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Background: Severe flares (ALT ≥ 10×ULN) are a well-recognised adverse outcome after nucleos(t)ide analogue (NA) cessation and may lead to liver failure. Thus, identification of patients at risk for these flares is of major importance., Methods: Data were used from two prospective studies on NA cessation conducted in the Netherlands and Canada. Patients were eligible based on EASL criteria. HBcrAg and anti-HBc levels were measured at end of treatment (EOT) and week 6 (FUW6). Logistic regression was used to study the association with severe flares., Results: Seventy-eight patients were analysed with a mean age of 49 years, 16 (21%) Caucasian and a majority (65%) were treated with Tenofovir. Overall, 22 patients (28%) developed a severe flare, and 29 (37%) patients were retreated. At EOT, higher HBcrAg levels (aOR: 1.97, p = 0.05; ≥ 4log: 47% severe flare vs. < 3log: 19%, p = 0.036), lower anti-HBc (aOR: 0.29, p = 0.036; < 2log: 50% vs. ≥ 3log: 11%, p = 0.029) and higher HBcrAg/anti-HBc-ratio (aOR: 3.17, p = 0.015; ≥ 2: 58% vs. < 1.5: 14%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBsAg. At FUW6, higher HBcrAg (aOR: 2.91, p = 0.035; ≥ 5log: 83%, < 3log: 4%, p < 0.001), lower anti-HBc (aOR: 0.46, p = 0.29; < 2log: 50% vs. ≥ 3log: 0%, p = 0.003) and higher HBcrAg/anti-HBc-ratio (aOR: 2.19, p = 0.048; ≥ 1.75: 52% vs. < 1.75: 8%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBV DNA and ALT., Conclusion: Higher HBcrAg, lower anti-HBc and higher HBcrAg/anti-HBc ratio at EOT and during the first weeks of post-treatment follow-up are associated with an increased risk of hepatic flares after NA withdrawal and could therefore potentially be used to select patients eligible for therapy cessation and to identify patients requiring retreatment., Trial Registration: This study was a post hoc and follow-up study of two previously registered clinical trials (NCT01911156 & NTR7001). No new patients were prospectively included., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Designing and carrying out a controlled human infection (CHI) model for hepatitis C virus (HCV) is critical for vaccine development. However, key considerations for a CHI model protocol include understanding of the earliest viral-host kinetic events during the acute phase and susceptibility of the viral isolate under consideration for use in the CHI model to antiviral treatment before any infections in human volunteers can take place. Humanized mouse models lack adaptive immune responses but provide a unique opportunity to obtain quantitative understanding of early HCV kinetics and develop mathematical models to further understand viral and innate immune response dynamics during acute HCV infection. We show that the models reproduce the measured HCV kinetics in humanized mice, which are consistent with early acute HCV-host dynamics in immunocompetent chimpanzees. Our findings suggest that humanized mice are well-suited to support development of a CHI model. In-silico and in-vivo modeling estimates provide a starting point to characterize candidate viruses for testing in CHI model studies., Competing Interests: Declarations. Competing interests: YI and CTM are PhoenixBio employees. KC has received honoraria from Bristol-Myers Squibb and MSD K.K., AbbVie, Gilead Science, Dainippon Sumitomo Pharma and Mitsubishi Tanabe Pharma and research funding from Gilead Science, Dainippon Sumitomo Pharma, MSD K.K., AbbVie, Eisai, TORAY, Otsuka Pharma, Chugai Pharma, Takeda Pharma and Roche. JJF reports research funding and consulting fees from AbbVie and Gilead. All other authors have nothing to disclose., (© 2024. The Author(s).)

Background: Stigma is a complex social phenomenon that leads to marginalization and influences the course of illness. In the context of hepatitis C virus (HCV), stigma is a well-documented barrier to accessing care, treatment, and cure. In recent years, HCV rates among women have increased, resulting in an urgent need to address stigma and its harmful effects. The purpose of this concept analysis was to investigate stigma in the context of women living with HCV using Rodgers' evolutionary method., Methods: PubMed, CINAHL, Scopus, Medline, PsycINFO, and Nursing and Allied Health were used to identify articles describing HCV stigma among women. Articles from peer-reviewed journals and geographic locations, published between 2002-2023, were included in the analysis. As specified in Rodgers' evolutionary method, articles were analyzed with a focus on the concept's context, surrogate and related terms, antecedents, attributes, examples, and consequences., Results: Following screening, 33 articles were selected for inclusion in the analysis. Discrimination and marginalization were identified as surrogate and related terms to stigma; and antecedents of stigma were identified as limited knowledge, fear of diagnosis, and disclosure. Prevalent attributes of stigma in the literature were described as feelings of decreased self-worth, negative stereotyping, and fear of transmission. Importantly, HCV stigma among women is unique in comparison to other forms of infectious disease-related stigma, primarily due its impact on women's identity as mothers and caregivers. Stigmatization of women living with HCV resulted in negative consequences to personal relationships and healthcare access due to decreased health-seeking behaviours. Although access to HCV treatment has changed considerably over time, a temporal analysis could not be completed due to the limited number of articles., Conclusions: Stigma in the context of women living with HCV has its own unique antecedents, attributes, and consequences. This enhanced understanding of stigma among women living with HCV has the potential to inform improved and more effective approaches to care, which will be required to reach HCV elimination. Furthermore, this analysis identifies stigma layering and stigma in the direct-acting antiviral  treatment era as areas for more in-depth future inquiry., (© 2024. The Author(s).)

Competing Interests: The author has no conflicts to report.

Background: Post-acute sequelae of COVID-19, or long COVID, is a condition characterized by persistent COVID-19 symptoms. As long COVID is defined by clinical criteria after an elapsed period, an opportunity for early intervention may aid in future prophylactic approaches; however, at present, the pathobiological mechanisms are multifactorial. By analyzing early virally infected upper respiratory tract tissue prior to eventual clinical diagnosis, it may be possible to identify biomarkers of altered immune response to facilitate future studies and interventions. Methods: This is a sub-group analysis of samples collected from those with confirmed COVID-19. RNA extraction from nasopharyngeal/mid-turbinate samples, sequencing, and bioinformatic analysis were performed to analyze long COVID and non-long COVID cohorts at day 14 post infection. Differences in mean viral load at various timepoints were analyzed as well as serological data. Results: We identified 26 upregulated genes in patients experiencing long COVID. Dysregulated pathways including complement and fibrinolysis pathways and IL-7 upregulation. Additionally, genes involved in neurotransmission were dysregulated, and the long COVID group had a significantly higher viral load and slower viral clearance. Conclusions: Uncovering early gene pathway abnormalities associated with eventual long COVID diagnosis may aid in early identification. We show that, post acute infection, in situ pathogenic deviations in viral response are associated with patients destined to meet consensus long COVID diagnosis that is entirely dependent on clinical factors. These results identify an important biological temporal window in the natural history of COVID-19 infection and long COVID pathogenesis amenable to testing from standard-of-care upper respiratory tract specimens.

Introduction: Progress toward hepatitis C virus (HCV) elimination is impeded by low testing and treatment due to the current diagnostic pathway requiring multiple visits leading to loss to follow-up. Point-of-care testing technologies capable of detecting current HCV infection in one hour are a 'game-changer.' These tests enable diagnosis and treatment in a single visit, overcoming the barrier of multiple visits that frequently leads to loss to follow-up. Combining point-of-care HCV antibody and RNA tests should improve cost-effectiveness, patient/provider acceptability, and testing efficiency. However, implementing HCV point-of-care testing programs at scale requires multiple considerations., Areas Covered: This commentary explores the need for point-of-care HCV tests, diagnostic strategies to improve HCV testing, key considerations for implementing point-of-care HCV testing programs, and remaining challenges for point-of-care testing (including operator training, quality management, connectivity and reporting systems, regulatory approval processes, and the need for more efficient tests)., Expert Opinion: It is exciting that single-visit testing, diagnosis, and treatment for HCV infection have been achieved. Innovations afforded through COVID-19 should facilitate the accelerated development of low-cost, rapid, and accurate tests to improve HCV testing. The next challenge will be to address barriers and facilitators for implementing point-of-care testing to deliver them at scale.

Background: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine., Methods: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants' level of HBV knowledge., Results: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% ( N = 552), were female, and 73.6% ( N = 656) have been in Canada for <30 years. The average questionnaire score was 70.7% correct, with 65.2% ( N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of $50,000 to <$75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing., Conclusions: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups., Competing Interests: JJF has received consulting support from AbbVie, Enanta, Gilead, Janssen, and Roche, and research funding from AbbVie, Abbott, Gilead, and Enanta. BEH has received consulting support from Intercept, Cymabay, Mirum, Albireo, Chemomab, and Caliditas, and research support from Intercept, Cymabay, Mirum, and Albireo. HLAJ has received research support from AbbVie, Arbutus, Bristol Myers, Squibb, Gilead Sciences, Janssen, Merck, and Roche, and consulting support from Aligos, Arbutus, Arena, Eiger, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Regulus, Roche, VBI Vaccines (Variation Biotechnologies), Vir Biotechnology, Inc, and Viroclinics. DW reports research support from Gilead, BMS, Vertex, and Boehringer. MJB has received research support from AbbVie, Gilead Sciences and Cepheid. CY has received consulting fees from Abbvie, and patient education grant from Gilead., (© Canadian Association for the Study of the Liver, 2024.)

Competing Interests: MJ Biondi reports receiving research support and consulting fees from AbbVie, Gilead, Abbott, Specialty Rx Solutions, and McKesson Canada. JJ Feld reports receiving research support and consulting fees from AbbVie and Gilead. No other competing interests were declared.

Background and Aims: Historical paired liver biopsy studies are likely to underestimate current progression of disease in patients with chronic hepatitis C virus (HCV) infection. We aimed to assess liver disease progression according to the non-invasive Fibrosis-4 (FIB-4) index in patients with chronic HCV and early disease., Methods and Results: Patients diagnosed with chronic HCV and FIB-4 <3.25 from four international liver clinics were included in a retrospective cohort study. Follow-up ended at start of antiviral therapy resulting in sustained virological response, at time of liver transplantation or death. Primary outcome of advanced liver disease was defined as FIB-4 >3.25 during follow-up. Survival analyses were used to assess time to FIB-4 >3.25.In total, 4286 patients were followed for a median of 5.0 (IQR 1.7-9.4) years, during which 41 071 FIB-4 measurements were collected. At baseline, median age was 47 (IQR 39-55) years, 2529 (59.0%) were male, and 2787 (65.0%) patients had a FIB-4 <1.45. Advanced liver disease developed in 821 patients. Overall, 10-year cumulative incidence of advanced disease was 32.1% (95% CI 29.9% to 34.3%). Patients who developed advanced disease showed an exponential FIB-4 increase. Among patients with a presumed date of HCV infection, cumulative incidence of advanced disease increased 7.7-fold from 20 to 40 years as opposed to the first 20 years after HCV infection., Conclusions: The rate of advanced liver disease is high among chronic HCV-infected patients with early disease at time of diagnosis, among whom liver disease progression accelerated over time. These results emphasise the need to overcome any limitations with respect to diagnosing and treating all patients with chronic HCV across the globe., Competing Interests: Competing interests: LK, NSE, CW, SvH, OC, JV and RAdM report no conflict of interest. RM received financial compensation for consultancy from AbbVie. AP is an employee of Merck & Co. RJdK declares that the Erasmus University Medical Center, on behalf of RJdK, received honoraria for consulting/speaking from Gilead, Janssen-Cilag, Bristol-Myers Squibb (BMS), AbbVie, MSD, Roche and Norgine, and received research grants from Gilead, Janssen-Cilag, BMS and Roche. BEH has consulted for and received grant/research support from Intercept Pharmaceuticals. SZ reports consultancies for AbbVie, BMS, Gilead, Janssen and Merck. TV has received grants from Gilead Sciences and BMS; is a consultant for Janssen Pharmaceuticals, Gilead Sciences, AbbVie and BMS; and a sponsored lecturer for W L Gore, Gilead Sciences, BMS and AbbVie. HLAJ has served as consultant for and has received grants from AbbVie, Arbutus, BMS, Enyo, Gilead Sciences, Janssen, Medimmune, Merck, Roche, Vir Biotechnology and Viroclinics. JJF has consulted for Abbott, AbbVie, Gilead, Enanta and Roche; and has received grant/research support from AbbVie, Eiger, Gilead, Janssen and Wako/Fujifilm. AJvdM received financial compensation for lecture activities for Zambon and research funding from Gilead, MSD, AbbVie and Zambon., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are no immunological biomarkers that predict control of chronic hepatitis B (CHB). The lack of immune biomarkers raises concerns for therapies targeting PD-1/PD-L1 because they have the potential for immune-related adverse events. Defining specific immune functions associated with control of HBV replication could identify patients likely to respond to anti-PD-1/PD-L1 therapies and achieve a durable functional cure., Methods: We enrolled immunotolerant, HBeAg+ immune-active (IA+), HBeAg- immune-active (IA-), inactive carriers, and functionally cured patients to test ex vivo PD-1 blockade on HBV-specific T cell functionality. Peripheral blood mononuclear cells were stimulated with overlapping peptides covering HBV proteins +/-α-PD-1 blockade. Functional T cells were measured using a 2-color FluoroSpot assay for interferon-γ and IL-2. Ex vivo functional restoration was compared to the interferon response capacity assay, which predicts overall survival in cancer patients receiving checkpoint inhibitors., Results: Ex vivo interferon-γ+ responses did not differ across clinical phases. IL-2+ responses were significantly higher in patients with better viral control and preferentially restored with PD-1 blockade. Inactive carrier patients displayed the greatest increase in IL-2 production, which was dominated by CD4 T cell and response to the HBcAg. The interferon response capacity assay significantly correlated with the degree of HBV-specific T cell restoration., Conclusions: IL-2 production was associated with better HBV control and superior to interferon-γ as a marker of T cell restoration following ex vivo PD-1 blockade. Our study suggests that responsiveness to ex vivo PD-1 blockade, or the interferon response capacity assay, may support stratification for α-PD-1 therapies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Patients with chronic hepatitis B (CHB) are at increased risk of hepatocellular carcinoma and (liver-related) mortality. In addition to hepatitis B-related factors, metabolic comorbidities may contribute to the progression of fibrosis. Therefore, we studied the association between metabolic comorbidities and adverse clinical outcomes in patients with CHB., Methods: We conducted a retrospective cohort study of CHB patients attending the Erasmus MC University Medical Center (Rotterdam, The Netherlands) and CHB patients who underwent liver biopsy at the Toronto General Hospital (Toronto, Canada). The presence of metabolic comorbidities (ie, overweight, diabetes mellitus, hypertension, and dyslipidemia) was assessed based on chart review. The primary end point was liver-related events, defined as the first composite of hepatocellular carcinoma, liver transplantation, or liver-related mortality., Results: We analyzed 1850 patients, of whom 926 (50.1%) were overweight, 161 (8.7%) had hypertension, 116 (6.3%) had dyslipidemia, and 82 (4.4%) had diabetes. During a median follow-up period of 7.3 years (interquartile range, 2.9-11.5 y), a total of 111 first events were recorded. Hypertension (hazard ratio [HR], 8.3; 95% CI, 5.5-12.7), diabetes (HR, 5.4; 95% CI, 3.2-9.1), dyslipidemia (HR, 2.8; 95% CI, 1.6-4.8), and overweight (HR, 1.7; 95% CI, 1.1-2.5) were associated with an increased risk for liver-related events. The presence of multiple comorbidities further increased the risk. Findings were consistent for patients with and without cirrhosis, among noncirrhotic hepatitis B e antigen-negative patients with hepatitis B virus DNA less than 2000 IU/mL and in multivariable analysis adjusting for age, sex, ethnicity, hepatitis B e antigen status, hepatitis B virus DNA, use of antiviral therapy, and the presence of cirrhosis., Conclusions: Metabolic comorbidities in CHB patients are associated with an increased risk for liver-related events, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in various clinically relevant subgroups, underscoring the need for thorough metabolic assessment in patients with CHB., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the proportion, clinical features, and outcomes of previously healthy children presenting to a large Canadian quaternary pediatric center with severe acute hepatitis of unknown etiology., Methods: All patients with serum alanine aminotransferase (ALT) > 500 U/L or aspartate aminotransferase (AST) > 500 U/L between June 1, 2018, and May 31, 2022, at The Hospital for Sick Children, were identified. Subjects with only AST > 500 U/L were excluded. Clinical characteristics, investigations, and outcomes for patients without clear etiology for ALT > 500 U/L (severe acute hepatitis of unknown etiology) for our study period and from October 1 to May 31 of each year 2018-2021 were reviewed., Results: Of 977 patients with ALT/AST> 500 U/L, 720 had only ALT > 500 U/L. We excluded age below 6 months (n = 99) or above 16 years (n = 66), known pre-existing liver conditions (n = 66), and ALT > 500 U/L in already admitted patients (n = 151). Among the remaining 338 children with ALT > 500 U/L at presentation, an etiology was identified in 303 subjects. 33 (9.8%) children [median age 6.1 y (range 0.5-15.5); 61% male] were confirmed as severe acute hepatitis of unknown etiology. Twenty patients (60.6%) were tested for blood adenovirus by PCR, and 1 (5%) was positive (serotype B7). Liver tissue specimens from 18 patients revealed no evidence of viral inclusions or adenovirus. Twelve (36.3%) presented with pediatric acute liver failure, with 8 (24.2%) requiring liver transplantation. There were no deaths. Hepatitis-associated aplastic anemia occurred in 5 (15%) patients., Conclusions: Of children presenting with severe acute hepatitis to a quaternary children's hospital over a 48-month period, 9.8% had unknown etiology with no change over time. Liver transplantation remains an important treatment strategy for those presenting with pediatric acute liver failure phenotype. The frequency of cases associated with human adenovirus infection was noncontributory., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection., Methods: Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation., Results: During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories., Conclusions: Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: Direct-acting antiviral (DAA) therapies have simplified HCV treatment, and publicly funded Canadian drug plans have eliminated disease-stage restrictions for reimbursement of DAA therapies. However other policies which complicate, delay, or prevent treatment initiation still persist. We aim to describe these plans' existing reimbursement criteria and appraise whether they hinder treatment access., Methods: We reviewed DAA reimbursement policies of 16 publicly funded drug plans published online and provided by contacts with in-depth knowledge of prescribing criteria. Data were collected from May to July 2022. Primary outcomes were: (1) if plans have arranged to accept point-of-care HCV RNA testing for diagnosis; testing requirements for (2) HCV genotype, (3) fibrosis stage, and (4) chronic infection; (5) time taken and method used to approve reimbursement requests; (6) providers eligible to prescribe DAAs; and (7) restrictions on re-treatment., Results: Fifteen (94%) plans have at least one policy in place which limits simplified HCV treatment. Many plans continue to require results of genotype or fibrosis staging, limit eligible prescribers, and take longer than 1 day to approve coverage requests. One plan discourages treatment for re-infection., Conclusion: Reimbursement criteria set by publicly funded Canadian drug plans continue to limit timely, equitable access to HCV treatment. Eliminating clinically irrelevant pre-authorization testing, expanding eligible prescribers, expediting claims processing, and broadening coverage of treatment for reinfection will improve access to DAAs. The federal government could further enhance efforts by introducing a federal HCV elimination strategy or federal high-cost drug PharmaCare program., Competing Interests: SR Bartlett has advised and spoken for Gilead Sciences and AbbVie (all personal payments given as unrestricted donations to BC Centre for Disease Control Foundation for Public Health) and has received investigator-initiated research funding from Gilead Sciences and AbbVie via her institution. CL Cooper has advised, spoken for, and received unrestricted clinical and research funding from Gilead Sciences and AbbVie. N Kronfli receives research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Healthcare, Merck, and AbbVie, and speaker fees from Gilead Sciences, AbbVie, and Merck, all outside of the submitted work. J Butler-McPhee has advised Gilead Sciences and Abbvie, and has received unrestricted research funding from Gilead Sciences, all outside of the submitted work. J Grebely is a consultant/advisor and has received research grants from AbbVie, Biolytical, Camurus, Cepheid, Gilead Sciences, Hologic, Indivior, and Merck, all outside the submitted work. All other authors have no other relevant interests to disclose. J Feld is a consultant/advisor and has received research grants from Gilead and AbbVie., (© Canadian Association for the Study of the Liver, 2023.)

Background: Few countries have implemented the necessary policy changes to reduce the number of steps in the cascade of care to achieve hepatitis C virus (HCV) elimination, including Canada. The aim of this study was to describe and compare legislation, scope of practice, and policy as it relates to the provision of HCV care in each province., Methods: We reviewed grey literature and regulatory and legislative documents which affect various aspects of the HCV cascade of care. Findings were verified by content experts., Results: HCV RNA reflex testing ensures those that are antibody positive get an HCV RNA test; however only 80% of provinces have reflex test. Point-of-care antibody testing can be offered in most community non-health care settings, yet many types of health care providers are unable to do this independently. Following a positive test, it may not be feasible to complete venipuncture; however only a single province processes HCV RNA dried blood spot cards. In many provinces, training and verification are required for novice prescribers, and in some provinces prescribing continues to be restricted to specialists. Only a single province has task-shifted treatment to a non-physician non-nurse practitioner model, where pharmacists can prescribe treatment. Finally, 80% of provinces require authorization forms, and 30% require proof of investigations for treatment., Conclusions: No single province is optimizing the use of diagnostic tools and task shifting and decreasing paperwork to expedite treatment initiation. Collaboration between provinces is needed to streamline practice, update policy, and promote equity in HCV diagnosis, care, and treatment., Competing Interests: MJ Biondi reports receiving research support and consulting fees from AbbVie, Gilead, and Specialty Rx Solutions. CH Dale is a paid employee of McKesson Canada, and receives consulting fees from AbbVie and Gilead. H Shah reports receiving consulting fees and research support from AbbVie and Gilead. JJ Feld reports receiving research support and consulting fees from AbbVie and Gilead. HLA Janssen reports receiving research support from AbbVie and Gilead. The other authors have nothing to disclose., (© Canadian Association for the Study of the Liver, 2023.)

A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of hepatitis B virus persistence has enabled the identification of novel treatment targets, drug discovery, and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is a strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogs will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new noninvasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Novel therapies for chronic hepatitis B (CHB), such as RNA interference, target all viral RNAs for degradation, whereas nucleoside analogues are thought to block reverse transcription with minimal impact on viral transcripts. However, limitations in technology and sampling frequency have been obstacles to measuring actual changes in HBV transcription in the liver of patients starting therapy., Methods: We used elective liver sampling with fine-needle aspirates (FNAs) to investigate the impact of treatment on viral replication in patients with CHB. Liver FNAs were collected from patients with CHB at baseline and 12 and 24 weeks after starting tenofovir alafenamide treatment. Liver FNAs were subjected to single-cell RNA sequencing and analysed using the Viral-Track method., Results: HBV was the only viral genome detected and was enriched within hepatocytes. The 5' sequencing technology identified protein-specific HBV transcripts and showed that tenofovir alafenamide therapy specifically reduced pre-genomic RNA transcripts with little impact on HBsAg or HBx transcripts. Infected hepatocytes displayed unique gene signatures associated with an immunological response to viral infection., Conclusions: Longitudinal liver sampling, combined with single-cell RNA sequencing, captured the dynamic impact of antiviral therapy on the replication status of HBV and revealed host-pathogen interactions at the transcriptional level in infected hepatocytes. This sequencing-based approach is applicable to early-stage clinical studies, enabling mechanistic studies of immunopathology and the effect of novel therapeutic interventions., Impact and Implications: Infection-dependent transcriptional changes and the impact of antiviral therapy on viral replication can be measured in longitudinal human liver biopsies using single-cell RNA sequencing data., Competing Interests: SK, JJW, and PM are employees of Gilead Sciences. AJG has received research funding from Gilead Sciences, Janssen Pharmaceuticals, and GSK, and performs consulting/scientific advisory services for Janssen Pharmaceuticals, Roche, GSK, Vir Biotech, Virion Therapeutics, and Bluejay Therapeutics. HLAJ received research funding from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen, Roche, and Vir Biotechnology Inc., and performs consulting/scientific advisory services for Aligos, Antios, Arbutus, Eiger, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, VBI Vaccines, Vir Biotechnology Inc., and Viroclinics. JJF received research funding from Abbvie, Gilead, GlaxoSmithKline, Janssen, Roche, Eiger, and Enanta, and performs consulting/scientific advisory services for Abbvie, Antios, Arbutus, Eiger, Enanta, Bluejay, GSK, Janssen, and Roche. SF receives speaking/teaching fees from Gilead Sciences and research funding from Gilead Sciences, and performs consulting/scientific advisory services for Gilead Sciences, Abbvie, Janssen, Spring Bank, Pfizer, and Novo-Nordisk. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

A hepatitis C virus (HCV) vaccine is urgently needed. Vaccine development has been hindered by HCV's genetic diversity, particularly within the immunodominant hypervariable region 1 (HVR1). Here, we developed a strategy to elicit broadly neutralizing antibodies to HVR1, which had previously been considered infeasible. We first applied a unique information theory-based measure of genetic distance to evaluate phenotypic relatedness between HVR1 variants. These distances were used to model the structure of HVR1's sequence space, which was found to have five major clusters. Variants from each cluster were used to immunize mice individually, and as a pentavalent mixture. Sera obtained following immunization neutralized every variant in a diverse HCVpp panel (n = 10), including those resistant to monovalent immunization, and at higher mean titers (1/ID 50 = 435) than a glycoprotein E2 (1/ID 50 = 205) vaccine. This synergistic immune response offers a unique approach to overcoming antigenic variability and may be applicable to other highly mutable viruses.

Background & Aims: Most patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years., Methods: Demographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA >10 7 IU/mL) were compared by age category, and to those with IA-HBeAg+ CHB in cross-sectional analysis. This study received institutional review board approval at all participating centers., Results: Of 107 adult IT participants, 52 (48%) were <30, 33 (31%) were 30 to 39, and 22 (21%) were ≥40 years old (maximum, 71 years). Among IT groups, the proportion born in Asia and duration of CHB were greater in older IT groups, but virologic and liver disease characteristics were similar. Compared with IA-HBeAg+ participants (n = 192), IT participants were younger, fewer were men, more were Asian, and platelets, qHBsAg, and qHBeAg levels were higher. Similar differences were observed when comparisons were made with the ≥40 years IT group. Among IT participants, 60 (56%) transitioned during 206 person-years of follow-up. The phase transition rate per 100 person-years was highest in the <30 years group (33.0 [95% confidence interval [CI], 23.4-46.7]) vs the 30 to 39 years group (24.8 [95% CI, 15.6-39.4]) and ≥40 group (27.4 [95% CI, 14.8-50.9]), but 95% CIs overlapped., Conclusions: In a large North American population, over 50% of adults in the IT phase of CHB were ≥30 years and 20% were ≥40 years old, but older IT patients had similar characteristics and rates of transition as younger IT patients., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: People who inject drugs (PWID) are at a high risk of hepatitis C virus (HCV) infection. HCV cure is associated with improved patient-reported outcomes (PROs), but there are little data among PWID. This study aimed to assess the change in PROs during and after HCV direct-acting antiviral (DAA) treatment., Methods: This analysis used data from 2 clinical trials of DAA treatment in PWID. PROs assessed included health-related quality of life, social functioning, psychological distress, housing, and employment. Generalized estimating equations and group-based trajectory modeling were used to assess changes in PROs over time., Results: No significant changes in the 3-level version of EQ-5D scores, EQ visual analogue scale scores, social functioning, psychological distress, and housing were observed over the 108-week study period. There was a significant increase in the proportion of participants employed (18% [95% confidence interval (CI) 12%-23%] at baseline to 28% [95% CI 19%-36%] at the end of the study). Participants were more likely to be employed at 24 weeks and 108 weeks after commencing treatment. Having stable housing increased the odds of being employed (odds ratio 1.70; 95% CI 1.00-2.90). The group-based trajectory modeling demonstrated that most outcomes remained stable during and after DAA treatment., Conclusions: Although no significant improvement was identified in health-related quality of life after HCV DAA treatment, there was a modest but significant increase in employment during study follow-up. The study findings support the need for multifaceted models of HCV care for PWID addressing a range of issues beyond HCV treatment to improve quality of life., (Copyright © 2023. Published by Elsevier Inc.)

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 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting 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 = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .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., Conclusions: 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)