Publications by authors named "Wai-Kay Seto"

202 Publications

Association between Recent Usage of Antibiotics and Immunogenicity within Six Months after COVID-19 Vaccination.

Vaccines (Basel) 2022 Jul 14;10(7). Epub 2022 Jul 14.

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

Gut microbiota can be associated with COVID-19 vaccine immunogenicity. We investigated whether recent antibiotic use influences BNT162b2 vaccine immunogenicity. BNT162b2 recipients from three centers were prospectively recruited. Outcomes of interest were seroconversion of neutralising antibody (NAb) at day 21, 56 and 180 after first dose. We calculated the adjusted odds ratio (aOR) of seroconversion with antibiotic usage (defined as ever use of any antibiotics within six months before first dose of vaccine) by adjusting for covariates including age, sex, smoking, alcohol, and comorbidities. Of 316 BNT162b2 recipients (100 [31.6%] male; median age: 50.1 [IQR: 40.0-57.0] years) recruited, 29 (9.2%) were antibiotic users. There was a trend of lower seroconversion rates in antibiotic users than non-users at day 21 (82.8% vs. 91.3%; = 0.14) and day 56 (96.6% vs. 99.3%; = 0.15), but not at day 180 (93.3% vs. 94.1%). A multivariate analysis showed that recent antibiotic usage was associated with a lower seroconversion rate at day 21 (aOR 0.26;95% CI: 0.08-0.96). Other factors associated with a lower seroconversion rate after first dose of the BNT162b2 vaccine included age ≥ 60 years (aOR: 0.34;95% CI: 0.13-0.95) and male sex (aOR: 0.14, 95% CI: 0.05-0.34). There were no significant factors associated with seroconversion after two doses of BNT16b2, including antibiotic use (aOR: 0.03;95% CI: 0.001-1.15). Recent antibiotic use may be associated with a lower seroconversion rate at day 21 (but not day 56 or 180) among BNT162b2 recipients. Further long-term follow-up data with a larger sample size is needed to reach a definite conclusion on how antibiotics influence immunogenicity and the durability of the vaccine response.
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http://dx.doi.org/10.3390/vaccines10071122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318721PMC
July 2022

Differential relapse patterns after discontinuation of entecavir vs tenofovir disoproxil fumarate in chronic hepatitis B.

Clin Gastroenterol Hepatol 2022 Jul 18. Epub 2022 Jul 18.

Toronto Centre for Liver Disease, Toronto General Hospital, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands. Electronic address:

Background And Aims: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy.

Methods: This study included 1,402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001-2020 from 13 participating centres across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weights was used to balance the treatment groups. Outcomes were analyzed using survival methods.

Results: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (p = 0.03); however, the association was no longer significant after statistical adjustment (p = 0.61). Virological relapse occurred earlier among TDF-treated patients (p < 0.01); nonetheless, rates became comparable after the first year off-therapy (p = 0.49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (p < 0.01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups.

Conclusion: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.
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http://dx.doi.org/10.1016/j.cgh.2022.07.005DOI Listing
July 2022

A randomized controlled trial enhancing viral hepatitis testing in primary care via digital crowdsourced intervention.

NPJ Digit Med 2022 Jul 19;5(1):95. Epub 2022 Jul 19.

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

Despite the availability of hepatitis B virus (HBV) and hepatitis C virus (HCV) testing in primary care, testing rates in China remain low. Social media is an inexpensive means of disseminating information and could facilitate hepatitis testing promotion. We evaluated the capacity of digitally crowdsourced materials to promote HBV/HCV testing uptake via a randomized controlled trial (identifier: ChiCTR1900025771), which enrolled 750 Chinese primary care patients. We randomized patients (1:1) to receive crowdsourced HBV/HCV promotion materials through social media or facility-based care without promotional materials for four weeks. Exposure to all intervention materials was associated with increased odds of HBV (aOR = 1.79, 95% CI: 1.09-3.00) and HCV (aOR = 1.95, 95% CI: 1.29-2.99) testing compared to facility-based care. There was a significant reduction in hepatitis stigma among intervention group participants (HBV slope: -0.15, p < 0.05; and HCV slope: -0.13, p < 0.05). Digitally crowdsourced promotion messages could enhance hepatitis testing uptake and should be considered in hepatitis reduction strategies.Trial registration: Chinese Clinical Trial Registry (ChiCTR1900025771) on September 9, 2019. Available from: http://www.chictr.org.cn/showproj.aspx?proj=42788.
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http://dx.doi.org/10.1038/s41746-022-00645-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296450PMC
July 2022

New strategies for the treatment of chronic hepatitis B.

Trends Mol Med 2022 Jun 29. Epub 2022 Jun 29.

Department of Medicine, School of Clinical 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:

Functional cure, as defined by seroclearance of hepatitis B surface antigen (HBsAg), is the desired treatment endpoint for chronic hepatitis B (CHB) infection, yet is rarely achieved with the currently approved therapy. Novel treatments currently in the clinical phase of development act by inhibiting viral replication/antigen reduction and/or by restoring host immune control. Although some agents are effective in reducing the viral antigen load, a greater magnitude of suppression is required to achieve functional cure. Compounds that target the covalently closed circular DNA (cccDNA) pool, hepatitis B X (HBx) protein inhibition, and mRNA destabilization are also in the preclinical phase of development. Challenges which remain include the clinical implications, immunological perturbations, and safety of these novel compounds to be used in the real-life setting.
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http://dx.doi.org/10.1016/j.molmed.2022.06.002DOI Listing
June 2022

Statins associate with lower risk of biliary tract cancers: A systematic review and meta-analysis.

Cancer Med 2022 Jun 13. Epub 2022 Jun 13.

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

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma (CCA), gallbladder (GBC), and ampulla of Vater cancers (AVC), are common hepatobiliary cancer after hepatocellular carcinoma with a high mortality rate. As there is no effective chemopreventive agent to prevent BTCs, this study aimed to explore the role of statins on the risk of BTCs.

Methods: PubMed, Embase, and Cochrane Library from inception until 24 April 2020 were searched according to the Meta-Analyses of Observational Studies in Epidemiology (MOOSE) guidelines. The adjusted risk ratios (aRRs) of BTCs and individual cancer were pooled using a random-effects model.

Results: Eight observational studies (3 cohort and 5 case-control studies) were included with 10,485,231 patients. The median age was 68.0 years (IQR: 67.0-71.5) and 48.3% were male. Statins were associated with a lower risk of all BTCs (aRR: 0.67; 95% CI: 0.51-0.87). The pooled aRR for CCA was 0.60 (95% CI: 0.38-0.94) and GBC was 0.78 (95% CI: 0.68-0.90). There was only one study on AVC with aRR of 0.96 (95% CI: 0.66-1.41). The pooled aRR for lipophilic and hydrophilic statins was 0.78 (95% CI: 0.69-0.88) and 0.70 (95% CI: 0.61-0.80), respectively. The effects were attenuated in studies that adjusted for aspirin and/or non-steroidal anti-inflammatory drugs (aRR: 0.80, 95% CI: 0.72-0.89) and metformin (aRR: 0.80, 95% CI: 0.72-0.90).

Conclusions: Statins, both lipophilic and hydrophobic, were associated with a lower risk of BTCs, particularly CCA and GBC.
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http://dx.doi.org/10.1002/cam4.4942DOI Listing
June 2022

What facilitates hepatitis B and hepatitis C testing and the role of stigma among primary care patients in China?

J Viral Hepat 2022 Aug 3;29(8):637-645. Epub 2022 Jun 3.

Department of Family Medicine & Primary Care, School of Clinical Medicine, Li Ka Shing Faculty Medicine, The University of Hong Kong, Hong Kong, China.

Approximately 80% of primary healthcare facilities in China were ready to deliver hepatitis care services by 2021. This study aimed to assess hepatitis B and C test uptake, identify the factors associated with testing and determine the predictors of hepatitis stigma among primary care patients. We conducted a cross-sectional survey among patients seeking care in the family medicine and primary care unit of the University of Hong Kong-Shenzhen Hospital, China. Participants were 30 years or older and had not tested for HBV and HCV in the preceding 12 months. Test uptake was defined as self-reported previous HBV and HCV testing. Descriptive statistics, Chi-square test, forward multivariable logistic regression and stepwise multiple linear regression were conducted, and a p-value <.05 was deemed statistically significant. A total of 750 eligible patients completed the survey, and 54.5% (404 ± 0.9) were between 30 and 40 years old. Most participants were heterosexuals 98.0% (n = 735), female 57.5% (n = 431), married 78.3% (587) and earned ≤1500 USD per month 54.4% (n = 408). A 66.1% (n = 496) and 13.7% (n = 103) self-reported previous HBV and HCV testing, respectively, and 62% (n = 468) were vaccinated. HCV testing was associated with HBV testing (aOR = 13.7, 95% CI:2.1-91.5); and HBV testing was associated with family history of HBV (aOR = 2.4, 95%CI:1.1-5.5). Overall hepatitis stigma was about average and decreased with family history of HBV (p = .017). In conclusion, HCV testing uptake among primary care patients was low and needs to be further promoted. Integrating HBV and HCV testing interventions and fostering family-based support for disclosure could effectively improve testing uptake.
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http://dx.doi.org/10.1111/jvh.13711DOI Listing
August 2022

Enhanced liver fibrosis score stratifies hepatocellular carcinoma risk in patients with hepatitis B surface antigen seroclearance.

Clin Infect Dis 2022 May 20. Epub 2022 May 20.

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

In this prospective study involving 337 chronic hepatitis B patients who achieved spontaneous HBsAg seroclearance (SC), serum Enhanced Liver Fibrosis (ELF) before SC was associated with hepatocellular carcinoma (HCC) (hazard ratio 2.588), and ELF <10.8 was associated with >97% reduction in risk of HCC development in patients with ageSC≥50 (n = 190).
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http://dx.doi.org/10.1093/cid/ciac387DOI Listing
May 2022

Effect of antiviral treatment on hepatitis B virus integration and hepatocyte clonal expansion.

Clin Infect Dis 2022 May 20. Epub 2022 May 20.

Department of Medicine.

Background: This study investigated the effect of nucleos(t)ide analogues (NUC) treatment on HBV DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B.

Methods: Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and seven had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse PCR.

Results: All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01×109 per liver and hepatocyte clone size of 2.41×105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After one year of treatment, HBV integration was still detectable in all patients, with a median of 5.74×108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22×105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84×107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55×104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively).

Conclusions: NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.
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http://dx.doi.org/10.1093/cid/ciac383DOI Listing
May 2022

The optimal screening strategy for chronic hepatitis B virus infection in China - Authors' reply.

Lancet Glob Health 2022 06;10(6):e793

China-Australia Joint Research Centre for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia; Artificial Intelligence and Modelling in Epidemiology Program, Melbourne Sexual Health Centre, Alfred Health, Melbourne, VIC, Australia; Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, China. Electronic address:

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http://dx.doi.org/10.1016/S2214-109X(22)00165-6DOI Listing
June 2022

Effect of moderate-to-severe hepatic steatosis on neutralising antibody response among BNT162b2 and CoronaVac recipients.

Clin Mol Hepatol 2022 07 11;28(3):553-564. Epub 2022 May 11.

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

Background/aims: Studies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects.

Methods: Two hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56.

Results: For BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%; P=0.037). For CoronaVac (n=67, 22.7%), there was no statistical differences in seroconversion rates (day21: 7.1% vs. 15.1%; day56: 64.3% vs. 83.0%) or vMN GMT (5.3 vs. 5.8,) at day28. However, moderate/severe HS patients had lower vMN GMT (9.1 vs. 14.8, P=0.021) at day 56 with lower proportion having highest-tier response (21.4% vs. 52.8%, P=0.036).

Conclusion: While there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.
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http://dx.doi.org/10.3350/cmh.2022.0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293606PMC
July 2022

Assessing the developing pharmacotherapeutic landscape in hepatitis B treatment: a spotlight on drugs in phase II clinical trials.

Expert Opin Emerg Drugs 2022 Jun 15;27(2):127-140. Epub 2022 May 15.

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

Introduction: Functional cure, defined as sustained HBsAg seroclearance, is associated with favorable outcomes in chronic hepatitis B (CHB). While nucleos(t)ide analogues (NAs) are effective in suppressing HBV replication, NAs are unable to induce functional cure at high rates. A range of novel HBV antivirals, aiming to induce functional cure, are currently under development.

Areas Covered: This article covered novel hepatitis B virus (HBV) antivirals that have entered phase II trials. Virus-directing agents covered include entry inhibitors, transcription inhibitors, RNA silencers, core protein allosteric modulators, noncompetitive polymerase inhibitors, and viral protein export inhibitors. Immunomodulators covered include innate immune stimulators, T-cell modulators, therapeutic vaccines, and monoclonal antibodies. Upcoming developmental directions would also be discussed.

Expert Opinion: Among novel HBV antivirals, RNA silencers, viral protein export inhibitors (with pegylated interferon), and entry inhibitors (with pegylated interferon) appear to be effective in suppressing HBsAg and may even induce functional cure. The other virus-targeting agents have variable effects on HBV DNA, HBsAg, HBeAg, and HBcrAg. Immunomodulators have modest effects on HBsAg but may have important roles in combination therapy. Upcoming trials will answer important questions on ideal dosing, long-term drug effects, and efficacy of combination regimens.
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http://dx.doi.org/10.1080/14728214.2022.2074977DOI Listing
June 2022

Association between antibiotic consumption and colon and rectal cancer development in older individuals: A territory-wide study.

Cancer Med 2022 Apr 29. Epub 2022 Apr 29.

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

Background: Antibiotics may alter colorectal cancer (CRC) risk due to gut dysbiosis. We aimed to study the specific and temporal effects of various antibiotics on CRC development in older individuals.

Methods: This was a territory-wide retrospective cohort study. Subjects aged 60 years and older who did not have CRC diagnosed on screening/diagnostic colonoscopy diagnosed between 2005 and 2013 were recruited. Exclusion criteria were history of CRC, colectomy, inflammatory bowel disease, and CRC diagnosed within 6 months of index colonoscopy. Exposure was use of any antibiotics up to 5 years before colonoscopy. The primary outcomes were CRC diagnosed >6 m after colonoscopy. Covariates were patient demographics, history of colonic polyps/polypectomy, concomitant medication use (NSAIDs, COX-2 inhibitors, aspirin, and statins), and performance of endoscopy centers (colonoscopy volume and polypectomy rate). Stratified analysis was conducted according to nature of antibiotics and location of cancer.

Results: Ninety seven thousand one hundred and sixty-two eligible subjects (with 1026 [1.0%] cases of CRC) were identified, 58,704 (60.4%) of whom were exposed to antibiotics before index colonoscopy. Use of antibiotics was associated with a lower risk of cancer in rectum (adjusted hazard ratio [aHR]: 0.64, 95% CI: 0.54-0.76), but a higher risk of cancer in proximal colon (aHR: 1.63, 95%CI: 1.15-2.32). These effects differed as regards the anti-anaerobic/anti-aerobic activity, narrow-/broad-spectrum, and administration route of antibiotics.

Conclusions: Antibiotics had divergent effects on CRC development in older subjects, which varied according to the location of cancer, antibiotic class, and administration route.
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http://dx.doi.org/10.1002/cam4.4759DOI Listing
April 2022

Magnetic resonance imaging metrics and the predictability of adverse outcomes in on-treatment Asian chronic hepatitis B.

J Gastroenterol Hepatol 2022 Jun 9;37(6):1139-1147. Epub 2022 Apr 9.

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

Background And Aim: Liver fibrosis and steatosis are important factors affecting chronic hepatitis B (CHB) disease outcome. Multiparametric magnetic resonance (MR) imaging of the liver measures fibroinflammation, fat, and iron through iron-corrected T1 relaxation time (cT1), proton density fat fraction (PDFF), and T2*-weighted imaging, respectively. We assessed the utility of MR metrics for prognostication in CHB.

Methods: Chronic hepatitis B patients receiving nucleos(t)ide analogs with advanced fibrosis documented by vibration-controlled transient elastography were recruited. Paired multiparametric MR liver and transient elastography were performed at baseline and after at least 2 years. Adverse outcomes including death, hepatocellular carcinoma (HCC), and liver decompensation were monitored.

Results: One hundred and ninety-two patients (mean age 60.3 ± 8.5 years; 76.0% male) were recruited. Eight patients (4.2%) developed HCC after 11.6 (8.8-22.8) months, and increased baseline liver iron independently predicted HCC (hazard ratio 2.329 [1.030-5.266]; P = 0.042). Liver MR metrics were not predictive of death or hepatic decompensation. Among 150 patients with follow-up liver MR at 30.3 (25.2-35.6) months, longitudinal liver PDFF increase was associated with liver cT1 increase (odds ratio 1.571 [1.217-2.029]; P = 0.001). Ninety patients received simultaneous multiparametric MR pancreas during the follow-up MR. Pancreatic PDFF correlated with liver PDFF (r = 0.501, P < 0.001), while pancreatic T1 had no correlation with liver cT1 (r = -0.092, P = 0.479). Pancreatic T1 and PDFF were not associated with adverse outcomes.

Conclusion: Among CHB patients with advanced disease, liver iron level on MR predicts HCC. Multiparametric MR can also simultaneously assess the pancreas and the liver. Multiparametric MR should be further studied as a one-stop option for monitoring and prognosticating CHB.
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http://dx.doi.org/10.1111/jgh.15846DOI Listing
June 2022

Hepatitis B virus X protein promotes hepatocarcinogenesis via the activation of HMGA2/STC2 signaling to counteract oxidative stress-induced cell death.

Carcinogenesis 2022 03 30. Epub 2022 Mar 30.

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

Chronic hepatitis B virus (HBV) infection can cause oxidative stress and induce cell death. The mechanisms by which cells overcome oxidative stress to survive remain largely unknown. Here, we used human sera, liver tissues and cell-lines to study how HBV modulates cellular pathways to counteract oxidative stress-induced cell death. We found high-mobility group AT-hook 2 (HMGA2), an architectural transcription factor is upregulated in HCC tissues and cell-lines. Elevated serum HMGA2 is significantly associated with viral load in HBV carriers, and HBV-related HCC. We showed that HBV X protein (HBx) encoded by HBV induced cell growth via HMGA2 activation. The growth-promoting effect is abolished when HMGA2 is suppressed. Ectopic HBx expression induced DNA damage and oxidative stress. HMGA2 silencing reduced oxidative stress in HBx-expressing cells. Cytoprotective stanniocalcin 2 (STC2) protein is a downstream target of HMGA2. Consistent with the findings in HMGA2, STC2 mRNA and protein expression are upregulated in HCC tissues. Elevated serum STC2 is also associated with viral load in HBV carriers, and HCC. STC2 is transcriptionally upregulated by HBx and HMGA2 to elicit cytoprotection against apoptosis. STC2 knockdown disrupted Bax/Bcl-2 balance that increased cytochrome c release, caspase 3/7 activity and apoptosis, and thus abolished the growth-promoting effect of HMGA2. Clinical relevance of HBx/HMGA2/STC2 signaling is evidenced by the significant correlation of serum HMGA2/STC2 in active HBV infection and HCC. These findings reveal a novel HBx regulatory HMGA2/STC2 pathway in counteracting ROS-induced cell death. HMGA2 and STC2 may be therapeutic targets for prevention of hepatocarcinogenesis in chronic HBV infection.
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http://dx.doi.org/10.1093/carcin/bgac030DOI Listing
March 2022

Magnetic resonance elastography and proton density fat fraction predict adverse outcomes in hepatocellular carcinoma.

Hepatol Int 2022 Apr 26;16(2):371-380. Epub 2022 Mar 26.

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

Background: Magnetic resonance (MR) elastography and proton density fat fraction (PDFF) are emerging techniques for non-invasive assessment of liver stiffness and steatosis, respectively. We investigated the role of MR metrics in pre-treatment prognostication of hepatocellular carcinoma (HCC).

Methods: Patients with newly diagnosed HCC were prospectively recruited. Pre-treatment MR elastography and PDFF were performed on tumor and non-tumor regions. HCC treatment was categorized as potentially curative (resection/ablation) or non-curative (locoregional/systemic therapy). HCC recurrence, liver-related complications (ascites/ variceal bleeding/ hepatic encephalopathy) and mortality were monitored.

Results: Of the 158 recruited patients (mean age 62.9 years, 84.2% male, 82.9% viral hepatitis), 58.2% (n = 92) and 41.8% (n = 66) received potentially curative and non-curative therapy, respectively. Pre-treatment non-tumor liver stiffness independently predicted liver-related complications, regardless of treatment type (HR 1.384, 95% CI 1.067-1.796, p = 0.014). In the potentially curative therapy group, non-tumor stiffness and non-tumor PDFF were independently associated with HCC recurrence (HR 1.308, 95% CI 1.022-1.673 & HR 1.080, 95% CI 1.009-1.156 respectively, both p < 0.05); and non-tumor PDFF predicted mortality (HR 1.160, 95% CI 1.038-1.296, p = 0.009). In the non-curative group, tumor stiffness independently predicted liver-related complications (HR 1.299, 95% CI 1.023-1.651, p = 0.032), and a combination of tumor stiffness ≥ 5.7 kPa plus non-tumor stiffness ≥ 3.7 kPa was associated with a two-fold risk of liver-related complications (86.7% vs 40.0%, p < 0.001).

Conclusion: Pre-treatment MR elastography and PDFF over tumor and non-tumor regions demonstrated prognosticating roles in HCC. Simultaneous measurements of both metrics during conventional MR liver should be considered in the diagnostic workup of HCC.
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http://dx.doi.org/10.1007/s12072-022-10305-yDOI Listing
April 2022

Alleviation of Hepatic Steatosis: Dithizone-Related Gut Microbiome Restoration During Paneth Cell Dysfunction.

Front Microbiol 2022 25;13:813783. Epub 2022 Feb 25.

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

Non-alcoholic fatty liver disease (NAFLD), the world's most common chronic liver disease, is increasingly linked to gut dysbiosis. Paneth cells secrete antimicrobial peptides that regulate the gut microbiome, but their role in the pathogenesis of NAFLD remains unclear. Here, we determine the changes in NAFLD development and gut microbial composition and function the injection of dithizone that can pharmacologically deplete the granules of Paneth cells. Eight-week-old C57BL/6J male mice ( = 31) were given a high-fat diet (HFD) or standard control diet for 12 weeks. Dithizone (10 mg/kg) was intravenously injected every 3 weeks during the period of diet feeding. Metagenomic DNA was extracted from fecal samples for PacBio Single-Molecule Real-Time sequencing to identify changes in microbial composition and predicted function. We observed dithizone-treated HFD mice, when compared to non-treated HFD mice, to have significant reductions in hepatic triglyceride content (28.98 vs. 53.52 mg/g, = 0.0419); plasma insulin level (2.18 vs. 6.63 ng/ml, = 0.0079); and relative mRNA levels of fatty acid synthase (0.52 vs. 1.57, = 0.0428) and stearoyl-CoA desaturase-1 (0.43 vs. 1.20, = 0.0121). Bacterial taxonomic profiling found dithizone-treated HFD mice, when compared to non-treated HFD mice, had a lower ratio (2.53 vs. 5.26, = 0.0541); a higher relative abundance of and (1.04 vs. 0.22%, = 0.0277 and 0.96 vs. 0.09%, = 0.0213); and a reduction in microbes belonging to (all < 0.05). species correlated positively with predicted microbial functions such as L-methionine ( = 0.54, = 0.0019) and tetrahydrofolate ( = 0.52, = 0.0029) biosynthesis. Collectively, dithizone treatment was associated with alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in , suggesting microbiome-targeted therapies may have a role in the treatment of NAFLD.
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http://dx.doi.org/10.3389/fmicb.2022.813783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8914291PMC
February 2022

Role of Serum M2BPGi Levels in Predicting Persistence of Advanced Fibrosis in Chronic Hepatitis B Virus Infection.

Dig Dis Sci 2022 Mar 8. Epub 2022 Mar 8.

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road 102, Hong Kong, China.

Background: Serum mac-2-binding protein glycosylation isomer (M2BPGi) is a novel marker for liver fibrosis assessment in patients with different liver diseases. For chronic hepatitis B infection (CHB), advanced fibrosis or cirrhosis is a risk factor for liver cancer and hepatic decompensation. We aimed to assess the role of serum M2BPGi in prediction of persistence of advanced fibrosis in CHB patients despite potent antiviral therapy.

Methods: CHB patients with advanced fibrosis or cirrhosis who were put on nucleos(t)ide analogs for ≥ 3 years with normal alanine aminotransferase and undetectable serum HBV DNA were prospectively recruited. Assessment of liver fibrosis with transient elastography (TE) and M2BPGi measurements were performed at baseline and repeated at 3 years. Advanced fibrosis and cirrhosis were defined by liver stiffness (LS) ≥ 9.0 kPa and ≥ 12.0 kPa, respectively.

Results: A total of 143 patients (M:F = 101:42; median age 58.7 years; 53.8% cirrhotic) were recruited and completed paired assessment. The median value of baseline LS and M2BPGi were 12.0 (IQR: 10.5-18.2) kPa and 0.99 cut-off-index (IQR: 0.75-1.74) (COI), respectively, with 96% concordance for diagnosing F3/F4. Ninety-six (67.1%) patients had persistent advanced fibrosis or cirrhosis at 3 years despite continuation of long-term antiviral treatment. Upon multivariate analysis, baseline M2BPGi (OR 2.128, 95% CI 1.037-4.366) and presence of central obesity (OR 4.648, 95% CI 1.742-12.402) were significantly associated with persistent advanced fibrosis or cirrhosis at 3 years. Baseline M2BPGi ≥ 1.265 COI has 50.6% sensitivity and 79.4% specificity for predicting persistent advanced fibrosis or cirrhosis at 3 years (area under the receiver-operating characteristic curve: 0.695). The presence of central obesity in combination with baseline M2BPGi ≥ 1.265 COI was associated with 95.7% patients having persistent advanced fibrosis or cirrhosis at 3 years. HCC development was observed in five patients during follow-up and was associated with bigger median increase in the level of serum M2BPGi compared to patients without HCC (46% vs 6.2%, P = 0.038).

Conclusion: Persistent advanced fibrosis or cirrhosis was observed in two-thirds of CHB patients despite potent antiviral therapy. High serum M2BPGi and central obesity were associated with more than twofold and fourfold increase in risk of persistent advanced fibrosis or cirrhosis, respectively.
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http://dx.doi.org/10.1007/s10620-022-07429-4DOI Listing
March 2022

Review article: switching patients with chronic hepatitis B to tenofovir alafenamide-a review of current data.

Aliment Pharmacol Ther 2022 04 17;55(8):921-943. Epub 2022 Feb 17.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are preferred treatment options for patients with chronic hepatitis B infection (CHB). However, resistance to ETV has been reported, especially with prior exposure to other NAs, and long-term TDF treatment has been associated with decline in renal function and loss of bone mineral density in some patients. Consequently, TAF may be preferable to ETV, TDF or other NAs in specific circumstances such as in patients with risk of bone or renal complications, elderly patients or those with previous NA experience.

Aim: To provide a summary of the available efficacy and safety data following switch to TAF from other NAs in patients with CHB in clinical studies and real-world settings.

Methods: Literature searches were performed on PubMed and abstracts from three major international liver congresses between 2019 and 2021. Studies that included efficacy and/or safety data for patients with CHB switching from any NA to TAF were selected.

Results: Thirty-six papers and abstracts were included in this narrative review. Switching from TDF to TAF maintained or improved virological and biochemical responses with improved bone and renal safety. Switching from ETV or other NAs to TAF maintained or improved virological and biochemical responses and varying results for bone and renal safety.

Conclusions: Switching to TAF appears to maintain or improve virological, biochemical and bone- and renal-related safety outcomes. These data support the concept of switching to TAF in some patients with CHB based on their individual circumstances.
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http://dx.doi.org/10.1111/apt.16788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304567PMC
April 2022

RNA interference as a novel treatment strategy for chronic hepatitis B infection.

Clin Mol Hepatol 2022 07 17;28(3):408-424. Epub 2022 Feb 17.

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

Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. Functional cure of CHB, defined as sustainable hepatitis B surface antigen (HBsAg) seroclearance, is associated with improved clinical outcomes. However, functional cure is rarely attainable by current treatment modalities. RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB. RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2-2.5 log. Incidences of HBsAg seroclearance after siRNA therapy have also been reported. ASOs have also been studied in early phase trials, and a phase Ib study using frequent dosing regimen within 4 weeks could achieve similar HBsAg reduction of 2 log from baseline. Given the established efficacy and safety of nucleos(t) ide analogues (NAs), future RNAi regimens will likely include NA backbone. While the current evidence on RNAi appears promising, it remains undetermined whether the potent HBsAg reduction by RNAi can result in a high rate of HBsAg seroclearance with durability. Data on RNAi from phase IIb/III trials are keenly anticipated.
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http://dx.doi.org/10.3350/cmh.2022.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293617PMC
July 2022

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.

J Hepatol 2022 05 29;76(5):1042-1050. Epub 2022 Jan 29.

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

Background & Aims: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined.

Methods: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders.

Results: We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p = 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p = 0.001).

Conclusions: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal.

Lay Summary: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.
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http://dx.doi.org/10.1016/j.jhep.2022.01.007DOI Listing
May 2022

Cost-effectiveness of universal screening for chronic hepatitis B virus infection in China: an economic evaluation.

Lancet Glob Health 2022 02;10(2):e278-e287

China-Australia Joint Research Centre for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Centre, Xi'an, China; Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia; Artificial Intelligence and Modelling in Epidemiology Program, Melbourne Sexual Health Centre, Alfred Health, Melbourne, VIC, Australia; and Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, China. Electronic address:

Background: China has the highest prevalence of hepatitis B virus (HBV) infection worldwide. Universal HBV screening might enable China to reach the WHO 2030 target of 90% diagnostics, 80% treatment, and 65% HBV-related death reduction, and eventually elimination of viral hepatitis. We evaluated the cost-effectiveness of implementing universal HBV screening in China and identified optimal screening strategies.

Methods: We used a Markov cohort model, inputting parameters based on data from previous studies and public databases, to assess the cost-effectiveness of four HBV serological screening strategies in China in different screening scenarios. We simulated universal screening scenarios in 15 adult age groups between 18 and 70 years, with different years of screening implementation (2021, 2026, and 2031) and compared to the status quo (ie, no universal screening); in total, we investigated 180 different screening scenarios. We calculated the incremental cost-effectiveness ratio (ICER) between the different screening strategies and the status quo (current screening strategy). We performed probabilistic and one-way deterministic sensitivity analyses to assess the robustness of our findings.

Findings: With a willingness-to-pay level of three times the Chinese gross domestic product (GDP) per capita (US$30 828), all universal screening scenarios in 2021 were cost-effective compared with the status quo. The serum HBsAg/HBsAb/HBeAg/HBeAb/HBcAb (five-test) screening strategy in people aged 18-70 years was the most cost-effective strategy in 2021 (ICER $18 295/quality-adjusted life-years [QALY] gained). This strategy remained the most cost-effective, when the willingness-to-pay threshold was reduced to 2 times GDP per capita. The two-test strategy for people aged 18-70 years became more cost-effective at lower willingness-to-pay levels. The five-test strategy could prevent 3·46 million liver-related deaths in China over the lifetime of the cohort. It remained the most cost-effective strategy when implementation was delayed until 2026 (ICER $20 183/QALY) and 2031 (ICER $23 123/QALY). Screening young people (18-30 years) will no longer be cost-effective in delayed scenarios.

Interpretation: The five-test universal screening strategy in people aged 18-70 years, implemented within the next 10 years, is the optimal HBV screening strategy for China. Other screening strategies could be cost-effective alternatives, if budget is limited in rural areas. Delaying strategy implementation reduces overall cost-effectiveness. Early screening initiation will aid global efforts in achieving viral hepatitis elimination.

Funding: National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S2214-109X(21)00517-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789560PMC
February 2022

Use of Antibiotics during Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Hepatocellular Carcinoma.

Liver Cancer 2021 Nov 18;10(6):606-614. Epub 2021 Aug 18.

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

Background: Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC).

Methods: This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein.

Results: A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6-44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0-16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08-2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17-2.28).

Conclusions: Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI.
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http://dx.doi.org/10.1159/000518090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647068PMC
November 2021

Detection of the Hepatitis B Surface Antigen in Patients with Occult Hepatitis B by Use of an Assay with Enhanced Sensitivity.

J Clin Microbiol 2022 02 22;60(2):e0220421. Epub 2021 Dec 22.

Department of Medicine, The University of Hong Konggrid.194645.b, Hong Kong.

Patients with occult hepatitis B infection (OBI) have undetectable hepatitis B surface antigen (HBsAg) by conventional assays but detectable hepatitis B virus (HBV) DNA in blood/liver. We evaluated the key performance characteristics of a sensitive HBsAg assay (Architect HBsAg Next qualitative assay, referred to as NEXT) with respect to HBsAg detection. Assay precision, sample carryover, and seroconversion sensitivity of NEXT were evaluated. HBsAg was measured by NEXT in 1,138 individuals, including 1,038 patients who attended liver clinics in a tertiary hospital (200 HBV DNA-positive blood donors whose HBsAg was undetectable by conventional assays, 38 patients receiving immunosuppressive therapy, and 800 chronic hepatitis B patients with HBsAg seroclearance) and 100 HBsAg-negative subjects recruited from a community project. The within-run and within-laboratory coefficients of variation were <6% for the positive sample pools. In 9 seroconversion panels tested, NEXT allowed an earlier HBsAg detection than conventional assays. NEXT detected HBsAg in 10/200 (5%) HBsAg-negative blood donors, 1/20 (5%) and 0/18 HBsAg-negative patients with and without HBV reactivation, respectively, and 59/800 (7.3%) patients with HBsAg seroclearance. HBsAg was detectable by NEXT in 27.8%, 8.2%, 6.9%, 3.8%, and 1.9% samples at <3, 3 to 5, >5 to 8, >8 to 11, and >11 years after HBsAg seroclearance, respectively. Seven out of 100 HBsAg-negative community-identified subjects were tested positive by NEXT. Compared with conventional HBsAg assays, NEXT demonstrated a higher sensitivity and conferred an increment of 5 to 7% detection rate in patients with OBI, thereby helping in identifying HBV carriers and prevention of OBI-associated HBV transmission and reactivation.
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http://dx.doi.org/10.1128/jcm.02204-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849216PMC
February 2022

Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study).

Gastroenterology 2022 03 9;162(3):757-771.e4. Epub 2021 Nov 9.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada. Electronic address:

Background & Aims: Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB).

Methods: This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation.

Results: Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma.

Conclusions: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
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http://dx.doi.org/10.1053/j.gastro.2021.11.002DOI Listing
March 2022

Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection.

Viruses 2021 06 18;13(6). Epub 2021 Jun 18.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102, Hong Kong, China.

Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host's immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host's immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB.
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http://dx.doi.org/10.3390/v13061169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235765PMC
June 2021

Circulating Thrombospondin-2 as a Novel Fibrosis Biomarker of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes.

Diabetes Care 2021 09 28;44(9):2089-2097. Epub 2021 Jun 28.

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

Objective: Preclinical studies have suggested that thrombospondin-2 (TSP2) is implicated in liver fibrosis. However, the clinical relevance of TSP2 in nonalcoholic fatty liver disease (NAFLD) remains undefined. Here, we investigated the cross-sectional and longitudinal associations of circulating TSP2 levels with advanced fibrosis (F3 or greater [≥FE] fibrosis) in NAFLD.

Research Design And Methods: Serum TSP2 levels were measured in 820 patients with type 2 diabetes and NAFLD. All participants received vibration-controlled transient elastography (VCTE) at baseline to evaluate their hepatic steatosis and fibrosis using controlled attenuation parameter (CAP) and liver stiffness (LS) measurements, respectively. Among those without advanced fibrosis at baseline, reassessment VCTE was performed to determine whether ≥F3 fibrosis had developed over time. Multivariable logistic regression analysis was used to evaluate the cross-sectional and longitudinal associations of serum TSP2 level with ≥F3 fibrosis.

Results: Baseline serum TSP2 level was independently associated with the presence of ≥F3 fibrosis (odds ratio [OR] 5.13, < 0.001). The inclusion of serum TSP2 level significantly improved the identification of ≥F3 fibrosis by clinical risk factors. Over a median follow-up of 1.5 years, 8.8% developed ≥F3 fibrosis. Baseline serum TSP2 level was significantly associated with incident ≥F3 fibrosis (OR 2.82, = 0.005), independent of other significant clinical risk factors of fibrosis progression, including BMI, platelet count, and CAP at baseline.

Conclusions: Circulating TSP2 level was associated with both the presence and the development of advanced fibrosis and might be a potentially useful prognostic biomarker for the development and progression of liver fibrosis in patients with type 2 diabetes and NAFLD.
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http://dx.doi.org/10.2337/dc21-0131DOI Listing
September 2021

Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection.

Hepatol Int 2021 Aug 21;15(4):901-911. Epub 2021 Jun 21.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road 102, Hong Kong, China.

Background: Concomitant chronic hepatitis B infection (CHB) and non-alcoholic fatty liver disease (NAFLD) is common, but the implications of NAFLD on clinical outcomes of CHB, including hepatocellular carcinoma (HCC), are not well-investigated.

Methods: CHB patients were recruited for transient elastography assessment for liver stiffness (LS), and controlled attenuation parameter (CAP), a non-invasive quantification of hepatic steatosis, and were prospectively followed up for development of HCC. Steatosis and severe steatosis were diagnosed by CAP ≥ 248 dB/m and ≥ 280 dB/m respectively, and advanced fibrosis/cirrhosis was diagnosed by LS ≥ 9 kPa. The independent effect of hepatic steatosis on HCC was examined via propensity score matching (PSM) of LS and other significant clinical variables.

Results: Forty-eight patients developed HCC among 2403 CHB patients (55.6% male, median age 55.6 years, 57.1% antiviral-treated, median ALT 26 U/L) during a median follow-up of 46.4 months. Multivariate Cox regression analysis showed age (HR 1.063), male (HR 2.032), Albumin-Bilirubin score (HR 2.393) and CAP (HR 0.993) were associated with HCC development. The cumulative probability of HCC was 2.88%, 1.56% and 0.71%, respectively for patients with no steatosis, mild-to-moderate steatosis, and severe steatosis, respectively (p = 0.01). The risk of HCC increased from 1.56 to 8.89% in patients without severe steatosis if advanced fibrosis/cirrhosis was present (p < 0.001). PSM yielded 957 pairs of CHB patients and hepatic steatosis was independently associated with HCC (HR 0.41).

Conclusion: Reduced hepatic steatosis was significantly associated with a higher risk of incident HCC in CHB infection. Routine CAP and LS measurements are important for risk stratification.
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http://dx.doi.org/10.1007/s12072-021-10218-2DOI Listing
August 2021

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

Hepatol Int 2021 Aug 14;15(4):881-891. 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
August 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
October 2021
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