Search Results (121)

Background: Although immune complex formation is widely acknowledged as the etiological agent for the development of systemic lupus erythematosus, polyarteritis nodosa, reactive arthritis, etc., its roles in chronic hepatitis are less understood. This study aims to compare the immunohistochemistry profile of immune complex deposition in patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH). Methods: Immunohistochemistry of C4d, a widely used marker for complement deposition was employed on liver biopsies from 72 and 15 patients with CHB and AIH, respectively. Statistical analysis was performed to analyze its prevalence and its association with a range of clinical and histological parameters. Results: Among the 15 AIH biopsies examined, C4d deposition was observed in 11 cases (73.3%), the majority of which showed a periportal staining pattern (10/11). In CHB, 61 (84.7%) of 72 cases tested positive for C4d, which did not differ significantly with that of AIH. While the periportal pattern was predominantly observed in CHB cases, positive staining in central veins, sinusoids, and hepatic parenchyma were also documented. In particular, C4d deposition is significantly associated with elevated serum ALT and liver inflammation in CHB. Of note, in specimens with a patchy parenchymal C4d staining pattern, a spatially correlated HBsAg IHC signal was observed in adjacent sections from the same tissue. Conclusions: These data suggest an involvement of immune complex-mediated immunopathy in autoimmune hepatitis and HBV-induced hepatitis. The positive intrahepatic C4d signal was associated with heightened liver inflammation. The colocalization of the C4d signal on hepatocytes with HBsAg strongly suggests a causal relationship between viral activity and complement deposition. These observations align with our recent evidence implicating the contribution of capsid–antibody complexes in the pathogenesis of CHB. Full article

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, immune-mediated inflammatory disorder of the gastrointestinal tract. Immunosuppressive therapy administration increases the risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) reactivation. This study aimed to investigate the hepatitis screening rate, serological status, and protective antibody levels among the Taiwanese IBD population. This single-center retrospective study included patients with IBD from January 2016 to December 2024. Hepatitis serological markers were analyzed. Patients were categorized into active HBV infection (HBsAg-positive), resolved HBV infection (HBsAg-negative and anti-HBc-positive), and non-HBV-infected groups, with prevalences of 7.5%, 32.5%, and 0.9%, respectively. This study included 347 patients with IBD (UC: 68.3%; CD: 31.7%), with a mean age of 47.1 ± 16.4 years. Patients born after 1984 demonstrated a significantly reduced HBsAg positivity (0.9% vs. 11.0%; p < 0.05) and resolved HBV infection (52.2% vs. 1.0%; p < 0.05). However, among non-HBV-infected individuals, only 42.0% had protective anti-HBs levels (≥10 mIU/mL), despite vaccination program initiation. In this study, we found an overall HBsAg positivity rate of 7.5% and an anti-HCV seropositivity rate of 0.9% in our IBD population. Taiwan’s HBV vaccination program has effectively reduced the HBV prevalence. However, a significant proportion of vaccinated individuals lack sufficient protective antibody levels, thereby requiring continued HBV screening and booster vaccinations. Full article

Hepatitis B virus (HBV) genetic variability, shaped by high mutation rates and selective pressures, complicates its management and increases the emergence of drug-resistant and immune-escape variants. This study aims to analyze immune escape mutations (IEMs) and drug resistance mutations (DRMs) in patients with HBV infection exposed to antiviral therapies and exhibiting detectable plasma HBV viremia. This monocentric retrospective real-life study was carried out at the ASST Spedali Civili di Brescia, Italy, from 2015 to 2023. A total of 102 consecutive patients with detectable serum HBV-DNA exposed to at least one NA and for whom a drug resistance assay was available were included in our study. HBV sequences were amplified, sequenced, and analyzed for mutations using Geno2pheno and Stanford University tools. Phylogenetic analysis and statistical regression were performed to confirm genotypes and identify mutation patterns and associated risk factors. Our study shows a 38.2% prevalence of DRMs, with M204I/V (95%) and L180M (64%) being the most common, and a 43% prevalence of IEMs, primarily in the major hydrophilic region. Genotype D3 exhibited a higher mutation burden than other genotypes. Significant associations were found between HBsAb presence and increased IEM burden, while HBeAg was protective against DRMs. Atypical serological profiles were observed in 18.6% of patients, including cases of HBV reactivation under immunosuppressive therapy. This study highlights the high prevalence of IEMs and DRMs in a real-world setting, particularly among HBV genotype D3 carriers. These findings underscore the importance of mutation surveillance to guide therapeutic strategies, vaccine design, and public health policies to address the challenges posed by HBV genetic variability. Full article

The liver is an active metabolic site that generates high levels of reactive oxygen species (ROS). Oxidative stress has been implicated in the chronicity of hepatitis and hepatitis B virus (HBV) infection. This study aimed to determine the involvement of oxidative stress in HBV-infected cells and the efficacy of natural Nrf2 activators. The intracellular HBV pregenomic RNA copy number relative to total RNA was measured by RT-PCR, and various protein expressions associated with oxidative stress were analyzed by a Western blot analysis. The results showed that the Nrf2, HO-1, Akt, and Bcl-xL proteins were decreased by the continuous infection, indicating that HBV-positive cells were exposed to oxidative stress. The present study evaluated the anti-HBV infection effects of the Nrf2 activator fucoxanthin (Fx), a marine carotenoid from edible biological resources, including the comparative natural Nrf2 activator pteryxin (Ptx). These Nrf2 activators suppressed the HBV pregenomic RNA production in the HBV-infected cells, thus increasing the expression of the proteins of Nrf2 and HO-1. In the persistently infected cells transfected with the HBV genome, the Bcl-xL and Keap1 proteins, which contribute to suppressing the HBx protein involved in the HBV replication, were overexpressed. In particular, the activity of these protein expressions was marked at low concentrations of Fx. This suggests that natural Nrf2 activators may play a significant role in the HBV infection and could be a valuable source for further development through the functional utilization of food resources. Full article

Background: Hepatitis B virus (HBV) remains a leading etiology for liver transplantation (LT). In a large cohort of HBsAg-positive patients, this study evaluates long-term patient and graft survival after LT over the past 30 years while analyzing trends and outcomes following waiting list (WL) inclusion over the last 15 years. Methods: HBsAg-positive patients who underwent transplantation between 1991 and 2020 and were waitlisted from 2006 to 2020 at Padua Hospital were included in the analysis. Patients were stratified according to hepatitis delta virus (HDV) coinfection, transplant indication (decompensated cirrhosis vs. hepatocellular carcinoma (HCC)), and WL inclusion period. Results: Among 321 HBsAg-positive LT recipients (31.5% HDV-coinfected, 46.4% HCC), 1-year and 5-year patient/graft survival rates were 87.6%/86.7% and 82.6%/82.2%, respectively. From 2006 to 2020, 284 HBsAg-positive patients were waitlisted (32.6% HDV-coinfected), with a significantly higher prevalence of HCC compared to non-HBV patients (p = 0.008). High-barrier nucleos(t)ide analogues (hbNUCs) significantly reduced mortality (p = 0.041) and improved survival post-WL inclusion (p = 0.007). Survival rates were consistent regardless of LT indication, HDV coinfection, or WL inclusion period. Post-transplant prophylaxis predominantly involved immunoglobulins (HBIG) + NUCs, resulting in only two cases of HBV reactivation, both clinically inconsequential. Conclusions: Over the past 30 years, HBV has remained a consistent indication for LT at our center. Thanks to hbNUCs, WL outcomes have improved and HCC has become the main indication for LT. Full article

Background: The MeMed BV^® BV score is a novel, promising host-protein score, differentiating bacterial from viral infections, that combines the expression levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP). The aim of our study was to determine its diagnostic accuracy in hospitalized febrile children. Methods: A prospective study was performed from December 2023 to April 2024 in two pediatric clinics at “Aghia Sophia” Children’s Hospital, Athens, Greece. Patients > 3 months old, presenting with fever, clinical suspicion of acute infection, and symptoms onset up to 7 days prior were considered eligible. Patients with cancer, Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Tuberculosis (TB), and immunodeficiency were excluded. Two pediatricians reviewed the clinical, laboratory, microbiological, and radiological data and assigned the final diagnosis. The experts were blinded to the BV scores. Results: One hundred and thirty-five patients were enrolled. The predominant medical condition was respiratory tract infection (59.3% lower, 26.7% upper). Twenty-nine (21.5%) patients were diagnosed with bacterial infections. The BV score demonstrated a sensitivity of 96.2%, specificity of 88.7%, and negative predictive value (NPV) of 98.9% for bacterial infections. Equivocal BV scores were reported in 8.9% of cases and were excluded from calculations. The area under the curve was 0.96 (95% CI: 0.93–0.99). A ROC curve analysis was performed, and the optimal cut-off score was estimated at 60, providing a sensitivity of 93.1%, specificity of 88.7%, and NPV of 97.9%. Conclusions: In our study population, the BV score showed high sensitivity and NPV in bacterial infection diagnosis. Further studies are needed to assess the possibility of replacing the “equivocal” range with a narrower one or a specific cut-off value. Full article

Hepatitis B virus (HBV) infection remains a global health challenge, affecting over 254 million individuals chronically and contributing significantly to cirrhosis, liver failure, and hepatocellular carcinoma. Despite advancements in antiviral therapy, HBV reactivation remains a critical concern, particularly in immunosuppressed individuals, including non-transplant patients undergoing immunosuppressive therapy and solid organ transplant recipients. This review provides screening and management strategies for HBV reactivation in these populations. Full article

Background/Objectives: In chronic hepatitis B infection (CHB), the hepatitis B surface antigen (HBsAg) continuously exhausts the hepatitis B surface antibody (HBsAb), which leads to the formation of immune tolerance. Accordingly, the hepatitis B virus (HBV) infection can be blocked by inhibiting the binding of the hepatitis B surface pre-S1/pre-S2 antigen to the hepatocyte receptor NTCP, but the clinical cure rate of pre-S-based vaccines for CHB is limited. Methods: In this study, we designed and prepared multivalent hepatitis B therapeutic mRNA vaccines encoding three hepatitis B surface antigen proteins (L, M, and S) at the cell membrane, verified via in vitro transfection and expression experiments. An in vivo immunization experiment in HBV transgenic (Tg) mice was first completed. Subsequently, an adeno-associated virus plasmid vector carrying the HBV1.2-fold genome (pAAV HBV1.2) model and the adeno-associated virus vector carrying HBV1.3-fold genome (rAAV HBV1.3) model were constructed and immunized with mRNA vaccines. The HBV antigen, antibodies, and HBV DNA in serum were detected. Indirect (enzyme-linked immunosorbent assay) ELISA were made to analyze the activated antigen-specific IgG in HBV Tg mice. Antigen-dependent T-cell activation experiments were carried out, as well as the acute toxicity tests in mice. Results: The L protein/pre-S antigens could be stably presented at the cell membrane with the support of the S protein (and M protein). After vaccinations, the vaccines effectively reactivated the production of high levels of HBsAb, disrupted immune tolerance, and activated the production of high-affinity antibodies against structural pre-S antigen in HBV Tg mice. The HBsAg seroconversion and serum HBV DNA clearance were achieved in two HBV mice models. Furthermore, pre-S antigen-dependent T-cell response against HBV infection was confirmed. The therapeutic vaccine also showed safety in mice. Conclusions: A novel therapeutic mRNA vaccine was developed to break through HBsAg-mediated immune tolerance and treat CHB by stably presenting the pre-S antigen at the membrane, and the vaccine has great potential for the functional cure of CHB. Full article

Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment. They fail to eradicate the HBV viral reservoir, called covalently closed circular DNA (cccDNA), which replicates in the nucleus of liver cells. The cccDNA serves as the sole template for viral replication, as it generates the pregenomic RNA (pgRNA) necessary for producing new viral genomes. This stable form of viral DNA can reactivate the virus when treatment is stopped. HBV cccDNA is therefore one of the main challenges in curing chronic HBV infections. By targeting steps such as cccDNA formation, capsid assembly, or particle secretion, researchers continue to seek ways to interfere with HBV replication and to reduce its persistence, ultimately to eradicate HBV as a global health problem. This review provides an overview of what is currently known about cccDNA formation and biogenesis and the ongoing efforts to target and eradicate it to cure chronic HBV infections. Full article

Background: This study addresses a particular aspect of the biological behavior of the Spike subunit S1 of SARS-CoV-2. Researchers observed S1 acting freely in the human organism during and after COVID-19 and vaccination. One of its properties is that it interacts one-to-one with human proteins. S1 interacts with 12 specific human proteins in the liver. Methods: We used these proteins as seeds to extract their functional relationships from the human proteome through enrichment. The interactome representing the set of metabolic activities in which they are involved shows several molecular processes (KEGG), including some linked to HBV (hepatitis B) and HCC (hepatocellular carcinoma) with many genes/proteins involved. Reports show that, in some COVID patients, HBV reactivated or progressed to cancer. Results: We analyzed the interactome with several approaches to understand whether the two pathologies have independent progressions or a common progression. All our efforts consistently showed that the molecular processes involving both HBV and HCC are significantly present in all approaches we used, making it difficult to extract any useful information about their fate. Through BioGRID, we extracted experimental data in vivo but derived it from model cell systems. The lack of patient data in STRING results prevents diagnosis or prediction of real disease progression; therefore, we can consider them “aseptic” model data. Conclusion: The interactome tells us that genes involved in HCC and HVB-related pathways have the potential to activate disease processes. We can consider them as a gold standard. It is the comparison with similar molecular interactions found in individual human phenotypes that shows us whether the phenotype favors or hinders their progression. This also suggests how to use these features. These sets of proteins constitute a molecular “toolkit”. In fact, if we compare them with similar molecular sets of the patient, they will provide us with information on the level of the phenotypic state that is driving the disease. The information derived from the composition of an entire group of proteins is broader and more detailed than a single marker. Therefore, these protein compositions can serve as a reference system with which doctors can compare specific cases for personalized molecular medicine diagnoses. Full article

This study utilized a genome-wide association study (GWAS) to investigate the genetic variations linked to the risk of hepatitis B virus (HBV) reactivation in patients who have undergone liver transplantation (LT), aiming to enhance understanding and improve clinical outcomes. Genotyping performed on a selected patients from the Korean Organ Transplantation Registry (KOTRY) data using high-throughput platforms with the Axiom Korea Biobank array 1.1. The discovery cohort included 21 patients who experienced HBV reactivation (cases) and 888 patients without HBV reactivation (controls) following LT. The replication cohort consisted of 5 patients with HBV reactivation (cases) and 312 patients without HBV reactivation (controls) after LT. Additive logistic regression analysis was conducted using PLINK software ver 1.9, with adjustments for age and gender. The GWAS findings from the discovery cohort were validated using the replication cohort. The GWAS identified several single-nucleotide polymorphisms (SNPs) in the RGL1, CDCA7L, and AQP9 genes that were significantly linked to HBV reactivation after LT, with genome-wide significance thresholds set at p < 10⁻⁷. Down-regulation of RGL1 cDNAs was observed in primary duck hepatocytes infected with duck HBV. Overexpression of CDCA7L was found to promote hepatocellular carcinoma cell proliferation and colony formation, whereas knocking down CDCA7L inhibited these processes. Additionally, the absence of AQP9 triggered immune and inflammatory responses, leading to mild and scattered liver cell pyroptosis, accompanied by compensatory liver cell proliferation. This study provides critical insights into the genetic factors influencing HBV reactivation after LT, identifying significant associations with SNPs in RGL1, CDCA7L, and AQP9. These findings hold promise for developing predictive biomarkers and personalized management strategies to improve outcomes for HBV-infected LT recipients. Full article

Cancer patients receiving non-endocrine therapies are at risk of hepatitis B virus (HBV) reactivation (HBVr). Guidelines recommend HBV screening prior to treatment. The Ottawa Hospital Cancer Center implemented a screening pilot for all patients receiving FOLFOX-based regimens between January and April 2023. We assessed the pilot from a quality improvement perspective. Charts were retrospectively reviewed, and patient and disease characteristics were collected. The primary endpoint was to identify the proportion of patients who underwent HBV screening prior to treatment start. Univariate analyses assessed the association between baseline characteristics and failure to screen. Quality metrics were also reviewed. There were 32/42 patients (76.2%) who completed screening, and 5 (11.9%) had a positive screen. The majority of eligible patients (59.5%) completed screening prior to the first treatment as intended. Four of five patients who tested positive were referred to Infectious Diseases. Of those, one received antivirals for chronic HBV. There were no treatment delays due to pending screening and no HBV reactivation. Receipt of prior systemic therapy was significantly associated with failure to screen (55 vs. 95%, OR 17.1 (95% CI 1.92–153), p = 0.011). The results of this pilot highlight the importance of building HBV screening into standardized treatment plans and engaging all team members to ensure high levels of screening. Prior systemic therapy receipt was associated with failure to screen, and thus, programs should include education on the necessity of screening as recommended by medical guidelines. Full article

Background: Psoriasis patients who are seropositive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) face an elevated risk of hepatitis B virus reactivation (HBVr) when treated with cytokine inhibitors. This study aims to elucidate the risk in this population. Methods: A retrospective chart review was conducted to assess the risk of HBVr in 73 psoriasis patients treated with cytokine inhibitors from 2013 to 2023. Additionally, a systematic review and meta-analysis were performed, pooling data from 10 studies (including our cohort) and adhering to PRISMA guidelines. Statistical heterogeneity was assessed using the I² statistic, and pooled proportions were calculated using a random effects model. Results: No HBVr cases were observed among the 11 HBsAg+ patients in the cohort. However, two of the sixty-two (3.2%) HBsAg−/HBcAb+ patients experienced reactivation during therapy, with outcomes ranging from spontaneous recovery in one case to death from hepatic failure despite antiviral treatment in the other. The meta-analysis, pooling data from 10 studies, revealed a reactivation rate of 21.2% (95% CI: 9.4–41.0%) in HBsAg+ patients without prophylaxis and 4.4% (95% CI: 2.2–8.7%) in HBsAg−/HBcAb+ patients. Conclusion: Antiviral prophylaxis is essential for HBsAg+ patients receiving cytokine inhibitors, given the high risk of reactivation. Despite the lower risk for HBsAg−/HBcAb+ patients, the potential severity of outcomes demands careful monitoring and timely action. Full article

The effects of a concomitant infection of hepatitis B virus (HBV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still debated, with a recognized major risk of HBV reactivation during immune-suppressive treatments. The aim of this study was to determine the prevalence and predictive factors of HBV reactivation in a cohort of hospitalized patients with coronavirus disease 2019 (COVID-19) and a current or past hepatitis B infection. In a monocentric retrospective observational study, we enrolled all consecutive hospital admitted patients with COVID-19 pneumonia and a positive HBV serology (N = 84) in our Infectious Diseases Unit from April 2021 to December 2023. We identified 18 (21%) HBsAg-positive/anti-HBc-positive, 41 (49%) HBsAg-negative/anti-HBc-positive/anti-HBs-positive, and 25 (30%) HBsAg-negative/anti-HBc-positive/anti-HBs-negative subjects. The overall rate of hepatitis flare was 10.7%, without any HBsAg seroreversion, severe HBV reactivation, and/or need for new HBV antiviral therapy introduction. Systemic corticosteroid treatment for COVID-19 and baseline anti-HBsAg status were associated with this risk of HBV reactivation. In conclusion, the overall risk of hepatitis flares in hospitalized COVID-19 was reasonably low, with higher doses of corticosteroids treatment being the major risk factor for HBV reactivation, and anti-HBs-positive serological status as a protective element. Full article

Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up. Full article