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The purpose of this study was to evaluate the efficacy of medical record administrative data as coded by the International Classification of Diseases, Ninth Revision, for triggering pneumococcal vaccination reminders of patients following discharge from a tertiary care adult teaching hospital. A retrospective computerized search was conducted using administrative discharge data to detect patients admitted to the medical teaching unit who met clinical criteria for pneumococcal vaccination according to Canadian immunization guidelines. For identification of persons eligible for vaccination, administrative discharge data showed a sensitivity of 83% (confidence interval [CI], 0.73-0.92) and a specificity of 78% (CI, 0.64-0.91), with a positive predictive value of 87% (CI, 0.83-0.90) and a negative predictive value of 72% (CI, 0.58-0.86). The reasonably high specificity and sensitivity of diagnostic codes in administrative data could be used to trigger appropriate pneumococcal vaccination among eligible patients after hospital discharge. [ABSTRACT FROM AUTHOR]

Background & Aims: Bepirovirsen, an antisense oligonucleotide, induces sustained hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA below lower limit of quantification (

Chronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) globally. We described and evaluated the outcomes of patients with CHB-HCC in Canada. In this retrospective cross-sectional cohort study, data were analysed from CHB mono-infected subjects seen between 1 January 2012 and 31 December 2022, and entered the Canadian Hepatitis B Network Registry. Descriptive analysis and chi-squared modelling were used to compare cohorts, followed by multivariable survival analysis regarding survival post-diagnosis. Statistical analyses were completed in R version 2.2. Of the 6711 patients with CHB who met inclusion criteria, 232 (3.5%) developed HCC. Compared with the CHB cohort, the majority of CHB-HCC cohort were male, SEA and HBeAg negative and born in endemic area (80% vs. 56%, 73% vs. 55%, 84% vs. 54%, 64% vs. 40% and all p < 0001). Overall, median HBV DNA level was log 2.54 (IQR: 0-4.04). Advanced liver disease, defined as minimum Fibrosis stage F3, was seen in 9.4% of overall cohort, but 92% of HCC cohort. At diagnosis, median tumour size was 2.5 cm (IQR: 1.7-4.0) and mean tumour number was 1.33 (SD: 1.33), with 81% of patients BCLC 0-A. Fifty-three per cent of patients were diagnosed with HCC as part of surveillance protocols. The survival rate after HCC diagnosis was 78.7%, during the median follow-up of 52.9 months (IQR: 17-90). In multivariable analysis, survival was significantly correlated with diagnosis through the screening programme. In this large cohort of patients with CHB-HCC, the majority of patients were detected with early-stage HCC and received treatment with curative intent, resulting in strong survival rates., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Co-existing chronic hepatitis B virus (CHB) infection and metabolic dysfunction associated steatotic liver disease (MASLD) can exert complex effects on hepatic metabolism, requiring mechanistic study. CHB participants were assessed for MASLD and the impact of hepatic steatosis/metabolic syndrome (MetS) on novel viral and immunological markers. In this prospective, cohort study, untreated CHB subjects were assessed for liver disease by non-invasive tests (i.e. FibroScan, controlled attenuation parameter, CAP). Subjects were tested for cytokines and IFN-γ ELISPOT assay to HBV Surface (S) and Core (C) proteins. Standard HBV serological, exploratory biomarkers and deep sequencing of HBV S and C genes were performed. In 53 subjects (median age 45 years [SD = 10.6], 35% F, 56% Asian, 20% Black, 3% White), 94% (50) HBeAg negative, 63% genotype B/C, mean HBV DNA 3.2 log 10 IU/mL (SD = 1.8), quantitative HBsAg 2.9 log 10 IU/mL (SD = 1.2) and HBV pgRNA 2.1 log 10 copies/mL (SD = 1.3). In enrolled subjects, the mean ALT was 41.9 U/L (SD = 24.0), FibroScan was 5.7 kPa (SD = 1.9) and CAP was 306.4 dB/m (SD = 49.0). The mean BMI was 28.2 kg/m 2 (SD = 4.2), 20% (11/53) had diabetes, 35% (19/53) dyslipidaemia and 24% (13/53) hypertension. Subjects with MetS and steatosis showed lower HBV markers (p < .01), higher HBV S diversity (p = .02) and greater frequency of HBV variants associated with host-anti-viral immune escape. Pro-inflammatory cytokine levels and HBV-specific cellular responses were higher in participants with hepatic steatosis. In CHB, MASLD/hepatic steatosis was associated with HBV variants and systemic immune responses potentially impacting liver disease progression despite low-level viraemia., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background: Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment., Methods: This open-label, multicentre, phase 2 study was done in eight countries or territories at 30 sites. We recruited adults (≥18 years) with chronic hepatitis B who were virally suppressed on nucleoside or nucleotide analogues and had renal impairment (part A: moderate or severe in cohort 1 [estimated glomerular filtration rate by the Cockcroft-Gault formula (eGFR CG ) 15-59 mL/min] or end-stage renal disease [eGFR CG <15 mL/min] on haemodialysis in cohort 2) or hepatic impairment including decompensation (part B: Child-Turcotte-Pugh score 7-12). Participants switched to 25 mg of tenofovir alafenamide given orally once daily for 96 weeks. The primary endpoint was the proportion of participants with viral suppression (HBV DNA <20 IU/mL) at week 24 by missing-equals-failure analysis. Efficacy (full analysis set) and safety (safety analysis set) analyses included all enrolled participants who received at least one dose of the study drug. Week 96 safety was assessed, including renal and bone parameters. This trial is registered at ClinicalTrials.gov, NCT03180619, and is completed., Findings: 124 participants (93 in part A [78 in cohort 1 and 15 in cohort 2] and 31 in part B) were enrolled between Aug 11, 2017, and Oct 17, 2018, and included in the full and safety analysis sets. 106 (85%) participants completed the study. There were 69 (74%) men and 24 (26%) women in part A and 21 (68%) men and ten (32%) women in part B. At week 24, 91 (97·8%, 95% CI 92·4 to 99·7) of 93 individuals in part A (76 [97·4%, 91·0 to 99·7] of 78 in cohort 1 and 15 [100·0%, 78·2 to 100·0] of 15 in cohort 2) and 31 (100·0%, 88·8 to 100·0) in part B had HBV DNA of less than 20 IU/mL. By week 96, the most common adverse event was upper respiratory tract infection, which occurred in 14 (15%) participants in part A and in six (19%) participants in part B. Serious adverse events occurred in 20 (22%) part A participants and in ten (32%) part B participants; none were related to treatment. No treatment-related deaths occurred. At week 96, median change in estimated glomerular filtration rate (Cockcroft-Gault method) was 1·0 mL/min (IQR -2·8 to 4·5) in cohort 1 and -2·4 mL/min (-11·4 to 10·7) in part B. Mean changes in spine and hip bone mineral density were 1·02% (SD 4·44) and 0·20% (3·25) in part A and -0·25% (3·91) and 0·28% (3·25) in part B., Interpretation: Tenofovir alafenamide might offer continued antiviral efficacy and a favourable safety profile for patients with renal or hepatic impairment and chronic hepatitis B switching from tenofovir disoproxil fumarate or other antivirals., Funding: Gilead Sciences., Competing Interests: Declaration of interests HLAJ has received grants from Gilead Sciences, GSK, Janssen, Roche, and Vir Biotechnology and consults for Aligos, Gilead Sciences, GSK, Janssen, Roche, Vir Biotechnology, and Precision Biosciences. Y-SL receives consulting fees and honoraria from Gilead Sciences. PL reports honoraria for lectures, presentations, speaker's bureaus, and manuscript writing or educational events from AbbVie, Aligos, Alnylam, Altona, Antios, Arrowhead, Bristol Myers Squibb, Eiger, Gilead Sciences, Grifols, GSK, Janssen, MSD, MYR Pharmaceuticals, Roboscreen, Roche, Spring Bank Pharmaceuticals, and Vir Biotechnology. JH has received grant support from Roche, consultant fees from AbbVie Korea, payments or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Oncolys, AstraZeneca, Gilead, Roche, and Yuhan Korea, and payments for expert testimony from Surrozen; has participated in a data safety monitoring board or advisory board for Medvir; and has participated in other boards or groups for AstraZeneca. CSC reports grants or research support from Gilead Sciences, Janssen Pharmaceuticals, Altimmune, GSK, and Roche; consulting fees from Gilead Sciences, Roche, GSK, and Altimmune; honoraria from ECHO HBV Global and PRIME Education; US and international patent applications for polypeptides used against viral infection; advisory board or data safety monitoring board participation with Altimmune; and receipt of woodchuck reagents from Gilead Sciences. HT has served as a speaker and advisor for, received research grants from, and holds stock in Gilead Sciences, and has received research grants from Intercept and Assembly Biosciences. JFF, FA, YZ, YL, and AL are employees of and stockholders in Gilead Sciences. PG was an employee of and stockholder in Gilead Sciences at the time of this study and holds stock in Cytokinetics. KA has previously received research grants from Gilead, Roche, and MSD; serves as an advisor for Aligos, Arbutus, Assembly, AbbVie, Biotest, Bluejay, Gilead, GSK, Janssen, Surrozen, and Vir Biotechnology; has received honoraria for lectures, speaker's bureaus, or other educational events for GSK; and participated in a data safety monitoring board or advisory board for DrugFarm. EG received speaking fees from AbbVie and Gilead Sciences and participated in advisory boards for AbbVie, Aligos, Assembly, Gilead Sciences, GSK, Intellia, Janssen, Roche, Vir Biotechnology, Virion, and Vaccitech. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Pregnant women with chronic hepatitis B (CHB) are a priority population for hepatitis B care. Identification of HBV status prior to pregnancy would facilitate timely maternal interventions and perinatal care. In our study, we aimed to study the epidemiology of CHB among women of childbearing age (WoCBA, 18-49 years) in Alberta, Canada. We retrospectively analysed Alberta Analytics databases to study CHB epidemiology, natural history and care linkage among WoCBA in Alberta, between April 2012 and March 2021. A Poisson regression was conducted to estimate incidence of newly identified CHB cases and prevalence trends, whereas predictors of care linkage were determined using logistic regression. Age/sex-adjusted incidence of newly identified CHB among WoCBA between 2015 and 2020 was 36.2/100,000 person/years, highest among individuals aged 30-39 years. Incidence of newly identified CHB decreased from 52.6 to 18.2/100,000 between 2015 and 2020, but prevalence increased from 131.7 to 248.6/100,000 in the same period. Newly identified CHB incident cases (n = 2124) had lower survival rates than age/sex-matched Canadians, with a standardized mortality ratio of 5.7 (95% CI 2.6-11.0). Increasing age (years) at diagnosis (HR, 1.2; 95% CI 1.1-1.3) was independently associated with mortality. Comorbid hepatocellular carcinoma, anti-HBV treatment and year of diagnosis were not significantly associated with mortality. Of the 1927 women with 2436 hepatitis B surface antigen-positive pregnancies from 2012 to 2020, only 27.6% had recommended HBV assessment during pregnancy. Of those women meeting criteria for antiviral therapy to prevent mother-to-child transmission (MTCT), only 66.4% received treatment. Suboptimal management during pregnancy and overall lower survival rates highlight the need to address care linkage barriers in women of childbearing age living with CHB., (© 2024 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Introduction and Objectives: Treatment of chronic hepatitis B (CHB) with nucelos(t)ide analogues (NA) can improve outcomes, but NA treatment is expensive for insurance plans., Materials and Methods: The Centers for Medicare & Medicaid Services database was assessed from 2012 to 2021 to assess the use of NA for CHB in patients on Medicaid. Data extracted included the number of claims, units, and costs of each agent stratified by originator and generic., Results: Over the study period, 1.9 billion USD was spent on NA, with spending peaking in 2016 at $289 million US, which has subsequently decreased. Lower expenditures since 2016 have been associated with increased use of generics. The use of generic tenofovir or entecavir led to savings of $669 million US over the study period., Conclusions: Increased generic use has significantly reduced expenditures for NA drugs; policy shifts towards generic drug use may help with sustainability., Competing Interests: Declaration of interests SEC reports grants from Gilead Sciences, Genfit, Allergan, Axcella Health, Inc, AstraZeneca, Merck, and Ipsen and personal fees from AstraZeneca and Novo Nordisk outside the submitted work. CSC reports investigator-initiated research grants/research materials from GlaxoSmithKline, Gilead Sciences, Inc., and Janssen Pharmaceutical; having served as a consultant for Gilead Sciences and Roche; and serving on an advisory board for Altimmune Pharmaceuticals with funds paid to the Canadian HBV Network, University of Calgary. MB has nothing to disclose., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Competing Interests: Su Wang received grants from Gilead. Carla S. Coffin consults for and received grants from Gilead and GSK. She received grants from Janssen Pharmaceuticals, Roche, and Altimmune. Chari Cohen advises and received grants from Gilead. She advises GSK. She received grants from Roche/Genentech and VBI Vaccines. The remaining authors have no conflicts to report.

To achieve a virological cure for hepatitis B virus (HBV), innovative strategies are required to target the covalently closed circular DNA (cccDNA) genome. Guanine-quadruplexes (G4s) are a secondary structure that can be adopted by DNA and play a significant role in regulating viral replication, transcription, and translation. Antibody-based probes and small molecules have been developed to study the role of G4s in the context of the human genome, but none have been specifically made to target G4s in viral infection. Herein, we describe the development of a humanized single-domain antibody (S10) that can target a G4 located in the PreCore (PreC) promoter of the HBV cccDNA genome. MicroScale Thermophoresis demonstrated that S10 has a strong nanomolar affinity to the PreC G4 in its quadruplex form and a structural electron density envelope of the complex was determined using Small-Angle X-ray Scattering. Lentiviral transduction of S10 into HepG2-NTCP cells shows nuclear localization, and chromatin immunoprecipitation coupled with next-generation sequencing demonstrated that S10 can bind to the HBV PreC G4 present on the cccDNA. This research validates the existence of a G4 in HBV cccDNA and demonstrates that this DNA secondary structure can be targeted with high structural and sequence specificity using S10., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Competing Interests: Competing interests:: Carla Coffin reports research support from GSK. No other competing interests were declared.

Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF)., Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log 10 IU/ml HBsAg decline at W24., Results: Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log 10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log 10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU., Conclusions: Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies., Impact and Implications: Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log 10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways., Clinical Trial Number: NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/., Competing Interests: Harry L. Janssen reports receiving grants from AbbVie; Arbutus Biopharma; Gilead Sciences, Inc.; Janssen; Merck; and Roche; and serving as a consultant for Arbutus Biopharma; Arena Pharmaceuticals; Enyo Pharma; Gilead Sciences, Inc.; GSK; Janssen; Merck; Roche; Vir Biotechnology; and Viroclinics Biosciences. Young-Suk Lim reports serving on the advisory board for Gilead Sciences, Inc., and receiving research funding from Bayer Healthcare and Gilead Sciences, Inc. Hyung Joon Kim reports no conflicts of interest. Leonard Sowah reports being an employee of and owning stock in Gilead Sciences, Inc. Cheng-Hao Tseng reports serving as a speaker for Abbvie; Bayer Healthcare; Bristol Myers Squibb; Gilead Sciences, Inc.; and Merck Sharp & Dohme. Carla S. Coffin reports investigator-initiated research grants/research materials from Arbutus Biopharma; Gilead Sciences, Inc.; GSK; and Janssen; having served as a consultant for Gilead Sciences, Inc., and Roche; and serving on an advisory board for Altimmune Pharmaceuticals with funds paid to the Canadian HBV Network, University of Calgary. Magdy Elkhashab reports receiving grants from AbbVie; Bristol Myers Squibb; Eisai; Gilead Sciences, Inc.; and Roche; and serving on advisory boards for AbbVie; Bristol Myers Squibb; Gilead Sciences, Inc.; and Merck. Sang Hoon Ahn has acted as an advisor and investigator for AbbVie; Aligos; Arbutus; Assembly Biosciences, Inc.; Brii; GeneOne Life Science; Gilead Sciences, Inc.; GSK; GreenCross; Ildong; Inovio; Janssen; Roche; Samil; SL Vaxigen; Vaccitech; Vir Biotechnology; and Yuhan. Anh-Hoa Nguyen reports being an employee of Gilead Sciences, Inc., and owning stock. Diana Chen reports being a former employee of Gilead Sciences, Inc., and owning stock. Jeffrey J. Wallin reports being an employee of Gilead Sciences, Inc., and owning stock. Simon P. Fletcher reports being an employee of Gilead Sciences, Inc., and owning stock. Circe McDonald reports being an employee of Gilead Sciences, Inc., and owning stock. Jenny C. Yang reports being a former employee of Gilead Sciences, Inc., and owning stock. Anuj Gaggar reports being a former employee of Gilead Sciences, Inc., and owning stock. Diana M. Brainard reports being a former employee of Gilead Sciences, Inc., and owning stock. Scott Fung reports receiving fees for speaking, teaching, and/or serving on advisory committees for AbbVie; Gilead Sciences, Inc.; Janssen; Lupin; Novo Nordisk; and Pfizer. Yoon Jun Kim reports no conflicts of interest. Jia-Horng Kao reports no conflicts of interest. Wan-Long Chuang reports serving as a consultant for AbbVie; Bristol Myers Squibb; Gilead Sciences, Inc.; Merck Sharp & Dohme; and PharmaEssentia; and has served as a speaker for AbbVie; Bristol Myers Squibb; Gilead Sciences, Inc.; Merck Sharp & Dohme; and PharmaEssentia. Anna E. Brooks reports consulting and conducting contract research for Gilead Sciences, Inc. P. Rod Dunbar reports consulting and conducting contract research for Arrowhead Pharmaceuticals, DrugFarm, and Gilead Sciences, Inc. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Background & Aims: Canadian clinical practice guidelines currently recommend risk-based screening for HCV in pregnant individuals. However, no provinces or territories have ever compared the effectiveness of risk-based vs. universal screening for the prenatal diagnosis of HCV. We aimed to evaluate and compare HCV screening programs after implementing a universal population-level pilot program among prenatal patients in Alberta, Canada., Methods: The Alberta Prenatal Screening Program for Select Communicable Diseases was amended to include universal HCV antibody screening. Cohorts of pregnant individuals screened for HCV through risk-based or universal programs were generated over 1-year periods. HCV screening rates and prevalence were analyzed and compared between cohorts to evaluate the effectiveness of screening methods. Social and demographic risk factors for HCV-positive individuals were compared between screening cohorts to identify which populations may be overlooked with risk-based guidelines., Results: HCV antibody screening rates were 11.9% and 99.9% among pregnant individuals in the risk-based and universal cohorts, respectively. HCV prevalence among the cohorts was 0.07% and 0.11% (difference = 0.04%, p = 0.032), with an average of 21 additional HCV-positive pregnant individuals identified annually with universal screening. HCV-positive pregnant patients diagnosed through universal screening were more likely to engage in high-risk sexual behaviours/sex work compared to those diagnosed through risk-based screening (47.6% vs. 12.5%, respectively p = 0.035), suggesting that these high-risk cases are being missed by risk-based screening., Conclusions: Universal HCV screening diagnoses significantly higher numbers of pregnant individuals infected with HCV compared to risk-based screening. Universal HCV screening or amending risk-based guidelines to incorporate more proxy variables for risk factors should be considered to improve prenatal HCV screening guidelines in Canada and help achieve HCV elimination in the next decade., Impact and Implications: HCV is a bloodborne pathogen that can cause severe liver disease and be vertically transmitted from a mother to her baby during pregnancy. Pregnant individuals in Alberta are currently only tested for HCV if they disclose engaging in activities that put them at risk of acquiring the infection (risk-based screening). Using a population-wide universal prenatal HCV screening program, our work shows that testing based on patient disclosed risk alone leads to the significant underdiagnosis of HCV in pregnant individuals and suggests individuals engaging in sex work or risky sexual behaviours are being overlooked by the current risk-based program. Our outcomes represent the first province-wide study to evaluate and compare prenatal HCV risk-based and universal screening programs in Canada and provide evidence to support the update of prenatal HCV screening policies across the country and in similar jurisdictions., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Individuals infected with hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency (HIV) viruses can experience compensated advanced chronic liver disease (cACLD) leading to esophageal varices (EV). In patients at low risk of esophageal varices needing treatment (EVNT), non-invasive criteria based on liver stiffness measurement (LSM) with platelets, or fibrosis biomarkers, may avoid unnecessary screening esophagogastroduodenoscopies (EGD). These approaches have not been compared among people infected with HIV, HBV, and HCV patients., Methods: Patients with a diagnosis of cACLD (LSM ≥10 kPa) and EGD availability were included from two cohorts. Baveno VI and expanded Baveno VI criteria (based on LSM and platelets), fibrosis biomarkers Fibrosis-4 Index (FIB-4), AST-to-Platelets Ratio Index (APRI), AST-to-ALT ratio (AAR), and RESIST criteria (based on platelets and albumin) were applied to determine the proportion of spared EGD and of missed EVNT., Results: Three hundred fifty three patients (30.6% with HIV, 25.3% monoinfected with HBV, and 44.1% with HCV) were included. The prevalence of EVNT was 8.2%. Both Baveno VI and expanded Baveno VI criteria performed well in patients with virus-related cACLD, by sparing 26.1% and 51.6% EGD, respectively, while missing <2% EVNT. The proportion of spared EGD were 48.2%, 58%, and 24.3% by FIB-4 (<2.78), APRI (<1.1), and AAR (<0.75), respectively, while missing <3% EVNT. RESIST criteria spared 47.8% EGD while missing 1.9% EVNT., Conclusions: Non-invasive criteria based on LSM can spare unnecessary EGD in virus-related cACLD. Simple fibrosis biomarkers can ameliorate resource utilization for EVNT screening in low resource settings., (© Canadian Association for the Study of the Liver, 2023.)

Background: Pegylated interferon (Peg-IFN) is recommended as first-line therapy for chronic hepatitis B (CHB) but has significant side effects and is rarely used compared to oral nucleos(t)ide analogues (NA). There are limited recent clinical efficacy or economic analysis data comparing approved CHB therapy in North America., Methods: This retrospective study examined clinical outcomes, off-treatment durability, and cost-effectiveness of Peg-IFN versus NA for CHB. Demographic (age, sex, ethnicity), clinical data (i.e., liver tests, hepatitis B virus DNA, serology, transient elastography) and documented side effects were collected by retrospective chart review of patients followed in the University of Calgary Liver Unit who received Peg-IFN therapy from January 2007 to December 2020. The cost-effectiveness of Peg-IFN versus NA therapy was modelled over a 10-year time horizon., Results: Sixty-eight CHB patients were treated with Peg-IFN (median age 45.65, 74% male, 84% Asian); 50/68 (74%) completed 48 weeks of treatment with a median follow-up of 6.54 years (interquartile range 5.07). At the last known follow-up, 23/68 (34%) have not required NA treatment and one had HBsAg loss; 27 have been started on NA. Predictors of obtaining a sustained virological response included being hepatitis B e antigen-negative at treatment end and a quantitative hepatitis B surface antigen <1000 IU/mL. Economic modelling showed that finite Peg-IFN was not cost-effective versus NA at a 10-year time horizon., Conclusions: PEG-IFN remains a potential treatment for CHB although there is a significant intolerance/failure rate. Using PEG-IFN based on patient preference is reasonable and optimal patient selection may improve treatment cost-effectiveness., (© Canadian Association for the Study of the Liver, 2023.)

Background: Hepatitis B virus (HBV)/Hepatitis D Virus (HDV) co-infection increases the risk of severe liver disease compared to HBV mono-infection. Adaptive immune responses to HDV are weakly detectable, and the involvement of innate immunity in the progression of HDV-related liver fibrosis is suggested. We hypothesize that an overall innate immune activation in HBV/HDV co-infection plays a role in liver disease progression and also impacts virus specific T cell response., Methods: Sixteen HBV/HDV-co-infected-patients (median age 42y/7F/6 Asian/4 White/6 Black/15 HBeAg-) and 8 HBV monoinfected-patients (median age 39y/4F/4 Asian/3 Black/1 White/HBeAg-) with median follow-up of 5 years were enrolled. Liver fibrosis was assessed by liver stiffness measurement (LSM, FibroScan ® ). Proliferation of CD3 + CD4+ T cells in response to viral antigens using CFSE assays and cytokine secreting monocytes was analyzed by flow cytometry., Results: Of 16 HBV/HDV, 11 were HDV-RNA+ (HBV-DNA 0-1,040 IU/mL), 5/11 Interferon (IFN) + Nucleos/tide Analog (NA), 3/11 NA monotherapy, median ALT 77 U/L at the time of sample collection, median LSM of 9.8. In 5 HDV RNA-, median HBV DNA 65 IU/mL, 4/5 prior IFN and/or NA, ALT 31 U/L, and median LSM 8.5 kPa. In 8 HBV controls, median HBV-DNA, ALT, LSM was 69 IU/mL, 33 U/L,5 kPa, respectively. PBMC stimulation with HBV core antigen (HBcAg) and HDV antigen (HDAg) showed weaker CD3 + CD4 + T-cell proliferation in HDV-RNA+ vs. HDV RNA- and HBV-mono-infected patients ( p  < 0.05). In HDV-RNA+ patients, a correlation between ALT and TNF-α ( r  = 0.76, p  = 0.008), higher IL-10 levels and increased proportion of CD14 + TNF-α+ cells were found., Conclusion: In summary, during HBV/HDV coinfection, HDV RNA+ patients had weaker HBV and HDV specific responses, associated with increased TNF-α + monocytes irrespective of IFN treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Joshi, Sadler, Patel, Osiowy, Fonseca and Coffin.)

Introduction: Serum hepatitis B virus (HBV) RNA is a promising new biomarker to manage and predict clinical outcomes of chronic hepatitis B (CHB) infection. However, the HBV serum transcriptome within encapsidated particles, which is the biomarker analyte measured in serum, remains poorly characterized. This study aimed to evaluate serum HBV RNA transcript composition and proportionality by PCR-cDNA nanopore sequencing of samples from CHB patients having varied HBV genotype (gt, A to F) and HBeAg status., Methods: Longitudinal specimens from 3 individuals during and following pregnancy (approximately 7 months between time points) were also investigated. HBV RNA extracted from 16 serum samples obtained from 13 patients (73.3% female, 84.6% Asian) was sequenced and serum HBV RNA isoform detection and quantification were performed using three bioinformatic workflows; FLAIR, RATTLE, and a GraphMap-based workflow within the Galaxy application. A spike-in RNA variant (SIRV) control mix was used to assess run quality and coverage. The proportionality of transcript isoforms was based on total HBV reads determined by each workflow., Results: All chosen isoform detection workflows showed high agreement in transcript proportionality and composition for most samples. HBV pregenomic RNA (pgRNA) was the most frequently observed transcript isoform (93.8% of patient samples), while other detected transcripts included pgRNA spliced variants, 3' truncated variants and HBx mRNA, depending on the isoform detection method. Spliced variants of pgRNA were primarily observed in HBV gtB, C, E, or F-infected patients, with the Sp1 spliced variant detected most frequently. Twelve other pgRNA spliced variant transcripts were identified, including 3 previously unidentified transcripts, although spliced isoform identification was very dependent on the workflow used to analyze sequence data. Longitudinal sampling among pregnant and post-partum antiviral-treated individuals showed increasing proportions of 3' truncated pgRNA variants over time., Conclusions: This study demonstrated long-read sequencing as a promising tool for the characterization of the serum HBV transcriptome. However, further studies are needed to better understand how serum HBV RNA isoform type and proportion are linked to CHB disease progression and antiviral treatment response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vachon, Seo, Patel, Coffin, Marinier, Eyras and Osiowy.)

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Measuring the incidence of HIV and hepatitis C virus (HCV) infection among people who inject drugs (PWID) is key to track progress towards elimination. We aimed to summarise global data on HIV and primary HCV incidence among PWID and associations with age and sex or gender., Methods: In this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies among PWID by searching MEDLINE, Embase, and PsycINFO, capturing studies published between Jan 1, 2000, and Dec 12, 2022, with no language or study design restrictions. We contacted authors of identified studies for unpublished or updated data. We included studies that estimated incidence by longitudinally re-testing people at risk of infection or by using assays for recent infection. We pooled incidence and relative risk (RR; young [generally defined as ≤25 years] vs older PWID; women vs men) estimates using random-effects meta-analysis and assessed risk of bias with a modified Newcastle-Ottawa scale. This study is registered with PROSPERO, CRD42020220884., Findings: Our updated search identified 9493 publications, of which 211 were eligible for full-text review. An additional 377 full-text records from our existing database and five records identified through cross-referencing were assessed. Including 28 unpublished records, 125 records met the inclusion criteria. We identified 64 estimates of HIV incidence (30 from high-income countries [HICs] and 34 from low-income or middle-income countries [LMICs]) and 66 estimates of HCV incidence (52 from HICs and 14 from LMICs). 41 (64%) of 64 HIV and 42 (64%) of 66 HCV estimates were from single cities rather than being multi-city or nationwide. Estimates were measured over 1987-2021 for HIV and 1992-2021 for HCV. Pooled HIV incidence was 1·7 per 100 person-years (95% CI 1·3-2·3; I 2 =98·4%) and pooled HCV incidence was 12·1 per 100 person-years (10·0-14·6; I 2 =97·2%). Young PWID had a greater risk of HIV (RR 1·5, 95% CI 1·2-1·8; I 2 =66·9%) and HCV (1·5, 1·3-1·8; I 2 =70·6%) acquisition than older PWID. Women had a greater risk of HIV (RR 1·4, 95% CI 1·1-1·6; I 2 =55·3%) and HCV (1·2, 1·1-1·3; I 2 =43·3%) acquisition than men. For both HIV and HCV, the median risk-of-bias score was 6 (IQR 6-7), indicating moderate risk., Interpretation: Although sparse, available HIV and HCV incidence estimates offer insights into global levels of HIV and HCV transmission among PWID. Intensified efforts are needed to keep track of the HIV and HCV epidemics among PWID and to expand access to age-appropriate and gender-appropriate prevention services that serve young PWID and women who inject drugs., Funding: Canadian Institutes of Health Research, Fonds de recherche du Québec-Santé, Canadian Network on Hepatitis C, UK National Institute for Health and Care Research, and WHO., Competing Interests: Declaration of interests AA acknowledges support through postdoctoral fellowships from the Canadian Institute of Health Research (CIHR), Fonds de recherche du Québec – Santé (FRQ-S), and the Canadian Network on Hepatitis C. MA reports grants paid to his institution from the Public Health Agency of Canada and grants from the Ministère de la santé et des services sociaux du Québec, during the conduct of this study, and grants from the CIHR, outside the submitted work. JA reports grants from the National Institutes of Health (NIH), during the conduct of this study. JB reports consulting fees from Gilead Sciences, AbbVie, and Cepheid; payment or honoraria from Gilead Sciences for an educational event; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gilead Sciences, as part of an NIH R01 grant, outside of the submitted work. CSC reports grants from Gilead Sciences, Janssen Pharmaceuticals, and GSK (paid to the University of Calgary); consulting fees from Roche Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals (paid to the University of Calgary, on behalf of the Canadian Hepatitis B Virus [HBV] Network), and Altimmune (paid to the University of Calgary, on behalf of the Canadian HBV Network); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events through Gilead Sciences; and patents planned, issued, or pending (PCT/CA2021/050234; international patent application title: polypeptides directed against viral infection and uses thereof; compositions and methodologies for the detection and treatment of HBV infection; USA; 62/982,474; Feb 28, 2020). SC reports payments for chairing or presenting at a European HIV Testing Week webinar from the Centre of Excellence for Health, Immunity and Infections, outside the submitted work. KH reports financial support for the present manuscript paid to her institution from the US National Institute of Drug Abuse (NIDA; Vancouver Drug Users Study: the impacts of evolving drug use patterns on HIV/AIDS; U01DA038886), the Michael Smith Foundation for Health Research Scholar Award, and St Paul's Foundation, and grants or contracts from the CIHR and the William and Ada Isabelle Steel Fund through Simon Fraser University (paid to institution) and the British Columbia Centre on Substance Use (paid to KH). GM reports grants or contracts from AbbVie (clinic support, advisory board, and speaker fees), the Canadian Network on Hepatitis C (research support), Coverdale (clinic support), Gilead Sciences (clinic support and speakers fees), International Network on Health and Hepatitis in Substance Users (INHSU; speaker fees), and TD Bank (clinic support); payment or honoraria from the Canadian Association for the Study of the Liver (scientific planning committee for web-based learning, conjoint with AbbVie; payment to institution), AbbVie (speakers fees for educational podcasts and brochure; payment partly to institution and partly to GM), Gilead Sciences (speaker fees; payment partly to institution and partly to GM), and ECHO plus (honorarium for speaking); and support for attending meetings or travel, or both, from INHSU and being on the advisory board for AbbVie and Gilead. JGW reports grants and contracts from Gilead Sciences and FIND, The Global Alliance for Diagnostics. MH reports having a leadership or fiduciary role as trustee of the Society for the Study of Addiction. All other authors declare no competing interests. Declaration of interests for the members of the HIV and HCV Incidence Review Collaborative Group are provided in the appendix (p 52)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background/aims: Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as 'functional cure'. Inarigivir (retinoic acid-inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection., Patients/methods: 80 treatment-naïve patients were randomized in 4 ascending dose cohorts to receive 12 weeks of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks., Results: Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group) (95% CI 0.9518-0.2011 and 1.921-1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from -0.3856 to -0.5794 versus -0.1474 and -0.0956 to -0.1818 versus +0.0026 in Inarigivir-treated versus placebo groups respectively. During the tenofovir-treated period, LS mean reductions in HBsAg in the Inarigivir-treated groups ranged from 0.1709 to 0.3529 versus 0.1984 in the placebo group. Inarigivir-treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 versus 0.7 U/L in the placebo group. Treatment-emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patients respectively., Conclusions: Twelve-week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Tenofovir alafenamide (TAF) achieves increased renal safety and improved alanine aminotransferase (ALT) normalization but increased lipid profile in hepatitis B virus (HBV)-monoinfected patients switched from tenofovir disoproxil fumarate (TDF). It is unclear whether HIV coinfection perturbs these biochemical changes. To this end, we assessed these parameters in HIV/HBV-coinfected patients switched from TDF to TAF., Design: Retrospective, multicenter, observational study., Methods: HIV/HBV-coinfected patients switched from TDF to TAF-based antiretroviral therapy (ART) at 6 Canadian Hepatitis B Network (CanHepB) academic sites were included. Changes in lipid profile, estimated glomerular filtration rate (eGFR), and ALT were evaluated using linear mixed effect model regression., Results: Eighty-two HIV/HBV-coinfected patients with a mean 103-week follow-up duration were identified. At time of TAF switch, 80 of 82 (98%) were HBV virally suppressed, 29 of 82 (35%) had elevated ALT levels, and 63 of 82 (77%) had eGFR of ≥60 mL/min per 1.73 m 2 . Twenty-six/Eighty-two (32%) had preexisting renal comorbidities. There were no changes in total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels 2 years after TAF switch. Those with elevated ALT levels achieved greater ALT normalization after TAF switch (-0.004 [-0.008 to 0.0] log 10 U/L/mo, P = 0.03). eGFR decline rate while on TDF (-0.66 [-0.23 to -1.08] mL/min/month, P &lt; 0.005) was diminished after switching to TAF (-0.02 [-0.16 to 0.11] mL/min/mo, P = 0.7) and those with eGFR of &lt;60 mL/min experienced increase in eGFR after TAF switch (0.45 [0.03-0.87] mL/min/mo, P = 0.04)., Conclusions: Our study supports switching from TDF to TAF with positive influence on overall long-term biochemical profile in HIV/HBV-coinfected individuals., Competing Interests: A.W. has received grants and honoraria from AbbVie, Gilead Sciences, ViiV Healthcare, and Merck. S.F. consults for Gilead, Abbvie, Assembly, Springbank, and Eisai. K.D. reports a grant from Gilead Sciences. A.R. consults for Abbvie, Gilead, Janssen, Intercept, and Merck. B.C. reports grants and honoraria from AbbVie, Gilead Sciences, Indivior, Merck, and Viiv Healthcare. C.S.C. reports investigator-initiated research grants/research materials from GlaxoSmithKline, Gilead Sciences, Arbutus Biopharma, and Bristol Myers Squibb and educational grants from Merck, Gilead Sciences, and Janssen Pharmaceutica. B.E.H. consults for and/or received grants from Intercept, Cymabay, Janssen, and Albirco. H.L.A.J. received grants from AbbVie, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Janssen, Medimmune, Medtronic, and Merck, Roche and is consultant for AbbVie, Benitec, Bristol Myers Squibb, Gilead Sciences, Janssen, Medimmune, Merck, Roche, and Arbutus. All authors have no potential personal, in addition to, financial conflict of interest related to this study. The remaining authors have nothing to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied., Methods: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses., Results: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001)., Conclusion: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.

BACKGROUND: Herpes simplex virus (HSV) is a rare cause of acute viral hepatitis but has high mortality rates and primarily affects immunocompromised hosts. We report a case of HSV hepatitis in a 20-year-old female kidney transplant recipient who had 1000-fold elevations in transaminases on post-transplant day 14, and the strategies employed for diagnoses and treatment. METHODS: Routine laboratory, serological, and molecular viral testing was completed, and she underwent a bone marrow biopsy given initial suspicion of hemophagocytic lymphohistiocytosis (HLH). HSV serologic results and high transaminases triggered a liver biopsy. RESULTS: The patient presented with elevated transaminases (ALT 1731 U/L and AST 1400) and ferritin (1431 μg/L). Transaminases and ferritin peaked with an ALT of 6609 U/L, AST of 6525 U/L, and ferritin >50000 μg/L. Bone marrow biopsy revealed no definitive HLH. HSV-DNA PCR of blood was positive, and she was empirically started on intravenous acyclovir 10 mg/kg 3 times per day. Liver biopsy confirmed the histological diagnosis of HSV hepatitis. CONCLUSIONS: Given the high mortality rates associated with HSV hepatitis, it is crucial to determine pre-transplant HSV status, initiate appropriate antiviral prophylaxis, and to have a low threshold for investigating for HSV hepatitis and initiating treatment in patients with a suspected diagnosis., (Copyright © 2022 Canadian Association for the Study of the Liver.)

BACKGROUND: Identifying strategies for stopping nucleos(t)ide analogues (NUC) in patients with chronic hepatitis B (CHB) is a major goal in CHB management. Our study describes our tertiary-centre experience stopping nucleos(t)ide analogues (NUC) in CHB. METHODS: We conducted a retrospective cohort study of all individuals with CHB seen at the Calgary Liver Unit between January 2009 and May 2020 who stopped NUC. We collected baseline demographics and HBV lab parameters before and after stopping NUC with results stratified by off-treatment durability. Clinical flare was defined as alanine aminotransferase (ALT) over twice the upper limit of normal and virological flare as HBV DNA >2000 IU/mL. RESULTS: Forty-seven (3.5%) of the 1337 individuals with CHB stopped NUC therapy. During follow-up, six patients (12.8%) restarted NUCs because of a flare. All flares occurred within six months of discontinuation. Median time to restart treatment was 90 days (Q1 65, Q3 133). Upon restarting, all showed suppression of HBV DNA and ALT normalization. Factors associated with restarting NUC therapy included hepatitis B e antigen (HBeAg) positive status at first appointment and longer NUC consolidation therapy. Age, sex, ethnicity, liver stiffness measurement, choice of NUC, and quantitative hepatitis B surface antigen (qHBsAg) level at stopping were not associated with sustained response off-treatment. Six patients had functional cure with HBsAg loss. CONCLUSIONS: Stopping long-term NUC is feasible in HBeAg negative CHB. Hepatic flares can occur despite low levels of qHBsAg. Finite NUC therapy can be considered in eligible patients who are adherent to close monitoring and follow-up, particularly in the first six months after stopping NUC therapy., (Copyright © 2022 Canadian Association for the Study of the Liver.)

Background: Hepatitis B virus (HBV) nucleos(t)ide analog (NA) therapy reduces liver disease but requires prolonged therapy to achieve hepatitis B surface antigen (HBsAg) loss. There is limited North American real-world data using non-invasive tools for fibrosis assessment and few have compared 1 st generation NA or lamivudine (LAM) to tenofovir disoproxil fumarate (TDF)., Aim: To assess impact of NA on virological response and fibrosis regression using liver stiffness measurement (LSM) ( i.e. , FibroScan ® )., Methods: Retrospective, observational cohort study from the Canadian HBV Network. Data collected included demographics, NA, HBV DNA, alanine aminotransferase (ALT), and LSM. Patients were HBV monoinfected patients, treatment naïve, and received 1 NA with minimum 1 year follow-up., Results: In 465 (median 49 years, 37% female, 35% hepatitis B e antigen + at baseline, 84% Asian, 6% White, and 9% Black). Percentage of 64 ( n = 299) received TDF and 166 were LAM-treated with similar median duration of 3.9 and 3.7 years, respectively. The mean baseline LSM was 11.2 kPa (TDF) vs 8.3 kPa (LAM) ( P = 0.003). At 5-year follow-up, the mean LSM was 7.0 kPa in TDF vs 6.7 kPa in LAM ( P = 0.83). There was a significant difference in fibrosis regression between groups ( i.e. , mean -4.2 kPa change in TDF and -1.6 kPa in LAM, P < 0.05). The last available data on treatment showed that all had normal ALT, but more TDF patients were virologically suppressed (< 10 IU/mL) ( n = 170/190, 89%) vs LAM-treated ( n = 35/58, 60%) ( P < 0.05). None cleared HBsAg., Conclusion: In this real-world North American study, approximately 5 years of NA achieves liver fibrosis regression rarely leads to HBsAg loss., Competing Interests: Conflict-of-interest statement: Dr. Alnoor Ramji and Dr. Carla S Coffin didn’t receive at any time payment from a third party for any aspect for the submitted work; there are no relevant conflict of interest; there are no patents related to this work; Dr. Alnoor Ramji and Dr. Carla S Coffin have nothing to disclosure., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hepatitis B virus (HBV) is a global health problem. Vertical transmission of HBV from HBV surface antigen (HBsAg)-positive mothers to their infants is the most common cause of HBV infection worldwide. The use of passive-active immunoprophylaxis is >90% effective in reducing the risk of vertical transmission, but immunoprophylaxis failure can occur in infants born to mothers with high viraemia. Thus, it is recommended that pregnant women with HBV-DNA level >200 000 IU/ml receive nucleos(t)ide analogue (NA) treatment [i.e. tenofovir disoproxil fumarate (TDF), lamivudine or telbivudine] during third trimester to prevent infant immunoprophylaxis failure. TDF is recommended as the first-line therapy based on available data on efficacy, safety and resistance profile. However, maternal immunological reconstitution following parturition can increase immune-mediated flares to viral antigens that is potentially exacerbated following TDF withdrawal. In this article, we review available data on the efficacy and safety of TDF administration to prevent HBV mother-to-child transmission. We also discuss changes in maternal viral markers [i.e. HBV-DNA, HBV e antigen and HBsAg] and alanine aminotransferase during follow-up post-partum in mothers received NA to prevent HBV vertical transmission., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Vaccination is the most important way to control infectious bronchitis (IB) in chickens. Since the end of 2015, the Delmarva (DMV)/1639 strain of infectious bronchitis virus (IBV) has caused significant damage to the layer flocks in Eastern Canada. The efficacy of a combination of existing IB vaccines licensed in Canada was assessed against experimental challenge with this IBV strain. The layer pullets were vaccinated during the rearing phase with live attenuated IB vaccines of Massachusetts (Mass) + Connecticut (Conn) types followed by an inactivated IB vaccine of Mass + Arkansas (Ark) types and then challenged with the Canadian IBV DMV/1639 strain at 30 weeks of age. Protection was evaluated based on the egg laying performance, immune responses, viral shedding, and viral genome loads and lesions in IBV target organs. The vaccinated challenged hens were protected from the drop in egg production observed in the non-vaccinated challenged hens. Early (5 dpi) anamnestic serum antibody response was measured in the vaccinated challenged hens as well as a significant level of antibodies was detected in the oviduct washes (14 dpi). In contrast, hens in the non-vaccinated challenged group showed delayed (12 dpi) and significantly lower serum antibody response. Viral RNA loads were reduced in the respiratory, alimentary, and reproductive tissues of the vaccinated challenged hens compared to the non-vaccinated challenged hens. Compared to the control groups, the vaccinated challenged hens had less marked microscopic lesions in the trachea, kidney, magnum, and uterus. Our experimental model demonstrated inconclusive results for cell-mediated immune responses and viral shedding. Overall, the vaccination program used in this study minimized viral replication and histopathological changes in most IBV target organs and protected challenged hens against drop in egg production.

Background & Aims: Coronavirus disease 2019 (COVID-19) pandemic lockdown and restrictions had significant disruption to patient care. We aimed to evaluate the impact of COVID-19 restrictions on hospitalizations of patients with alcoholic and nonalcoholic cirrhosis as well as alcoholic hepatitis (AH) in Alberta, Canada., Methods: We used validated International Classification of Diseases (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for nonalcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta between March 2018 and September 2020. We used the provincial inpatient discharge and laboratory databases to identify our cohorts. We used elevated alanine aminotransferase or aspartate aminotransferase, elevated international normalized ratio, or bilirubin to identify AH patients. We compared COVID-19 restrictions (April-September 2020) with prior study periods. Joinpoint regression was used to evaluate the temporal trends among the 3 cohorts., Results: We identified 2916 hospitalizations for nonalcoholic cirrhosis, 2318 hospitalizations for alcoholic cirrhosis, and 1408 AH hospitalizations during our study time. The in-hospital mortality rate was stable in relation to the pandemic for alcoholic cirrhosis and AH. However, nonalcoholic cirrhosis patients had lower in-hospital mortality rate after March 2020 (8.5% vs 11.5%; P = .033). There was a significant increase in average monthly admissions in the AH cohort (22.1/10,000 admissions during the pandemic vs 11.6/10,000 admissions before March 2020; P < .001)., Conclusions: Before and during COVID-19 monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis; however, there was a significant increase in AH admissions. Because alcohol sales surged during the pandemic, future impact on alcoholic liver disease could be detrimental., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

IBV infection may lead to reduced egg production and poor egg quality in layer flocks. The DMV/1639 strain was recently identified as one of the most dominant IBV variants isolated from Canadian layer flocks with egg production problems. The current study aimed to investigate the immunopathogenesis of the Canadian DMV/1639 strain in laying chickens. Specific-pathogen-free (SPF) layers were infected at the peak of lay (29 weeks; n = 10) with an uninfected control group (n = 10). Egg production in the infected group dropped to 40% by the fifth day post-infection (dpi). Five birds from the infected and the control groups were euthanized at 5 and 10 dpi. Ovarian regression and shortened oviduct with marked histopathological changes were observed in the infected group at 10 dpi. An increase in the IBV viral load in reproductive tissues was accompanied by a significant recruitment (p < 0.05) of KUL01+ macrophages and CD4 + and CD8 + T cell subsets at 10 dpi. Additionally, anti-IBV antibody response was detected in serum and locally in the reproductive tract washes of the infected group. Overall, our findings contribute to the understanding of the pathogenicity of the Canadian DMV/1639 strain and the subsequent host responses in the reproductive tract of chickens., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network., Methods: Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications., Results: Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort., Conclusions: Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada., Lay Summary: Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected patients., Competing Interests: CSC within past 36 months: Grant or contract from Gilead Sciences, Janssen Pharmaceuticals, GSK; Consulting fees from Janssen Pharmaceuticals; Payment or honoraria from Gilead Sciences (all made to the University of Calgary). The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Crown Copyright © 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Background and Aims: The obesity epidemic has increased the risk of nonalcoholic fatty liver disease (NAFLD) in both the general and chronic hepatitis B (CHB) populations. Our study aims to determine the prevalence of NAFLD in patients with CHB based on controlled attenuation parameter (CAP) and the epidemiological, clinical, and virological factors associated with severe hepatic steatosis., Methods: The Canadian Hepatitis B Network cohort was utilized to provide a cross-sectional description of demographics, comorbidities, antiviral treatment, and hepatits B virus (HBV) tests. Liver fibrosis and steatosis were measured by transient elastography and CAP, respectively. Any grade and severe steatosis were defined as CAP >248 and >280 dB/m, respectively. Advanced liver fibrosis was defined as transient elastography measurement >10.7 kPa., Results: In 1178 patients with CHB (median age: 47.4%, 57.7% males, 75.7% Asian, 13% African, 6.5% White, 86% HBV e antigen negative, median HBV DNA of 2.44 log 10 IU/mL, 42.7% receiving treatment), the prevalence of any grade and severe steatosis was 53% and 36%, respectively. In the multivariate analysis, obesity was a significant predictor for severe steatosis (adjusted odds ratio: 5.046, 95% confidence interval: 1.22-20.93). Severe steatosis was a determinant associated with viral load (adjusted odds ratio: 0.385, 95% confidence interval: 0.20-0.75, P  < .01; r = -0.096, P  = .007) regardless of antiviral therapy, age, and alanine aminotransferase levels., Conclusion: In this large multiethnic CHB population, hepatic steatosis is common. Severe steatosis is independently associated with higher fibrosis, but negatively with HBV DNA, regardless of antiviral therapy history., (© 2022 The Authors.)

Infectious bronchitis virus (IBV) infection causes significant economic losses to various sectors of the poultry industry worldwide. Over the past few years, the incidence of false layer syndrome in Eastern Canadian layer flocks has been associated with the increased prevalence of the IBV Delmarva (DMV)/1639 strain. In this study, 1-day-old specific-pathogen-free (SPF) hens were infected with the Canadian DMV/1639 strain and observed until 16 weeks of age in order to determine if the IBV DMV/1639 strain is causing false layer syndrome. Early after infection, the virus showed a wide tissue distribution with characteristic gross and histopathological lesions in the respiratory tract and kidney. Around 60-70% of the infected hens demonstrated continuous cloacal viral shedding until the end of the experiment (at 16 weeks) which was associated with high IBV genome loads detected in the cecal tonsils. The experiment confirmed the field observations that the Canadian DMV/1639 strain is highly pathogenic to the female reproductive tract causing marked cystic lesions in the oviduct. Moreover, significant histopathological damage was observed in the ovary. Our study provides a detailed description of the pathological consequences of the IBV DMV/1639 strain circulating in an important poultry production sector.

The coronavirus disease 2019 (COVID-19) pandemic created a crisis that disproportionately affected populations already disadvantaged with respect to access to health care systems and adequate medical care and treatments. Understanding how and where health care disparities are most widespread is an important starting point for exploring opportunities to mitigate such disparities, especially within our patient population with liver disease. In a webinar in LiverLearning, we discussed the impact of the pandemic on the United States, United Kingdom and Canada, highlighting the disproportionate effects on infection rates and death for certain ethnic minorities, those socioeconomically disadvantaged and living in higher density areas, and those working in health care and other essential jobs. We set forth a "call to action" for members of the American Association for the Study of Liver Diseases and the larger community of providers of liver disease care to generate viable solutions to improve access to care and vaccination rates of our patients against COVID-19, and in general help reduce health care disparities and improve the health of disadvantaged populations within their communities. Solutions will likely involve personalized interventions and messaging for communities that honor local leaders and embrace the diverse needs and different cultural sensitivities of our unique patient populations., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Since the discovery of hepatitis B virus (HBV) over five decades ago, there have been many independent studies showing presence of HBV genomes in cells of the immune system. However, the nature of HBV lymphotropism and its significance with respect to HBV biology, persistence and the pathogenesis of liver and extrahepatic disorders remains underappreciated. This is in contrast to studies of other viral pathogens in which the capability to infect immune cells is an area of active investigation. Indeed, in some viral infections, lymphotropism may be essential, and even a primary mechanism of viral persistence, and a major contributor to disease pathogenesis. Nevertheless, there are advances in understanding of HBV lymphotropism in recent years due to cumulative evidence showing that: (i) lymphoid cells are a reservoir of replicating HBV, (ii) are a site of HBV-host DNA integration and (iii) virus genomic diversification leading to pathogenic variants, and (iv) they play a role in HBV resistance to antiviral therapy and (v) likely contribute to reactivation of hepatitis B. Further support for HBV lymphotropic nature is provided by studies in a model infection with the closely related woodchuck hepatitis virus (WHV) naturally infecting susceptible marmots. This animal model faithfully reproduces many aspects of HBV biology, including its replication scheme, tissue tropism, and induction of both symptomatic and silent infections, immunological processes accompanying infection, and progressing liver disease culminating in hepatocellular carcinoma. The most robust evidence came from the ability of WHV to establish persistent infection of the immune system that may not engage the liver when small quantities of virus are experimentally administered or naturally transmitted into virus-naïve animals. Although the concept of HBV lymphotropism is not new, it remains controversial and not accepted by conventional HBV researchers. This review summarizes research advances on HBV and hepadnaviral lymphotropism including the role of immune cells infection in viral persistence and the pathogenesis of HBV-induced liver and extrahepatic diseases. Finally, we discuss the role of immune cells in HBV diagnosis and assessment of antiviral therapy efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Coffin, Mulrooney-Cousins and Michalak.)

Tenofovir alafenamide fumarate (TAF) has high plasma stability resulting in fewer renal adverse events compared to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. We aimed to study the effectiveness and renal safety of TAF in a real-world setting, in patients with or without compromised kidney function. CHB patients (Nucleos(t)ide Analogue [NA]-naïve or experienced) who received TAF >1 year from 11 academic institutions as part of the Canadian Hepatitis B Network (CanHepB) were included. Kidney function was measured by estimated glomerular filtration rate (eGFR) as per Cockcroft-Gault. Patients were followed for up to 160 weeks. Of 176 patients receiving TAF, 143 switched from NA (88% TDF), and 33(19%) were NA naïve. Majority of NA-naïve patients (75%) achieved undetectable HBV DNA after one year of TAF treatment. Majority of patients with eGFR <60 mL/min who had renal deterioration during TDF (76%) reversed to eGFR increase after one year of TAF (p=0.009). Among patients with stage 2 chronic kidney disease (CKD) (eGFR 60-89), the estimated eGFR decline during TDF was halted after switching to TAF (p=0.09). NA-experienced patients with abnormal ALT before TAF showed a significant decline after switching to TAF: -0.005 [-0.006 - -0.004] log 10 ULN U/L/month, p<0.001). In CHB patients, TAF was safe, well-tolerated and effective in this real-world cohort. Switching to TAF led to improved kidney function, particularly in those with stage 2 CKD, which suggests that the indication for TAF in the guidelines could be extended to patients with an eGFR higher than 60 mL/min., (© 2021 John Wiley & Sons Ltd.)

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., Competing Interests: Calvin Pan has received research grants from Gilead Sciences (Gilead) and Merck. He also serves as a consultant or advisor for Gilead, and speakers’ bureau for Gilead, Abbvie, and Intercept. Ting-Tsung Chang and Si Hyun Bae declare no conflicts of interest. Wai Kay Seto serves on the advisory boards of Gilead, Abbvie and CSL Behring, and is a speaker for Gilead, AbbVie and Mylan. Maurizia Brunetto has received research grants from AbbVie, BMS, MSD, has served on advisory Boards for AbbVie, Gilead, Janssen; Roche, and has served as a speaker for AbbVie, Gilead, MSD. Carla S. Coffin has served as an investigator or received research grants from GlaxoSmithKline, Gilead, Arbutus Biopharma, Bristol-Myers Squibb, has received educational grants from Merck, Gilead, Janssen, has served on advisory boards for Merck, Gilead, GlaxoSmithKline, has served on Clinical Trial and Publication Committee for Spring Bank Pharmaceuticals, and has participated as a primary investigator in clinical trials for Gilead, Spring Bank, Transgene, and Janssen. The following authors are employees of Gilead Sciences and hold stock interest in the company: Susanna Tan, Shuyuan Mo, John Flaherty, and Anuj Gaggar. Mindie H. Nguyen has received research support from Gilead and Pfizer, has served on advisory boards and/or as a consultant for Novartis, Spring Bank, Janssen, Gilead, Eisai, Bayer. Exact Science, and LAM. Mustafa Kemal Çelen has no conflicts of interest to disclose. Alexander Thompson has received research support from Gilead, AbbVie, and Merck, and has served on advisory boards and/or as a consultant for Gilead, AbbVie, Merck, BMS, Eisai. Edward J. Gane has served as a consultant or advisor for Gilead, AbbVie, Roche, Janssen and at speakers’ bureaus for Gilead and AbbVie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Due to shared modes of exposure, HIV-HBV co-infection is common worldwide. Increased knowledge of the demographic and clinical characteristics of the co-infected population will allow us to optimize our approach to management of both infections in clinical practice. The Canadian Hepatitis B Network Cohort was utilized to conduct a cross-sectional evaluation of the demographic, biochemical, fibrotic and treatment characteristics of HIV-HBV patients and a comparator HBV group. From a total of 5996 HBV-infected patients, 335 HIV-HBV patients were identified. HIV-HBV patients were characterized by older median age, higher male and lower Asian proportion, more advanced fibrosis and higher anti-HBV therapy use (91% vs. 30%) than the HBV-positive / HIV seronegative comparator group. A history of reported high-risk exposure activities (drug use, high-risk sexual contact) was more common in HIV-HBV patients. HIV-HBV patients with reported high-risk exposure activities had higher male proportion, more Caucasian ethnicity and higher prevalence of cirrhosis than HIV-HBV patients born in an endemic country. In the main cohort, age ≥60 years, male sex, elevated ALT, the presence of comorbidity and HCV seropositivity were independent predictors of significant fibrosis. HIV seropositivity was not an independent predictor of advanced fibrosis (adj OR 0.75 [95%CI: 0.34-1.67]). In conclusion, Canadian co-infected patients differed considerably from those with mono-infection. Furthermore, HIV-HBV-infected patients who report high-risk behaviours and those born in endemic countries represent two distinct subpopulations, which should be considered when engaging these patients in care., (© 2020 John Wiley & Sons Ltd.)

Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B ® , or Twinrix ® , GlaxoSmithKline). Anti-HBs titers were measured at 1-3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses.

Approximately 250 million people worldwide are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing cirrhosis and hepatocellular carcinoma. The HBV genome persists as covalently closed circular DNA (cccDNA), which serves as the template for all HBV mRNA transcripts. Current nucleos(t)ide analogs used to treat HBV do not directly target the HBV cccDNA genome and thus cannot eradicate HBV infection. Here, we report the discovery of a unique G-quadruplex structure in the pre-core promoter region of the HBV genome that is conserved among nearly all genotypes. This region is central to critical steps in the viral life cycle, including the generation of pregenomic RNA, synthesis of core and polymerase proteins, and genome encapsidation; thus, an increased understanding of the HBV pre-core region may lead to the identification of novel anti-HBV cccDNA targets. We utilized biophysical methods (circular dichroism and small-angle X-ray scattering) to characterize the HBV G-quadruplex and the effect of three distinct G to A mutants. We also used microscale thermophoresis to quantify the binding affinity of G-quadruplex and its mutants with a known quadruplex-binding protein (DHX36). To investigate the physiological relevance of HBV G-quadruplex, we employed assays using DHX36 to pull-down cccDNA and compared HBV infection in HepG2 cells transfected with wild-type and mutant HBV plasmids by monitoring the levels of genomic DNA, pregenomic RNA, and antigens. Further evaluation of this critical host-protein interaction site in the HBV cccDNA genome may facilitate the development of novel anti-HBV therapeutics against the resilient cccDNA template., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There are limited long-term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)-treated women during pregnancy., Aims: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post-partum in a low HBV endemic region., Methods: Retrospective real-world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post-partum., Results: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7-39.5) post-partum, 19% (65/341) received TDF (11 initiated pre-pregnancy, 53 for mother-to-child transmission (MTCT) prevention). During follow-up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re-treated. In all TDF-treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow-up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post-partum, requiring re-treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post-partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post-partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23-40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12-26) post-partum., Conclusions: Post-partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long-term follow-up., (© 2020 John Wiley & Sons Ltd.)

Background: Occult hepatitis B (OHB) is a major concern in HIV infected patients as it associates with a high risk of HBV reactivation and disease progression. However, data on the prevalence of OHB among HIV positive patients in Ethiopia is lacking. This study aims to determine the prevalence of OHB in HBV/HIV co-infected patients from Gondar, Ethiopia., Methods: A total of 308 consented HIV positive patients were recruited from the University of Gondar Teaching Hospital, Ethiopia. Clinical and demographic data of the participants were recorded. Plasma was tested for HBsAg and anti-HBc using commercial assays (Abbott Architect). In HBsAg negative anti-HBc positive patient samples, total DNA was isolated and amplified using nested PCR with primers specific to HBV polymerase, surface and pre-core/core regions, followed by Sanger sequencing and HBV mutational analysis using MEGA 7.0., Results: Of the total study subjects, 62.7% were female, median age 38.4 years, interquartile range (IQR): 18-68, and 208 (67.5%) had lifestyle risk factors for HBV acquisition. Two hundred and ninety-one study subjects were HIV+/HBsAg-, out of which 115 (39.5%) were positive for anti-HBc. Occult hepatitis B was detected in 19.1% (22/115) of anti-HBc positive HIV patients. HBV genotype D was the predominant genotype (81%) among OHB positive patients. Mutations associated with HBV drug resistance, HBV reactivation, and HCC risk were detected in 23% (5/22), 14% (3/22) and 45.5% (10/22) of patients, respectively., Conclusion: This study found a high rate of occult hepatitis B in HIV patients. Further, high rates of mutations associated with HBV reactivation, drug resistance, and HCC risk were detected in these patients. These data highlighted the need for integrating OHB screening for proper management of liver diseases in HIV patients., Competing Interests: The authors have declared that no competing interests exist.

Background: The greatest risk of chronic hepatitis B (CHB) is from mother-to-child transmission. Approximately 20% of individuals in sub-Saharan Africa are hepatitis B virus (HBV) surface antigen-positive (HBsAg+), but the prevalence of occult hepatitis B (OHB) is unknown. Aim: This study investigated CHB and OHB prevalence and viral variants in a cohort of pregnant women in Gondor, Ethiopia., Methods: Patients were prospectively recruited from the University of Gondar Hospital ( N = 200; median age 27 [inter-quartile range] 8.3y) from March through June 2016. Data were collected using an investigator-administered questionnaire. Plasma was tested for HBsAg and HBV core antibody (anti-HBc), and HBV genotype and presence of HBV variants (ie, vaccine escape mutants [VEMs]) were determined by polymerase chain reaction, Sanger sequencing, and phylogenetic analysis., Results: Of women tested, 1% (2/200) were HBsAg+; 26.8% (47/182) of HBsAg-negative patients were anti-HBc+, of whom 37/47 (78.7%) had detectable HBV DNA. The overall rate of OHB was 20.3%. Both HBsAg+ cases were HBV genotype D, and 36/37 (97.3%) of OHB individuals were genotype D. None carried VEM, but both HBsAg+ cases and 32/37 (86.5%) of the OHB cases showed lamivudine-resistant mutations., Conclusions: Twenty-seven percent of pregnant women in this cohort showed evidence of CHB or prior HBV exposure (ie, HBsAg+ or anti-HBc+) and clinically relevant HBV variants. Data from this single-centre study suggests high HBV prevalence, reinforcing the World Health Organization's recommendation for universal prenatal HBV screening and infant vaccination., Competing Interests: None declared., (Copyright © 2020 Canadian Association for the Study of the Liver.)

Coronavirus disease 2019 (COVID-19) has challenged how care is delivered to patients with chronic liver disease (CLD). In an attempt to update Canadian health care practitioners taking care of individuals with CLD, the Canadian Association for the Study of the Liver (CASL) hosted a webinar on May 7, 2020, with more than 120 participants. The resultant article is a partnership between members of CASL's executive and education committees to provide best practice management principles on liver disease during COVID-19 to the broader hepatology community., Competing Interests: Dr Brahmania reports personal fees from Roche, Eisai, and Abbvie; grants and personal fees from Merck; and grants from Allergan. Dr Congly reports grants from Gilead Sciences, Boehringer Ingelheim, Genfit, Allergan, and Sequana Medical and personal fees from Intercept Pharmaceuticals and Eisai. Dr Coffin reports grants for the Canadian HBV Network from Janssen; grants from Glaxo Smith Kline and Gilead Sciences; and personal fees from Springbank Pharmaceuticals and Altimmune. Dr Jayakumar and Dr Burak have no disclosures to report. Dr Feld reports receiving grants and consulting fees from AbbVie, Arbutus Biopharma, Enanta Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, and Roche., (Copyright © 2020 Canadian Association for the Study of the Liver.)

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare. , (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.