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The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.

Introduction and Objectives: Liver fibrosis remains a complication derived from a chronic Hepatitis C Virus (HCV) infection even when it is resolved, and no liver antifibrotic drug has been approved. Molecular mechanisms on hepatocytes and activation of hepatic stellate cells (HSCs) play a central role in liver fibrogenesis. To elucidate molecular mechanisms, it is important to analyze pathway regulation during HSC activation and HCV infection. Materials and Methods: We evaluate the fibrosis-associated molecular mechanisms during a co-culture of human HSCs (LX2), with human hepatocytes (Huh7) that express HCV NS5A or Core protein. We evaluated LX2 activation induced by HCV NS5A or Core expression in Huh7 cells during co-culture. We determined a fibrosis-associated gene expression profile in Huh7 that expresses NS5A or Core proteins during the co-culture with LX2. Results: We observed that NS5A induced 8.3-, 6.7- and 4-fold changes and that Core induced 6.5-, 1.8-, and 6.2-fold changes in the collagen1, TGFβ1, and timp1 gene expression, respectively, in LX2 co-cultured with transfected Huh7. In addition, NS5A induced the expression of 30 genes while Core induced 41 genes and reduced the expression of 30 genes related to fibrosis in Huh7 cells during the co-culture with LX2, compared to control. The molecular pathways enriched from the gene expression profile were involved in TGFB signaling and the organization of extracellular matrix. Conclusions: We demonstrated that HCV NS5A and Core protein expression regulate LX2 activation. NS5A and Core-induced LX2 activation, in turn, regulates diverse fibrosis-related gene expression at different levels in Huh7, which can be further analyzed as potential antifibrotic targets during HCV infection.

Liver disease affects millions of people in the world, and China has the highest prevalence of liver disease in the world. Small ubiquitin-related modifier (SUMO) modification is a highly conserved post-translational modification of proteins. They are widely expressed in a variety of tissues, including the heart, liver, kidney and lung. SUMOylation of protein plays a key role in the occurrence and development of liver disease. Therefore, this study reviewed the effects of SUMO protein on non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis (HF), hepatocellular carcinoma (HCC), and other liver diseases to provide novel strategies for targeted treatment of liver disease.

Background: Fujian Province has one of the highest reported incidences of hepatitis B virus infection in China. This study aimed to provide a theoretical framework for preventing and controlling hepatitis B in Fujian Province, and to assess the trends and the spatial-temporal distribution patterns of hepatitis B in this region. Methods: Data on hepatitis B cases were extracted from the National Notifiable Infectious Disease Surveillance System. Spatial autocorrelation analysis, trend surface analysis, and spatial-temporal scanning statistics were used to identify the spatial and aggregation patterns at the county level. The Joinpoint was used to assess the reported incidence trends. Results: The average reported incidence of hepatitis B in Fujian from 2012 to 2021 was 14.46/10,000 population, with 583,262 notified cases. The age-adjusted reported incidence of hepatitis B decreased from 17.44/10,000 population in 2012 to 11.88/10,000 population in 2021, with an average reduction in the annual percentage change of 4.5%. There were obvious spatial-temporal aggregation characteristics in hepatitis B cases, and a high-incidence area was located in eastern Fujian. Spatio-temporal scanning statistics revealed four levels of aggregation of hepatitis B reporting rates. The first level of aggregation area included Minhou, Gulou, Jin'an, Taijiang, and nine other districts and counties. Conclusions: The incidence of hepatitis B is declining in Fujian Province. Spatial clusters of hepatitis B cases in Fujian Province were identified, and high-risk areas in eastern Fujian still exist. Closely monitoring the general patterns in the occurrence of hepatitis B and implementing focused control and preventative strategies are important.

Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020.Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption.Screening for NAFLD in high-risk subjects and screening for excessive drinking and alcohol use disorders at every level of medical care is relevant. Efforts should also focus on the early treatment of occult liver disease to try to reduce liver disease burden and, in the case of occult viral hepatitis infection, prevent further spreading.

Summary: Chronic viral hepatitis is a significant public health concern in the Western Pacific, including in Vietnam and the Philippines. To accelerate progress toward meeting the 2030 elimination goals, the World Health Organization (WHO) encourages countries to adopt an integrated, people-centered health sector response to hepatitis, grounded in Primary Health Care (PHC). A review of the academic and grey literature, along with policy documents, was conducted to describe the national health system and PHC response to hepatitis B and C in Vietnam and the Philippines. Information was analyzed against the four strategic levers of the WHO Operational Framework for PHC to identify challenges and opportunities. The findings suggest that both countries have relatively robust policy frameworks, with some room for improvement. Vietnam may have stronger political commitment and funding than the Philippines, while the Philippines appears to be stronger in community engagement. Both countries share challenges and opportunities for learning to actualize viral hepatitis elimination utilizing a PHC approach.

Summary: Background: Liver disease is linked to series of extrahepatic multisystem manifestations. However, little is known about the associations between liver and eye diseases, especially cataract, the global leading cause of blindness. We aimed to investigate whether severe liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, and liver fibrosis and cirrhosis, were associated with an increased risk of the cataract. Methods: A total of 326,558 participants without cataract at baseline enrolled in the UK Biobank between 2006 and 2010 were included in this prospective study. The exposures of interest were severe liver diseases (defined as hospital admission), including NAFLD, ALD, viral hepatitis and liver fibrosis and cirrhosis. The outcome was incident cataract. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Each liver disease was first treated as a binary time-varying variable to investigate its association with cataract, and then was treated as a ternary time-varying variable to examine the recent (liver disease within 0–5 years) vs. long-term (liver disease > 5 years) state associations with the risk of cataract. Findings: After a median follow-up of 13.3 years (interquartile range, 12.5–14.0 years), 37,064 individuals were documented as developing cataract. Higher risk of cataract was found in those with severe NAFLD (HR, 1.47; 95% CI, 1.33–1.61), ALD (HR, 1.57; 95% CI, 1.28–1.94) and liver fibrosis and cirrhosis (HR, 1.58; 95% CI, 1.35–1.85), but not in individuals with viral hepatitis when exposure was treated as a binary time-varying variable (P = 0.13). When treating exposure as a ternary time-varying variable, an association between recently diagnosed viral hepatitis and cataract was also observed (HR, 1.55; 95% CI, 1.07–2.23). Results from the combined model suggested they were independent risk factors for incident cataract. No substantial changes were found in further sensitivity analyses. Interpretation: Severe liver diseases, including NAFLD, ALD, liver fibrosis and cirrhosis and recently diagnosed viral hepatitis, were associated with cataract. The revelation of liver-eye connection suggests the importance of ophthalmic care in the management of liver disease, and the intervention precedence of patients with liver disease in the early screening and diagnosis of cataract. Funding: National Natural Science Foundation of China, Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission, Clinical Research Plan of Shanghai Shenkang Hospital Development Center, Shanghai Municipal Key Clinical Specialty Program, the Guangdong Basic and Applied Basic Research Foundation and Shenzhen Science and Technology Program.

Within the United States (US), 2.4 million individuals are living with chronic hepatitis B, but less than 20% are diagnosed. Isolated anti-hepatitis B core (iAHBc) antibodies indicate serology in an individual that is positive for anti-HBc antibodies, while negative for surface antigen (HBsAg) and surface antibodies (anti-HBs). A result of iAHBc could indicate a chronic occult bloodstream infection, necessitating further testing. This study assesses the prevalence and risk factors associated with anti-HBc and iAHBc within community high-risk screening in Greater Philadelphia. Participants (n = 177) were screened for HBsAg, anti-HBs, and anti-HBc during community screening events in 2022. Chi-square tables and Firth logistic regression were used to describe the data and to assess the odds of iAHBc. The findings indicate that there was an iAHBc prevalence of 7.3% (n = 13) within our study. The odds of anti-HBc were increased for immigrants from the Western Pacific (4.5%) and Africa (11.9%). Individuals born in Africa had 7.93 greater odds for iAHBc than those born in the Americas, and these odds are multiplied by 1.01 for every 1-year increase in age. Our data show a high burden of iAHBc within high-risk and often hard-to-reach communities. Triple panel screening should be incorporated into all HBV screening programs, in accordance with current Centers for Disease Control and Prevention (CDC) universal screening recommendations, to ensure a comprehensive picture of the disease burden and reduce the risk of missing people with occult hepatitis B and those at risk for viral reactivation or liver complications.

Background & Aims: Globally, one-third of individuals infected with HBV live in China. Eliminating HBV in China would therefore be paramount in achieving the World Health Organization’s (WHO’s) targets of viral hepatitis elimination as a worldwide public health threat. Methods: We constructed a dynamic HBV transmission model in China, structured by age and sex. We calibrated the model by HBsAg prevalence, acute HBV incidence, and nationally reported HBV-related cancer mortality. We investigated seven intervention scenarios (A–G) based on assumptions in diagnostic, linkage-to-care, and treatment coverages in achieving the WHO’s HBV elimination goals. Results: With the status quo, HBsAg prevalence among children 1–4 years would reduce to 0.09% (95% CI 0.09–0.10%) by 2025; acute HBV incidence would drop to

Introduction and Objectives: Hepatitis E virus (HEV) is not routinely screened in blood banks in low- and middle-income countries, and no specific biomarkers of exposure to this virus have yet been identified. We aimed to identify HEV seropositivity and detect virus RNA among blood donors from Mexico to further correlate risk factors related to infection and levels of interleukin-18 (IL-18) and interferon-gamma (IFN-γ) as potential biomarkers. Materials and Methods: This cross-sectional, single-center study included 691 serum samples of blood donors obtained in 2019. Anti-HEV IgG and IgM antibodies were detected in sera and the viral genome was screened in pooled samples. A statistical comparison of risk factors for infection, demographic and clinical features was performed; IL-18 and IFN- γ values were tested in sera. Results: Of all the individuals, 9.4% were positive for anti-HEV antibodies and viral RNA detection was confirmed in one of the pools positive for anti-HEV. From the analysis of risk factors, age and having pets were statistically significant for anti-HEV antibody detection. Seropositive samples showed significantly higher IL-18 concentrations relative to samples from seronegative donors. Interestingly, IL-18 values were similar when HEV seropositive samples were compared to samples from clinically acute previously confirmed HEV patients. Conclusions: Our findings highlight the need to follow up on HEV in blood banks in Mexico and underscore that IL-18 could represent a biomarker of HEV exposure.

Background & Aims: Bulevirtide (BLV) is a novel antiviral drug licensed for the treatment of chronic hepatitis D. Data on the safety and efficacy of stopping BLV therapy upon long-term HDV-RNA suppression are scarce. Methods: A total of seven patients (age, 31–68 years, four with cirrhosis) included in a prospective Austrian HDV registry discontinued BLV treatment (duration, 46–141 weeks) upon long-term HDV suppression (HDV-RNA negativity, 12–69 weeks). Pegylated interferon-ɑ2a was used in combination with BLV in two patients. HDV-RNA, alanine aminotransferase, and quantitative HBsAg levels were closely monitored during treatment-free follow-up. Results: The seven patients were followed up for 14 to 112 weeks. Six patients completed ≥24 weeks of follow-up. HDV-RNA became detectable again in three patients within 24 weeks, whereas one additional patient showed an HDV-RNA relapse after almost 1 year. All patients who relapsed at any point had undergone BLV monotherapy. Meanwhile, HDV-RNA remained undetectable in two patients who were treated with BLV + pegylated interferon-ɑ2a. Only one patient showed significant alanine aminotransferase increases within 24 weeks of follow-up. BLV was reintroduced in three patients after 13–62 BLV-free weeks and was well tolerated, and all patients achieved virologic response again. Conclusions: BLV discontinuation upon long-term HDV-RNA suppression seems safe. Retreatment with BLV was effective in case of virologic relapse. These findings are within a limited number of patients, and future studies are needed to define stopping rules and further investigate the safety of stopping BLV. Impact and Implications: Limited data exist on stopping bulevirtide (BLV) treatment in patients who achieve long-term HDV-RNA suppression. In a small cohort of seven Austrian patients discontinuing BLV therapy, HDV-RNA relapses were observed in four patients during long-term follow-up, whereas significant alanine aminotransferase increases were recorded in only one. Retreatment with BLV was effective in relapsers. The safety and efficacy of stopping BLV needs to be further studied in larger cohorts.

Liver diseases are a major cause of morbidity and mortality globally. In the Philippines, a lower middle-income country in Southeast Asia, liver diseases accounted for 27.3 cases per 1000 deaths. In this review, we discussed the prevalence, risk factors, and management of hepatitis B, hepatitis C and other viral hepatitis, non-alcoholic fatty liver disease, alcohol-associated liver disease, liver cirrhosis, and hepatocellular carcinoma. The true burden of liver disease in the Philippines is likely underestimated due to limited epidemiological studies. Thus, surveillance of liver disease should be strengthened. Clinical practice guidelines tailored to the local needs of the country have been developed for important liver diseases. Multisectoral cooperation among different stakeholders is needed to manage the burden of liver disease in the Philippines.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Spleen micro-perfusion level can be evaluated by DDVD (diffusion derived vessel density): DDVD (unit: au/pixel) = Sb0/ROIarea0 – Sb2/ROIarea2, where Sb0 and Sb2 refer to the spleen signal when b is 0 or 2 (s/mm2) and ROI is ‘region-of-interest’. This study investigated whether spleen DDVD is altered in patients with viral hepatitis-b (VHB) liver fibrosis. Three datasets were retrospectively analysed. Shenzhen data-1 had 25 healthy volunteers and 15 VHB liver fibrosis patients. Changsha data had 24 healthy volunteers and 31 patients with VHB liver fibrosis. Shenzhen data-2 had 67 healthy volunteers. Shenzhen data-2 were measured by reader-1. Shenzhen data-1 were measured by reader-1 and reader-2. For Changsha data, reader-1 measured all subjects, while Reader-2 measured a random selection of 10 healthy volunteers and two patients from each liver fibrosis grade (total=8). Shenzhen data-2 showed in healthy volunteers there was no age-dependent change of spleen DDVD during 20 ∼71 years old, and women had higher spleen DDVD values than those of men's (16.17±7.34 vs. 12.88±5.91, p=0.04). Changsha data by reader-1 showed patients with liver fibrosis had lower spleen DDVD values than those of healthy volunteers (median=16.24 vs. 23.54, p=0.0031). Results of reader-2 showed the same trend (median=11.64 vs. 23.33, p=0.0165). Shenzhen data-1 measured by reader-1 showed medians of spleen DDVD for patients and volunteers were 8.535 and 12.33 respectively; and those measured by reader-2 were 13.89 and 14.31 respectively. We conclude that diffusion MRI shows spleen DDVD, i.e., micro-circulation per volume tissue, is decreased in VHB liver fibrosis patients.

Objectives: We analysed hepatitis A (HepA) notifications and hospitalisations in Italy, the Netherlands, Norway, Spain, and Sweden for available periods between 1995 and 2014. We aimed to investigate whether decreasing HepA incidence is associated with increasing age at infection and worsening HepA presentation and to identify groups at risk of severe disease. Methods: We performed a retrospective cohort study including 36 734 notified and 36 849 hospitalised patients. We used negative binomial regressions to identify over time: i) trends in hospitalisation and notification rates; ii) proportion of hospitalised and notified patients aged ≥40 years; iii) proportion of “severe hospitalisations”; and iv) risk factors for severe hospitalisation. Results: During the study period both HepA notifications and hospitalisations decreased, with notification rates decreasing faster, patients aged ≥40 years increased, however, the proportion of severe HepA hospitalisations remained stable. Older patients and patients with comorbidities, particularly liver diseases, were more likely to experience severe disease. Conclusions: We used digitalised health information to confirm decreasing trends in HepA hospitalisations and notifications, and the increasing age of patients with HepA in Europe. We did not identify an increase in the severity of the clinical presentation of patients with HepA. Older patients with liver diseases are at increased risk of severe disease and should be prioritised for vaccination.

Background & Aims: Elimination of chronic HBV/HDV infection remains a major global health challenge. Targeting excessive hepatitis B surface antigen (HBsAg) release may provide an interesting window of opportunity to break immune tolerance and to achieve a functional cure using additional antivirals. Methods: We evaluated a HBsAg-specific human monoclonal antibody, as part of either a prophylactic or therapeutic strategy, against HBV/HDV infection in cell culture models and in human-liver chimeric mice. To assess prophylactic efficacy, mice were passively immunized prior to infection with HBV or HBV/HDV (coinfection and superinfection setting). Therapeutic efficacy was assessed in HBV and HBV/HDV-coinfected mice receiving 4 weeks of treatment. Viral parameters (HBV DNA, HDV RNA and HBsAg) were assessed in mouse plasma. Results: The antibody could effectively prevent HBV/HDV infection in a dose-dependent manner with IC50 values of ∼3.5 ng/ml. Passive immunization showed complete protection of mice from both HBV and HBV/HDV coinfection. Moreover, HDV superinfection was either completely prevented or at least attenuated in HBV-infected mice. Finally, antibody treatment in mice with established HBV/HDV infection resulted in a significant decline in viremia and a concomitant drop in on-treatment HBsAg, with a moderate viral rebound following treatment cessation. Conclusion: We present data on a valuable antibody candidate that could complement other antivirals in strategies aimed at achieving functional cure of chronic HBV and HDV infection. Impact and implications: Patients chronically infected with HBV may eventually develop liver cancer and are at great risk of being superinfected with HDV, which worsens and accelerates disease progression. Unfortunately, current treatments can rarely eliminate both viruses from chronically infected patients. In this study, we present data on a novel antibody that is able to prevent chronic HBV/HDV infection in a mouse model with a humanized liver. Moreover, antibody treatment of HBV/HDV-infected mice strongly diminishes viral loads during therapy. This antibody is a valuable candidate for further clinical development.

Introduction and Objectives: Hepatitis E virus (HEV) superinfection is a common excerbating event in patients with chronic hepatitis B, but the impact on the long-term prognosis is not clear. This study investigates the specific role of HEV superinfection in the long-term outcome of hepatitis B virus (HBV) patients with liver cirrhosis. Patients and Methods: A retrospective, observational cohort study was conducted using clinical, laboratory, and survival data collected from patients suffering from hepatitis B cirrhosis with or without HEV superinfection. Disease progression and mortality rates were analyzed. Results: After a two-year follow-up, HEV superinfection was identified in 27 of 811 patients. The transplantation-free mortality was significantly increased (51.9% vs. 14.3%, p< 0.001) in HEV superinfection compared to that in hepatitis B cirrhosis patients without HEV superinfection. Logistic regression analysis demonstrated that elderly people were independent host risk factors for hepatitis B cirrhosis patients with HEV superinfection before and after propensity score matching (PSM). Moreover, HEV superinfection was a risk factor for patients with hepatitis B cirrhosis with new acute decompensation (AD) and acute-on-chronic liver failure (ACLF) during hospitalization. A multivariate Cox proportional hazards regression model demonstrated that acute HEV co-infection is associated with two-year mortality (hazard ratio [HR]: 2.49; 95% CI: 1.40–4.43; p= 0.002; and HR: 5.79; 95% CI: 1.87–17.87; p= 0.002) in patients with hepatitis B cirrhosis before and after PSM. Conclusions: Elder patients with hepatitis B cirrhosis are susceptible to HEV superinfection, accelerating disease progression and increasing long-term mortality in hospitalized patients with HBV-related decompensated liver cirrhosis.

Introduction: Patients with cancer and hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are underrepresented in several clinical trials testing immune checkpoint inhibitors (ICIs). Consequently, safety and efficacy of ICI therapy in this population have not been completely defined. We aimed to evaluate the attitudes of oncologists on this topic. Methods: We conducted a 14-item European anonymous online survey. Results: Physicians from 56 oncology departments (26 from Italy, 15 from France, and 15 from Spain) took part in the survey. They mainly used to prescribe ICIs for treating patients with lung cancer, melanoma, and renal cell carcinoma. Of them, 95% recognized the need for specific guidelines addressing the management of patients with cancer and HBV or HCV treated with ICIs. Just 63% of the respondents screened patients for HBV and HCV status before ICIs initiation, although the risk of immune-related hepatotoxicity or viral reactivation was a major concern for most of them. Only 9% of the surveyed oncologists considered HBV and HCV infection a major exclusion criterion for receiving ICIs. Furthermore, 29% of the respondents would start a prophylactic treatment of active infection at ICIs initiation. Conclusions: ICIs administration in patients with cancer and HBV or HCV infection is of concern for most of the surveyed European oncologists. Nonetheless, active screening and treatment of viral hepatitis should be improved. Data in this specific setting are needed for an evidence-based management and should be generated by broadening inclusion criteria of clinical trials to allow the enrollment of patients with HBV and HCV.

ABSTRACT: Viral hepatitis is among the top four causes of mortality globally, causing 1.4 million deaths each year, exceeding tuberculosis, malaria and human immunodeficiency virus. Hepatitis B and C are responsible for 90% of hepatitis deaths, and the remaining 10% are caused by other hepatitis viruses. The annual number of deaths from hepatitis C is declining, whereas the numbers of deaths from hepatitis B and D are increasing. Hepatitis B alone represents the seven highest cause of mortality worldwide. Spurred on by development of curative antivirals for hepatitis C and expanding access to hepatitis B virus (HBV) vaccination, the World Health Organization has committed to eliminating viral hepatitis as a public health threat by 2030.Like the majority of current antivirals, those available for HBV are virostatic. They are capable of suppressing viral replication but cannot eliminate the virus from infected patients. Therefore, treatment is lifelong. Long-term adherence to medication continues to represent a major challenge. Importantly, HBV often reactivates, leading to potential life-threatening events in immunosuppressed patients. Therapeutic options are limited for hepatitis D; however, promising new, effective antivirals are on the horizon.Recent advances have emerged in medicinal chemistry and drug delivery approaches to produce ultra-long-acting (XLA) antivirals. These can extend antiviral activity from months to 1 year or even longer. These new formulations can overcome the challenges of daily dosing and maximize drug exposure. The development of XLA antivirals targeting viral hepatitis may also facilitate cure strategies.

Background/Purpose: Concurrent sexually transmitted infections (STIs) are not uncommon in at-risk populations, for which control requires integrated testing, treatment and prevention. Methods: From May, 2019 to February, 2020, multiplex real-time PCR assays were prospectively performed to detect Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) in the urine and rectal/vaginal swab specimens collected from HIV-positive patients with a history of STIs or symptoms suggestive of STIs. Patients confirmed to have acquired STIs were treated according to treatment guidelines. Results: During the study period, 430 participants (99.1% men who have sex with men and median age 37 years) were included. The overall prevalence of CT, NG, and/or TV infection was 30.0%, including 24.7%, 12.1%, and 0.2% for CT, NG, and TV infection, respectively. The factors associated with CT, NG, and/or TV infection were hepatitis B surface antigen (HBsAg) seropositivity (AOR, 2.76; 95% CI, 1.22–6.26), recently acquired hepatitis C virus (HCV) infection (AOR, 5.62; 95% CI, 1.99–15.88), using mobile dating application (AOR, 2.08; 95% CI, 1.13–3.83), and oral sex (AOR, 2.12; 95% CI, 1.04–4.32). The rates of CT, NG, and/or TV infection were 50.0% in participants with recent HCV infection, 44.2% in those with HBsAg positivity, and 35.9% in those with incident syphilis. Among participants completing test-of-cure visits, the microbiological cure rate was 91.7% and 90.0% for chlamydia and gonorrhea, respectively. Conclusion: HIV-positive participants had a high prevalence of CT and/or NG, especially those coinfected with viral hepatitis and syphilis. Our results strongly support integrated STI services in the population.

Summary: Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the incidence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and management, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex-presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region.

Viral hepatitis during pregnancy is common globally. In this review, we focus on the antenatal screen for hepatitis A, B, C and E, the prevention of mother-to-child transmission (MTCT) of hepatitis B and C, and the management of hepatitis A, B, C and E during pregnancy. Neonatal timely administration of hepatitis B immunoglobulin and hepatitis B vaccine is the cornerstone for preventing MTCT of hepatitis B virus (HBV), and perinatal antiviral prophylaxis with tenofovir disoproxil fumarate in mothers with positive HBeAg or HBV DNA >2 × 10 5 IU/ml also plays important roles in further reducing MTCT. Avoidance of risk practices in managing labor and delivery process of women with HCV infection may be useful to reduce MTCT of HCV. Early recognition of severe hepatic injury or liver failure associated with hepatitis viruses by regular liver function tests is critical to prevent maternal mortality associated with hepatitis., Competing Interests: Declaration of competing interest The author has no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background & Aims: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context., Methods: Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort., Results: Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p <0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p <0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p <0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients., Conclusions: Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D., Impact and Implications: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to assess the impact of the COVID-19 pandemic on national surveillance of viral hepatitis in Italy., Study Design: Interrupted time series analysis., Methods: Using an interrupted time series analysis with a customised AutoRegressive Integrated Moving Average model on hepatitis cases reported to the Integrated Epidemiological System of Acute Viral Hepatitis from 2006 to 2022, we examined trends in incidence, time to diagnosis and time to epidemiological investigations for hepatitis A, hepatitis B and hepatitis C., Results: The quarterly incidence of hepatitis B (-0.251, P = 0.05) and hepatitis C (-0.243, P = 0.003) significantly decreased with the onset of the pandemic. Surveillance times for hepatitis B (5.496, P < 0.001) and hepatitis C (35.723, P < 0.001), measured as days lost per quarter, significantly increased 12 and 24 months after the pandemic's start. This aligns with a notable rise in quarterly incidence at 36 months for both (0.032, P = 0.030 for hepatitis B; 0.040, P < 0.001 for hepatitis C)., Conclusions: The decrease in reported cases could be due to an increase in infection prevention control and containment measures put in place in a pandemic context. However, a delay in the initiation of epidemiological investigations was observed, which could lead to a further increase in incidence in the future., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC., Methods: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC., Results: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC., Conclusions: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis., Impact and Implications: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with high morbidity and mortality in the developing world. The global mortality caused by viral hepatitis is higher than that caused by HIV infection. Screening of two different populations – blood donors and patients with suspected hepatic cirrhosis – can help to estimate the seroprevalence in the population and what the burden of the infection is on liver disease. Methods: This was a cross-sectional, descriptive study performed in Vanga, a rural region of the Democratic Republic of Congo. Data were used from 2016 to 2018 for blood donors, and patients with ascites and abnormal liver ultrasound. Results: A total of 3,497 blood donors were recruited, among whom 92.5% were male; 3% were positive for HCV antibodies; 3.4% were positive for HBsAg; and 0.4% for HBsAg and HCV, respectively. There were 190 patients with suspected cirrhosis on ultrasound: 71 (37.4%) were female and 119 (62.4%) male; 32.6% and 10.6% were positive for HBV and HCV, respectively; 2.6% were co-infected with HBV and HCV. Conclusion: Blood donors and patients with ascites and liver abnormalities were frequently infected by HBV, HCV, and/or HIV in a rural region of the DRC. Detection is essential for limiting the risk of transmission and treating those infected.

Background & Aims: HBV exhibits wide genetic diversity with at least 9 genotypes (GTs), which differ in terms of prevalence, geographic distribution, natural history, disease progression, and treatment outcome. However, differences in HBV replicative capacity, gene expression, and infective capability across different GTs remain incompletely understood. Herein, we aimed to study these crucial aspects using newly constructed infectious clones covering the major HBV GTs. Methods: The replicative capacity of infectious clones covering HBV GTs A-E was analyzed in cell lines, primary hepatocytes and humanized mice. Host responses and histopathology induced by the different HBV GTs were characterized in hydrodynamically injected mice. Differences in treatment responses to entecavir and various HBV capsid inhibitors were also quantified across the different genetically defined GTs. Results: Patient-derived HBV infectious clones replicated robustly both in vitro and in vivo. GTs A and D induce more pronounced intrahepatic and proinflammatory cytokine responses which correlated with faster viral clearance. Notably, all 5 HBV clones robustly produced viral particles following transfection into HepG2 cells, and these particles were infectious in HepG2-NTCP cells, primary human hepatocytes and human chimeric mice. Notably, GT D virus exhibited higher infectivity than GTs A, B, C and E in vitro, although it was comparable to GT A and B in the human liver chimeric mice in vivo. HBV capsid inhibitors were more readily capable of suppressing HBV GTs A, B, D and E than C. Conclusions: The infectious clones described here have broad utility as genetic tools that can mechanistically dissect intergenotypic differences in antiviral immunity and pathogenesis and aid in HBV drug development and screening. Lay summary: The hepatitis B virus (HBV) is a major contributor to human morbidity and mortality. HBV can be categorized into a number of genotypes, based on their specific genetic make-up, of which 9 are well known. We isolated and cloned the genomes of 5 of these genotypes and used them to create valuable tools for future research on this clinically important virus.

Background & Aims: HBV has a narrow host restriction, with humans and chimpanzees representing the only known natural hosts. The molecular correlates of resistance in species that are commonly used in biomedical research, such as mice, are currently incompletely understood. Expression of human NTCP (hNTCP) in mouse hepatocytes enables HBV entry, but subsequently covalently closed circular (cccDNA) does not form in most murine cells. It is unknown if this blockade in cccDNA formation is due to deficiency in repair of relaxed circular DNA (rcDNA) to cccDNA. Methods: Here, we deployed both in vivo and in vitro virological and biochemical approaches to investigate if murine cells contain a complete set of repair factors capable of converting HBV rcDNA to cccDNA. Results: We demonstrate that HBV cccDNA does form in murine cell culture or in mice when recombinant rcDNA without a protein adduct is directly introduced into cells. We further show that the murine orthologues of core components in DNA lagging strand synthesis, required for the repair of rcDNA to cccDNA in human cells, can support this crucial step in the HBV life cycle. It is worth noting that recombinant HBV rcDNA substrates, either without a protein adduct or containing neutravidin to mimic HBV polymerase, were used in our study; it remains unclear if the HBV polymerase removal processes are the same in mouse and human cells. Conclusions: Collectively, our data suggest that the HBV life cycle is blocked post entry and likely before the repair stage in mouse cells, which yields critical insights that will aid in the construction of a mouse model with inbred susceptibility to HBV infection. Lay summary: Hepatitis B virus (HBV) is only known to infect humans and chimpanzees in nature. Mouse models are often used in modeling disease pathogenesis and preclinical research to assess the efficacy and safety of interventions before they are then tested in human participants. However, because mice are not susceptible to HBV infection it is difficult to accurately model human infection (and test potential treatments) in mouse models. Herein, we have shown that mice are able to perform a key step in the HBV life cycle, tightening the net around the possible reason why HBV can not efficiently infect and replicate in mice.

Background/purpose: This multicenter study aimed to evaluate the seroprevalence of hepatitis B virus (HBV) and the use of combination antiretroviral therapy (cART) among patients receiving HIV care in Taiwan. Methods: We retrospectively reviewed the medical records of HIV-infected adult patients who initiated cART at 11 designated hospitals in Taiwan between 2012 and 2016. The clinical information collected included serological profiles on HBV, hepatitis C virus (HCV), and syphilis, plasma HIV RNA load, nadir CD4 cell count, and antiretrovirals with activity against both HBV and HIV (tenofovir disoproxil fumarate [TDF], lamivudine [LAM], and emtricitabine [FTC]). Results: We analyzed 1800 HIV-infected patients; 1742 (96.8%) were male and 794 (44.1%) were born after July, 1986, when nationwide universal neonatal HBV vaccination was implemented. HBsAg positive results were 11.6% (209/1800), which decreased significantly from 18.1% (182/1006) in those born before July 1986 to 3.4% (27/794) in those born after. In multivariable analysis, HBsAg positivity was significantly associated with age (adjusted odds ratio [aOR] 1.06, 95% confidence interval [CI] 1.05–1.08), CD4≧200 cells/μL (aOR 0.73, 95% CI 0.53–0.99), and HCV seropositivity (aOR 1.62, 95% CI 1.06–2.50). Of 209 HBV/HIV-coinfected patients, 31.1% started cART containing only LAM with anti-HBV activity, while 68.9% started cART containing TDF plus LAM or coformulated TDF/FTC. Conclusions: The overall prevalence of HBV/HIV coinfection remained high among HIV-infected patients in Taiwan. Despite recommendations of the HIV treatment guidelines for the management of HBV infection, a substantial proportion of HIV/HBV-coinfected patients received cART containing only LAM for HBV infection.

Summary: Cure from chronic HBV infection is rare with current therapies. Basic research has helped to fundamentally improve our knowledge of the viral life cycle and virus-host interactions, and provided the basis for several novel drug classes that are currently being developed or are being tested in clinical trials. While these novel compounds targeting the viral life cycle or antiviral immune responses hold great promise, we are still lacking a comprehensive understanding of the immunological and virological processes that occur at the site of infection, the liver. At the International Liver Congress 2021 (ILC 2021), a research think tank on chronic HBV infection focused on mechanisms within the liver that facilitate persistent infection and looked at the research questions that need to be addressed to fill knowledge gaps and identify novel therapeutic strategies. Herein, we summarise the discussion by the think tank and identify the key basic research questions that must be addressed in order to develop more effective strategies for the functional cure of HBV infection.

Background: Chronic viral hepatitis (CVH) is a leading contributor to the UK liver disease epidemic, with global migration from high prevalence areas (e.g., South Asia). Despite international guidance for testing high-risk groups in line with elimination targets, there is no consensus on how to achieve this. The objectives of this study were to assess the following: (1) the feasibility of recruiting South Asian migrants to view an educational film on CVH, (2) the effectiveness of the film in promoting testing and increasing knowledge of CVH, and (3) the methodological issues relevant to scale-up to a randomized controlled trial. Methods: South Asian migrants were recruited to view the film (intervention) in community venues (primary care, religious, community), with dried blood spot CVH testing offered immediately afterwards. Pre/post-film questionnaires assessed the effectiveness of the intervention. Results: Two hundred and nineteen first-generation migrants ≥18 years of age (53% female) were recruited to view the film at the following sites: religious, n = 112 (51%), community n = 98 (45%), and primary care, n = 9 (4%). One hundred and eighty-four (84%) underwent CVH testing; hepatitis B core antibody or hepatitis C antibody positivity demonstrated exposure in 8.5%. Pre-intervention (n = 173, 79%) and post-intervention (n = 154, 70%) questionnaires were completed. Conclusions: This study demonstrated the feasibility of recruiting first-generation migrants to view a community-based educational film promoting CVH testing in this higher risk group, confirming the value of developing interventions to facilitate the global World Health Organization plan for targeted case finding and elimination, and a future randomized controlled trial. We highlight the importance of culturally relevant interventions including faith and culturally sensitive settings, which appear to minimize logistical issues and effectively engage minority groups, allowing ease of access to individuals ‘at risk’.

Objectives: In Sierra Leone, very little data are available on hepatitis B virus (HBV) and hepatitis C virus (HCV) prevalence. Blood donor screening permits estimation of the prevalence of transfusion transmissible infections in a general open population. We analyzed blood donor data in Sierra Leone to estimate national viral hepatitis prevalence and identify risk factors for hepatitis infection among the donor population. Methods: We conducted a retrospective data analysis in five government hospitals. We collected HBV and HCV screening results, donor demographics, and donation type (family replacement or voluntary donor; first-time or repeat). Univariate and multivariate analyses were performed to determine associations between infections and socio-demographic factors. Results: The number of donors screened was 29,713. The overall prevalence was: 10.8% (3200) for HBV and 1.2% (357) for HCV. HBV infection was most strongly associated with male sex (p:

The presence of elevated levels of bilirubin (icterus) in serum or plasma specimens has the potential to interfere with clinical chemistry and other laboratory assays. Along with hemolysis and lipemia, icterus represents one of the most common endogenous interferences with laboratory tests. There are two common mechanisms by which icterus can cause assay interference. The first common mechanism is spectral interference due to absorption at wavelengths used in assays by bilirubin and/or bilirubin breakdown products. The second common mechanism involves chemical reaction of bilirubin with the reagents used in some enzymatic assays. Most automated clinical chemistry platforms can perform rapid estimates of indices for hemolysis, icterus, and lipemia (HIL), typically by measuring absorbance at wavelengths impacted by these interferences. The data in this article provides results from a detailed 12-month retrospective review of icteric indices and the impact on 114 clinical chemistry assays at an academic medical center in the United States. The data include 414,502 specimens from 94,081 unique patients (51,851 females; 42,230 males), with a total of 2,791,591 discrete clinical chemistry assays performed on the specimens. Detailed chart review was performed for all patients who had one or more specimens with an icteric index of 40 or higher (‘severe icterus’), including determination of the medical diagnoses likely causing icterus and the mortality of these patients within 1 and 3 years following laboratory testing. Data for all specimens include patient location at time of testing (emergency department, inpatient unit, or outpatient site), sex, age, HIL indices, specific clinical chemistry assays performed, and number of times specimens had icteric indices exceeding the icteric index threshold in the package inserts for the clinical chemistry assays performed. The dataset reported is related to the research entitled “Frequency of Icteric Interference in Clinical Chemistry Laboratory Tests and Causes of Severe Icterus” [S. Mainali, A.E. Merrill, M.D. Krasowski, Frequency of icteric interference in clinical chemistry laboratory tests and causes of severe icterus, Pract. Lab. Med. (2021) 27: e00259]

Background & Aims: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24., Methods: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log 10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA., Results: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV., Conclusions: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96., Impact and Implications: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96., Gov Identifier: NCT03852719., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Renal dysfunction is a common finding in cirrhotic patients and has a great physiologic, and therefore, prognostic relevance. The combination of liver disease and renal dysfunction can occur as a result of systemic conditions that affect both the liver and the kidney, although primary disorders of the liver complicated by renal dysfunction are much more common. As most of the renal dysfunction scenarios in cirrhotic patients correspond to either prerenal azotemia or hepatorenal syndrome (HRS), physicians tend to conceive renal dysfunction in cirrhotic patients as mainly HRS. However, there are many systemic conditions that may cause both a “baseline” chronic kidney damage and a superimposed kidney dysfunction when this systemic condition worsens. The main aim of this article is to review some of the most important non prerenal non-HRS considerations regarding acute on chronic kidney dysfunction in cirrhotic patients, including renal manifestation of related to non-alcoholic steatohepatitis (NASH) viral hepatitis, the effect of cardiorenal syndrome in cirrhotics and corticosteroid-deficiency associated renal dysfunction.

Abstract Objective: To assess the impact of an enhanced viral hepatitis surveillance program on data completeness and on epidemiological assessment of affected populations. Methods: Notified cases of non‐acute hepatitis B and C were analysed to determine demographic characteristics and risk factors during the period prior to July 2015–June 2016, and during enhanced surveillance of the period July 2016–June 2017, during which time doctors were contacted for information about new diagnoses. Results: During the enhanced period, completeness for country of birth and Indigenous status doubled for both hepatitis B and hepatitis C, from 18–37% to 48–65%. The incidence ratio of hepatitis C among Aboriginal and Torres Strait Islander people increased from eight‐fold to 11.4‐fold, and the proportion of hepatitis B cases reported as born in China and Vietnam relative to other countries increased. New data fields identified that 12% of hepatitis C diagnoses occurred in a correctional facility, and 2% of hepatitis B cases were healthcare workers. Conclusions: Improved data completeness highlighted the underlying epidemiology of chronic viral hepatitis, demonstrating the increased burden of infection among specific priority populations. Implications for public health: Enhanced surveillance provides greater insight into the epidemiology of chronic viral hepatitis, identifying groups at risk and opportunities for public health action.

Background & Aims: Currently available HDV PCR assays are characterized by considerable run-to-run and inter-laboratory variability. Hence, we established a quantitative reverse transcription real-time PCR (RT-qPCR) assay on the open channel of a fully automated PCR platform (cobas6800, Roche) offering improved consistency and reliability. Methods: A primer/probe-set targeting a highly conserved region upstream of the HDV antigen was adapted for use on the cobas6800. The lower limit of detection (LLOD) was determined using a dilution panel of the HDV WHO standard (n = 21/dilution). Linearity and inclusivity were tested by preparing 10-fold dilution series of cell culture-derived virus (genotype [GT]1-8; n = 5/dilution). Patient samples containing a variety of bloodborne viral pathogens were tested to confirm exclusivity (n = 60). Results: The LLOD of the HDV utility-channel (HDV_UTC) assay was determined as 3.86 IU/ml (95% CI 2.95–5.05 IU/ml) with a linear range from 10–10ˆ8 IU/ml (GT1). Linear relationships were observed for all HDV GTs with slopes ranging from -3.481 to -4.134 cycles/log and R2 from 0.918 to 0.994. Inter-run and intra-run variability were 0.3 and 0.6 Ct (3xLLOD), respectively. No false-positive results were observed. To evaluate clinical performance, 110 serum samples of anti-HDV-Ab+ patients were analyzed using the HDV_UTC and CE-IVD RoboGene assays. 58/110 and 49/110 samples were concordant positive or negative, respectively (overall agreement 97.3%). Quantitative comparison demonstrated a strong correlation (R2 0.8733; 95% CI 0.8914–0.9609; p value

Objectives: The aims of this study were to identify the causes of severe icterus in an academic medical center patient population and to assess the impact of icterus on clinical chemistry testing using assay package insert thresholds. Design: and Methods: In this retrospective study at an academic medical center core clinical laboratory, icteric, hemolysis, and lipemia indices were available for all serum and plasma chemistry specimens analyzed on Roche Diagnostics cobas 8000 analyzers over a 12-month period, encompassing 414,502 specimens from 94,081 unique patients (51,851 females; 42,230 males) including children, inpatient, outpatient, and emergency department patients. Extensive chart review was done for all 57 patients (4 pediatric, 53 adult; 534 total specimens) who had one or more samples with an icteric index of 40 or higher (defined as severe icterus). Results: Specimen icteric index exceeded package insert icteric index thresholds in 0.14% of clinical chemistry assays, with the highest number of instances for creatinine (1358 samples, 0.6% of total tests), total protein (1194 samples, 2.2%), and ammonia (161 samples, 3.9%). The 57 patients with an icteric index of 40 or higher accounted for 49.7% of all instances where the icteric index exceeded the specific assay package insert limit. The most common etiologies of this group of 57 patients were alcohol-related liver disease (34 patients), biliary tract disease (7 patients), and neoplasms (6 patients). Conclusions: Approximately half of all instances where specimen icteric index exceeded assay package insert thresholds occurred in a small cohort of patients with severe liver/biliary tract disease.

Summary: The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.

Spatial analysis of infectious diseases can play an important role in mapping the spread of diseases and can support policy making at local level. Moreover, identification of disease clusters based on local geography and landscape forms the basis for disease control and prevention. Therefore, this study aimed to examine the spatial-temporal variations, hotspot areas, and potential risk factors of infectious diseases (including Viral Hepatitis, Typhoid and Diarrhea) in Ahmedabad city of India. We used Moran's I and Local Indicators of Spatial Association (LISA) mapping to detect spatial clustering of diseases. Spatial and temporal regression analysis was used to identify the association between disease incidence and spatial risk factors. The Moran's I statistics identified presence of positive spatial autocorrelation within the considered diseases, with Moran's I from 0.09 for typhoid to 0.21 for diarrhea (p < 0.001). This indicates a clustering of affected wards for each disease, suggesting that cases were not randomly distributed across the city. LISA mapping demonstrated the clustering of hotspots in central regions of the city, especially towards the east of the river Sabarmati, highlighting key geographical areas with elevated disease risk. The spatial clusters of infectious diseases were consistently associated with slum population density and illiteracy. Furthermore, temporal analysis suggested illiteracy rates could increase risk of viral hepatitis by 13 % (95 % Confidence Interval (CI): 1.01-1.26) and of diarrhea by 18 % (95 % CI: 1.07-1.31). Significant inverse association was also seen between viral hepatitis incidence and the distance of wards from rivers. Conclusively, the study highlight the impact of socio-economic gradients, such as slum population density (indicative of poverty) and illiteracy, on the localized transmission of water and foodborne infections. The evident social stratification between impoverished and affluent households emerges as a notable contributing factor and a potential source of differences in the dynamics of infectious diseases in Ahmedabad., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: CD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open reading frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells targeting ORF1, 2 and 3 and antibodies against nHEV or eHEV in immunocompetent individuals with acute and resolved HEV infection., Methods: HEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico-predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multiparametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined., Results: HEV-specific CD4 T-cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells strongly target the ORF2-derived capsid and ORF3-specific CD4 T cells are hardly detectable. NAbs targeting nHEV are found in high titers while eHEV particles are less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time., Conclusion: The viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute-resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction several years after infection., Impact and Implications: The interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target capsid-derived epitopes. This correlates with efficient neutralization of naked virions while quasi-enveloped particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of the composition and longevity of HEV-specific CD4 T-cell and antibody immunity., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Our study aimed to describe epidemiological and diagnostic features in an outpatient's cohort with chronic HBeAg-negative hepatitis B. Patients and methods: A cross-sectional descriptive study with a retrospective data collection was implemented from January 2004 to April 2016 in the hepato-gastroenterology department of the University Teaching Hospital Yalgado Ouédraogo (CHU-YO) in Burkina Faso. Results: Overall 325 HBeAg negative patients met the inclusion criteria. The sex ratio was 1.5 and the mean age 38.7 years. The most frequent circumstance of diagnosis was the health check-up (54.5%). The mean HBsAg concentration and viral load were 7861.6 IU/mL and 32 237.20 IU/mL, respectively. Low or moderate inflammatory activity was found in 44% and 24% of patients, respectively at the liver biopsy; 32% presented a portal fibrosis with some septa (F2). 43.9% and 41.6% had low (A1) or moderate (A2) inflammatory activity, respectively at the hepatic fibrosis blood test, while 59.1% and 20.4% had low (F1) or moderate (F2) fibrosis stage, respectively. Of the five biochemical and virological profiles among the untreated patients, the profile 1 represented 67.2% of the sample. Conclusion: The proportions of negative HBeAg in chronic hepatitis B patients are increasing in Burkina Faso. Most of the patients have a high viral load, a low to moderate inflammatory activity or fibrosis stage.

Background & Aims: Health-related quality of life (HRQoL) determined by patient-reported outcomes (PROs) is impaired in chronic hepatitis B (CHB) and C patients, but there are no data regarding patients with chronic hepatitis D (CHD). The aim of this study was to assess PRO scores in untreated patients with CHD and compare them with those obtained for patients with CHB. Methods: Patients with CHD completed 3 PRO instruments (Chronic Liver Disease Questionnaire [CLDQ], Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F], and Work Productivity and Activity Impairment [WPAI]), and the results were compared with those of patients mono-infected with CHB. Results: In total, 125 patients were included: 43 with CHD and 82 with CHB. Overall, baseline PROs showed differences between both groups. Several assessments, such as the worry score from CLDQ (p = 0.0118), functional well-being from FACIT-F (p = 0.0281), and activity impairment from WPAI (p = 0.0029) showed a significant trend to worse scores in patients with CHD than with CHB. In addition, the linear regression model supports the finding that having CHD as opposed to having CHB was a predictor of a higher worry score (CLDQ) and a higher activity impairment (WPAI). Conclusions: In this first assessment in CHD, PROs recorded in patients with CHD showed a significant impairment in some domains of HRQoL questionnaires in comparison with those with CHB. Studies in larger cohorts with lengthier follow-up are needed to fully assess patient-reported quality of life over the course of CHD. Lay summary: Chronic hepatitis D (CHD) is a viral disease that causes rapid evolution to liver cirrhosis, amongst other severe complications, when compared to patients with chronic hepatitis B (CHB). Health-related quality of life in chronic hepatitis C and CHB has been reported widely, but no studies have been performed on patient-reported outcomes in patients with CHD. Results showed that CHD patients reported worse outcomes in psychological domains such as worry and emotional well-being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in comparison with patients with CHB.

Introduction and Objectives: The fibrosis score 4 (FIB-4) has been identified as a biochemical surrogate for histological fibrogenesis and fibrosis in cirrhosis. This study investigates the impact of preoperative FIB-4 on postoperative liver failure of patients with hepatocellular carcinoma (HCC). Materials and methods: Data from 205 patients who underwent curative resection for HCC were retrospectively analyzed. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the FIB-4. Univariate analysis and multivariate analysis were performed to identify risk factors for postoperative liver failure. The clinical outcomes were compared between patients with high FIB-4 and low FIB-4. Results: The optimal cutoff value of the FIB-4 was set at 5.92 for postoperative liver failure according to ROC curve. By univariate and multivariate analysis, the number of resected segments, FIB-4, and model for end-stage liver disease score were identified as independent risk factors for postoperative liver failure. Patients with preoperative FIB-4 > 5.92 had poorer liver function and higher occurrence of postoperative liver failure. Conclusions: Preoperative FIB-4 was associated with postoperative liver failure. Patients with preoperative FIB-4 > 5.92 carry a high risk of postoperative liver failure.

Abstract Objective: This study describes and compares prevalence trends of markers for hepatitis B (HBV) from 2004 to 2013 and HBV risk factors between Indigenous and non‐Indigenous prison entrants. Methods: A cross‐sectional survey carried out over two weeks in 2004, 2007, 2010 and 2013 in reception prisons in New South Wales, Queensland, Western Australia and Tasmania. Results: The study included 2,223 prison entrants; 544 were Indigenous. Indigenous prison entrants had significantly higher hepatitis B core antibody (anti‐HBc) prevalence than non‐Indigenous prisoners in 2004 (29% vs. 18%, P=0.026), 2007 (40% vs. 15%, P

Introduction: The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis and recently characterized group 2 innate lymphoid cells (ILC2) were identified as profibrotic immune cells in the liver of mouse models. Our aim was to elucidate whether ILC2 might be present in human liver tissue and whether ILC2 contribute to liver fibrosis. Materials and methods: To identify ILC2 in liver tissue and blood, we purified mononuclear immune cells from needle biopsies, cirrhotic explant specimen, and paired peripheral blood samples. Cell suspensions were incubated with specific markers for ILC2 and analyzed by flow cytometry. The CD69 marker was included to assess the activation level of ILC2. In addition, we determined the IL-33 plasma level. Results: Results were correlated with the METAVIR fibrotic score of patients enrolled in this study. We detected ILC2 in a higher percentage of CD45+ cells in liver tissue than in paired peripheral blood. The number of ILC2 was significantly increased in fibrotic tissue, but only slightly increased in paired peripheral blood. A higher percentage of CD69+ ILC2 was observed in fibrotic tissue, and this increase correlates positively with aggravation of liver fibrosis measured by fibrotic METAVIR score. A higher level of plasma IL-33 was only detected in samples obtained from cirrhotic patients. Conclusion: Our study indicates that ILC2 are present in the human liver and are activated in tissue contributing to the immunopathology of human liver fibrosis, independently of the etiology; which might be a potential new therapeutic target.

Introduction and aim: Real-world epidemiologic data to guide hepatitis C virus (HCV)-related public health initiatives are lacking. The aim of this study was to describe the prevalence and epidemiological characteristics of a large cohort of patients with an HCV diagnosis evaluated in one of the largest health systems in the United States. Materials and methods: De-identified demographic and clinical data were extracted from the electronic health record for patients actively followed within the Providence Health & Services health care system. Rates of HCV prevalence and co-morbid illnesses among HCV-infected patients were determined. Results: Among 2,735,511 active patients, 23,492 (0.86%) were found to have evidence of HCV infection, the majority of which were Caucasian (78.2%) and born between the years 1945 and 1965 (68.3%). In comparison to Caucasians, higher rates of HCV infection were found among Native Americans (2.5% vs. 0.95%, p