health promotion materials and has been found to increase HIV testing uptake, including in China. This trial aims to evaluate crowdsourcing as a strategy to improve HCV awareness, testing and linkage-to-care in China.

Methods: A randomized controlled, two-armed trial (RCT) is being conducted in Shenzhen with 1006 participants recruited from primary care sectors of The University of Hong Kong-Shenzhen Hospital. Eligible participants are ≥30 years old; a resident in Shenzhen for at least one month after recruitment; no screening for HCV within the past 12 months and not known to have chronic HCV; and, having a WeChat social media account. Allocation is 1:1. Both groups will be administered a baseline and a follow-up survey (4-week post-enrollment). The intervention group will receive crowdsourcing materials to promote HCV testing once a week for two weeks and feedback will be collected thereafter, while the control group will receive no promotional materials. Feedback collected will be judged by a panel and selected to be implemented to improve the intervention continuously. Those identified positive for HCV antibodies will be referred to gastroenterologists for confirmation and treatment. The primary outcome will be confirmed HCV testing uptake, and secondary outcomes include HCV confirmatory testing and initiation of HCV treatment with follow-ups with specialist providers. Data will be collected on Survey Star via mobile devices.

Discussion: This will be the first study to evaluate the impact of crowdsourcing to improve viral hepatitis testing and linkage-to-care in the health facilities. This RCT will contribute to the existing literature on interventions to improve viral hepatitis testing in primary care setting, and inform future strategies to improve HCV care training for primary care providers in China.

Trial Registration: Chinese Clinical Trial Registry. ChiCTR1900025771. Registered September 7th, 2019, http://www.chictr.org.cn/showprojen.aspx?proj=42788.
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http://dx.doi.org/10.1186/s12889-020-09152-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330974PMC
July 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

Association Between Nonvitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study.

Am J Gastroenterol 2020 09;115(9):1513-1524

Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Introduction: The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests.

Methods: Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression.

Results: After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury.

Discussion: Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.
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http://dx.doi.org/10.14309/ajg.0000000000000678DOI Listing
September 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990846PMC
April 2021

Nonsteroidal anti-inflammatory drugs but not aspirin are associated with a lower risk of post-colonoscopy colorectal cancer.

Aliment Pharmacol Ther 2020 05 22;51(9):899-908. Epub 2020 Mar 22.

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

Background: Although nonsteroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer (CRC) risk, their role in preventing post-colonoscopy CRC (PCCRC) remains undetermined.

Aims: To investigate whether NSAIDs reduce PCCRC risk after a negative baseline colonoscopy METHODS: This is a retrospective cohort study based on a territory-wide healthcare database of Hong Kong. All patients (aged 40 or above) who underwent colonoscopies between 2005 and 2013 were identified. Exclusion criteria included CRC detected within 6 months of index colonoscopy, prior CRC, inflammatory bowel disease and prior colectomy. The primary outcome was PCCRC-3y diagnosed between 6 and 36 months after index colonoscopy. Sites of CRC were categorised as proximal (proximal to splenic flexure) and distal. The adjusted hazards ratio (aHR) of PCCRC-3y with NSAID and aspirin use (defined as cumulative use for ≥90 days within 5 years before index colonoscopy) was derived by propensity score (PS) regression adjustment of 22 covariates (including patient factors, concurrent medication use and endoscopy centre's performance).

Results: Of 187 897 eligible patients, 21 757 (11.6%) were NSAID users. 854 (0.45%) developed PCCRC-3y (proximal cancer: 147 [17.2%]). NSAIDs were associated with a lower PCCRC-3y risk (aHR: 0.54, 95% CI: 0.41-0.70), but not CRC that developed >3 years (aHR: 0.78, 95% CI 0.56-1.09). The aHR was 0.48 (95% CI: 0.24-0.95) for proximal and 0.55 (95% CI: 0.40-0.74) for distal cancer. A duration- and frequency response relationship was observed (P  < 0.001). For aspirin, the aHR was 1.01 (95% CI: 0.80-1.28).

Conclusions: Non-aspirin NSAIDs were associated with lower PCCRC risk after a negative baseline colonoscopy.
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http://dx.doi.org/10.1111/apt.15693DOI Listing
May 2020

Modelling NAFLD disease burden in four Asian regions-2019-2030.

Aliment Pharmacol Ther 2020 04 4;51(8):801-811. Epub 2020 Mar 4.

Lafayette, CO, USA.

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) account for an increasing proportion of liver disease in the Asia-Pacific region. Many areas in the region are experiencing epidemics of metabolic syndrome among rapidly ageing populations.

Aims: To estimate using modelling the growth in NAFLD populations, including cases with significant fibrosis that are most likely to experience advanced liver disease and related mortality.

Methods: A disease progression model was used to summarise and project fibrosis progression among the NAFLD populations of Hong Kong, Singapore, South Korea and Taiwan. For each area, changes in the adult prevalence of obesity was used to extrapolate long-term trends in NAFLD incidence.

Results: In the areas studied, prevalent NAFLD cases were projected to increase 6%-20% during 2019-2030, while prevalent NASH cases increase 20%-35%. Incident cases of hepatocellular carcinoma are projected to increase by 65%-85%, while incident decompensated cirrhosis cases increase 65%-100% by 2030. Likewise, NAFLD-related mortality is projected to increase between 65% and 100% from 2019 to 2030. NAFLD disease burden is expected to increase alongside rising trends in metabolic syndrome and obesity among populations in the region. This leads to more cases of advanced liver disease and associated mortality.

Conclusions: Preventing the growth of diabetic and obese populations will be a key factor in reducing ongoing increases in NAFLD-related disease burden in the Asia-Pacific region.
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http://dx.doi.org/10.1111/apt.15673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154715PMC
April 2020

HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA.

Sci Rep 2020 01 21;10(1):802. Epub 2020 Jan 21.

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

The hepatitis B X protein (HBx) plays a role in the epigenetic regulation of hepatitis B virus (HBV) replication. This study investigated the effects of HBx mutations on HBV transcription and the recruitment of HBx, histone acetyl-transferase P300 and histone deacetylase 1 (HDAC1) to circularized HBV DNA (which resembles covalently closed circular DNA [cccDNA]). Compared with wild type, majority of mutants had lower levels of intracellular HBV RNA (44-77% reduction) and secretory HBsAg (25-81% reduction), and 12 mutants had a reduction in intracellular encapsidated HBV DNA (33-64% reduction). Eight mutants with >70% reduction in HBV RNA and/or HBsAg were selected for chromatin immunoprecipitation analysis. Four HBx mutants with mutations in amino acid residues 55-60 and 121-126 had a lower degree of HBx-cccDNA association than wild type HBx (mean % input: 0.02-0.64% vs. 3.08% in wild type). A reduced association between cccDNA and P300 (mean % input: 0.69-1.81% vs. 3.48% in wild type) and an augmented association with HDAC1 (mean % input: 4.01-14.0% vs. 1.53% in wild type) were detected. HBx amino acid residues 55-60 and 121-126 may play an important role in HBV transcription regulation, via their impeded interaction with cccDNA and altered recruitment of histone modifying enzymes to cccDNA.
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http://dx.doi.org/10.1038/s41598-020-57637-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972884PMC
January 2020