The significance of occult hepatitis B virus (HBV) infection (OBI) has been increasingly recognized while the underlying mechanisms remain incompletely understood. This study aimed to identify high-frequency OBI-related mutations in HBV surface antigen (HBsAg)-negative samples tested by the ultrasensitive Lumipulse G HBsAg-Quant assay. OBI samples were collected from 32 blood establishments across 14 provinces in China. Lumipulse G HBsAg-Quant assay was performed for the re-testing and reclassification of OBI. Mutations in genotypes B (GTB) and C (GTC) were analyzed to identify high-frequency single and combined mutations. Additionally, the efficacy of commercial reagents commonly employed in clinical diagnostics for detecting mutant HBsAg was evaluated. Western Blot was used for the confirmation of extracellular HBsAg as well as the detection of intracellular HBsAg. Hydrophilicity analysis and transmembrane distribution prediction of HBsAg were utilized for further validation. Single mutations at 17 sites and 9 combined mutations in GTB indicated a significantly elevated mutation frequency. In GTC, there were single mutations at 16 sites and 9 combined mutations. Several commercial reagents commonly demonstrated limited capacity toward mutant HBsAg with T123A/P, K141C, and P142R/I/K/L (GTB) and S114A/P (GTC). The findings indicated that mutations including T123A/C/K/S, S132G/Y, P142L/R/S/T, T143M, D144G, G145A, K160R+V168A, I4T+V168A, M103I+K122R, and M103I+Q181R (GTB), along with Q101H, M103I, R160K+C221Y (GTC), were associated with reduced levels of HBsAg both extracellularly and intracellularly. Additionally, K160R (GTB) and E2G (GTC) were associated with intracellular aggregation. This study elucidates the mutations associated with decreased extracellular HBsAg with ultrasensitive HBsAg assay, providing insight for further investigation into the mechanisms of OBI.

The sensitivity of HBsAg detection reagents directly impacts the identification of occult hepatitis B virus (HBV) infection (OBI). This study aims to identify high-frequency OBI-related mutations in HBV surface antigen (HBsAg)-negative samples evaluated using a Fujirebio-Lumipulse ultrasensitive HBsAg assay and to investigate the implications of these mutations on the antigenicity of HBsAg, the detection capacities of various HBsAg assays, and the effects on intracellular and extracellular levels of HBsAg. Generally, our study offers a new perspective on OBI-related mutations by ultrasensitive HBsAg assay and lays the groundwork for further research on the OBI mechanism and the enhancement of HBsAg detection reagents.

Viral hepatitis remains a global health challenge and immune status affects outcomes. In patients with haematological malignancies, including haematopoietic stem-cell transplantation recipients, viral hepatitis can be life-threatening due to the direct effects of the virus or the need to modify or delay chemotherapy. Additionally, haematopoietic stem-cell donors with past or current viral hepatitis infections might transmit the virus to recipients. The growing recognition of hepatitis E virus (HEV), advances in haematological therapies, and the availability of direct-acting antivirals for hepatitis C virus (HCV), led the 2022 9th European Conference on Infections in Leukaemia (ECIL-9) to update the 2013 ECIL-5 guidelines on viral hepatitis. The ECIL organising committee convened a panel of 13 impartial international experts (all authors of this Review) in viral hepatitis, both within and outside the fields of haematological malignancies and immunosuppression. The ECIL-9 panel conducted a review of the literature on hepatitis B virus (HBV), HCV, and HEV, grading the evidence based on the European Society for Clinical Microbiology and Infectious Diseases system. The panel identified key clinical questions and outcomes and built on the recommendations established during ECIL-5. A consensus conference was held in Sofia Antipolis, France, from Sept 15-17, 2022, bringing together 49 experts from 19 countries. The ECIL-9 panel presented the proposed recommendations, which were revised following expert discussions. A final consensus on updated guidelines was reached in a second plenary session. The updated ECIL-9 guidelines provide evidence-based recommendations on the prevention, screening, treatment, and long-term surveillance of viral hepatitis in patients with haematological malignancies and haematopoietic cell transplantation recipients.

Nucleos(t)ide analogues (NUCs) are first-line agents for chronic hepatitis B (CHB). Current guidelines provide recommendations for NUC initiation, yet the guidelines are complex and restrictive. Accumulating data on hepatitis B virus (HBV) replication and HBV integration suggests that there are no real quiescent disease phases in CHB, and treatment-ineligible patients in current guidelines still have substantial risks of cirrhosis and hepatocellular carcinoma. Expanding CHB treatment indications can effectively reduce the risks of liver-related complications. Furthermore, treatment indication expansion can be cost-effective, and can simplify care pathways to remove treatment barriers. Potential caveats for treatment expansion include risks of non-compliance, long-term side effects from NUCs, and poor patient acceptability. Nonetheless, these caveats are not insurmountable, and the benefits of treatment expansion outweigh the disadvantages. There is consensus among hepatologists in supporting treatment indication expansion, although expert panels have varying recommendations on treatment strategies. A treat-all approach, which involves treating all CHB patients, has also been proposed. A treat-all strategy is straightforward, and should yield the greatest benefits from a population health perspective. However, the feasibility of new treatment strategies, especially the treat-all approach, is influenced by multiple factors including local epidemiology, healthcare resource availability, and socioeconomic factors. A one-size-fits-all approach is not optimal, and treatment expansion strategies that are tailored based on local data should yield the greatest impact toward hepatitis elimination.

The correlation between intrahepatic covalently closed circular DNA (cccDNA) levels and serum hepatitis B virus (HBV) markers in patients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative and antibody to hepatitis B core antigen [anti-HBc]-positive) is unclear. We therefore examined the utility of anti-HBc titers as a surrogate marker of intrahepatic cccDNA levels in patients with resolved HBV infections.

Among 1005 patients who underwent hepatectomy between 2010 and 2018, a retrospective review was performed in 114 patients (76 with resolved HBV infection and 38 HBsAg-positive) with frozen specimens of the background liver. Clinical, biochemical, and virological data, including intrahepatic cccDNA levels, were retrospectively evaluated. Intrahepatic cccDNA levels were measured using droplet digital polymerase chain reaction.

Intrahepatic cccDNA levels positively correlated with serum HBsAg levels (r = 0.609, p < 0.001) and anti-HBc titers (r = 0.542, p < 0.001). An intrahepatic cccDNA level of 22.2 copies/μg was the optimal cut-off for HBsAg positivity, with a sensitivity of 86.8% and specificity of 89.5%. Of the 76 cases with resolved HBV infection, 8 had high levels of intrahepatic cccDNA (≥22.2 copies/μg). Multivariate analyses showed that anti-HBc ≥ 11.0 sample/cut-off (S/CO) was an independent risk factor for high intrahepatic cccDNA levels (odds ratio, 12.6; 95% confidence interval, 2.4-66.156; P = 0.003).

Anti-HBc titers were positively correlated with intrahepatic cccDNA levels. Even in patients with resolved HBV infection, anti-HBc ≥ 11.0 S/CO was considered to indicate high intrahepatic cccDNA levels, comparable to those in HBsAg-positive cases. In this group, careful monitoring is required during immunosuppressive therapy to prevent HBV reactivation.

Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.

It is unclear whether nucleos(t)ide analogs (NUCs) continuation provides clinical benefits following HBsAg seroclearance with pegylated interferon (PEG-IFN)-based therapy. This study aims to investigate the role of NUCs continuation in HBsAg seroreversion.

Patients who experienced serum HBsAg loss after PEG-IFN-based therapy were enrolled and followed up for 96 weeks. Propensity score matching (PSM) was performed using a 1:1 ratio to adjust for the associated factors. A multivariate logistic regression analysis was used to determine the factors associated with HBsAg seroreversion.

In total, 220 patients with HBsAg seroclearance were divided into NUCs (n = 54) and non-NUCs (n = 166) consolidation therapy groups. At week 96, the HBsAg seroreversion (12/54 vs. 31/166, P = 0.709) and virological relapse (2/54 vs. 10/166, P = 0.759) rates were similar in the NUCs and non-NUCs groups. After PSM, HBsAg seroreversion (12/53 vs. 13/53; P = 1.000) and virological relapse (2/53 vs. 4/53; P = 0.674) rates were not significantly different between the two groups. Serum hepatitis B surface antibody titer (odds ratio, 0.388; 95% confidence interval, 0.245-0.616; P < 0.001) was found to be associated with HBsAg seroreversion, while NUCs continuation was not related to HBsAg seroreversion.

NUCs continuation is not associated with a lower risk of HBsAg seroreversion in patients with serum HBsAg loss following PEG-IFN-based therapy.

HBeAg-positive chronic hepatitis B (CHB) with low HBsAg levels represents a relatively rare serological pattern and is closely associated with the severity of liver disease. However, the underlying mechanisms in such cases remain largely unclear.

Treatment-naïve HBeAg-positive CHB patients with low HBsAg levels in China were enrolled and analysed. In vitro cell experiments and immunoassays were conducted to investigate the effects of the preS2 deletion mutation on virus reproduction and host immune response.

Treatment-naïve HBeAg-positive CHB patients with low HBsAg levels (low HBsAg group) exhibited higher fibrosis scores and a greater prevalence of quasispecies mutations introduced by preS2 deletion compared to patients with positive HBeAg and high HBsAg levels (high HBsAg group). Further analysis revealed that fibrosis scores in CHB patients with the preS2 deletion mutations were significantly higher compared to both in wild-type patients and the high HBsAg group. In vitro assays indicated that while this mutation may not impact HBV replication, it significantly reduced viral infectivity. The number of viral-specific IFN-γ-secreting cells induced by the mutant was significantly lower than that induced by the wild-type strain. Additionally, the levels of HBs-specific B cells and cytokine secretion from lymphocytes triggered by the mutant strain were significantly reduced.

HBeAg-positive CHB patients with low HBsAg and genotype C exhibited higher noninvasive fibrosis indexes compared with typical patients, accompanied by a significant increase in quasispecies variants associated with preS2 deletion. The emergence of the preS2 deletion mutants in patients could be due to its enhanced ability to evade the host immunity.

The implementation of effective blood donation screening for hepatitis B virus (HBV) anti-core antibodies with highly sensitive molecular HBV DNA detection in low-endemic countries like the United Kingdom has improved blood safety. However, the linkage to care and management for blood donors with occult HBV infection (OBI) is a complex dilemma involving virological, clinical, methodological, and social issues. Limited evidence suggests that OBI may accelerate the progression of liver disease and cancer. The need for a specialist referral for donors identified with OBI carries mixed opinions from blood establishments, hepatologists, and public health. Following extensive multidisciplinary discussions, experts agree upon a need for clear messaging for donors and to consider the oncogenic implications of OBI. Proposals for future studies are identified, and the applicability of the recommendations in low-resource, high-endemic regions is considered, as well as the inclusion of OBI in global hepatitis elimination targets.

The posttransplantation recurrence rate of hepatitis B virus (HBV) infection in patients with chronic hepatitis B (CHB) is underestimated and linked with unfavorable outcomes. We investigated HBV recurrence by serum assays in patients with CHB following liver transplantation. We enrolled patients with CHB who underwent liver transplantation between March 2001 and July 2021 to participate in cross-sectional testing for HBV-related serum markers, including biochemical analysis for HBsAg and hepatitis B core-related antigen (HBcrAg) and real-time RT-PCR/PCR for HBV RNA and HBV DNA, in 2022. HBV recurrence in this study was defined as positive results of at least one posttransplantation HBV-related serum markers. Next-generation sequencing was performed for those with posttransplantation virological breakthroughs. Ninety-six patients with CHB who underwent liver transplantation were enrolled. Among 84 patients who received grafts negative for HBsAg, 41 (48.8%) exhibited HBV recurrence, and they tested positive for either HBsAg or HBcrAg, or both. High-risk patients, identified using a risk stratification model, had a higher likelihood of recurrence than low-risk patients (odds ratio: 2.59, 95% confidence interval: 1.06-6.35, p = 0.038). In 51 patients who tested negative for HBsAg after receiving HBsAg-negative grafts, 8 (15.7%) had positive HBcrAg, indicating occult HBV infection (OBI). We identified immune escape mutations and altered N-glycosylation patterns on the surface protein in patients experiencing virological breakthroughs following lamivudine resistance. HBsAg plus HBcrAg levels can be used to detect posttransplantation HBV recurrence. The OBI prevalence was higher in patients transplanted with HBsAg-negative liver grafts compared to blood donors, vaccinated young population, and community-based populations reported in literatures, possibly because of immune escape mutations or altered N-glycosylation patterns of surface proteins.

Immunization with the hepatitis B vaccine is the most effective means of preventing acute HBV infection. However, whether the primary vaccination of infants confers lifelong immunity remains controversial. Therefore, the ongoing surveillance of vaccine recipients is required.

A longitudinal study was carried out based on LongAn county, one of the five clinical trial centers for hepatitis B immunization in China in the 1980s. Serum samples were collected and tested for HBV serological markers and DNA.

A total of 637 subjects born in 1987-1993 were recruited, including 503 males and 134 females. The total prevalence of HBsAg was 3.9%. The prevalence in females (8.2%) was significantly higher than that in males (2.8%) (p = 0.004). The prevalence of anti-HBc in females (52.2%) was also significantly higher than that in males (41.2%) (p = 0.021). The prevalence of anti-HBs was 42.7% and did not differ significantly between males (41.7%) and females (46.3%) (p = 0.347). Compared to data from surveillance over the last ten years, the positivity rate of HBsAg did not increase. The positivity rate of anti-HBs decreased significantly (p = 0.049) while that of anti-HBc increased significantly (p = 0.001). The prevalence of occult HBV infection (OBI) in 2024 (6.0%) was significantly higher than that in 2017 (1.6%) (p = 0.045). Subjects diagnosed with OBI in 2017 maintained occult infection in 2024.

Neonatal HBV vaccination maintained effective protection for at least 37 years. However, the prevalence of OBI increases with age in those vaccinated at birth, raising a new issue of how to prevent and control OBI in the post-universal infant vaccination era.

The presence of the Hepatitis B virus (HBV) is considered as a valuable risk factor of hepatocellular carcinoma (HCC). To more deeply comprehend the molecular mechanism and transcriptome of HBV-induced HCC, we utilized tandem mass tagging (TMT)-based quantitative proteomics analysis and whole-transcriptome sequencing to analyze three sets of matched HepG2 hepatoma cells and HBV-positive HepAD38 cells. The differentially expressed (DE) proteins (1596), mRNAs (5263), miRNAs (581), lncRNAs (2672) and circRNAs (222) were subjected to differential expression and enrichment analyses in order to thoroughly assess the gene-regulatory circuits of HBV-induced HCC. Subsequently, the amounts of 321 DEproteins-DEmRNAs with common alterations were confirmed. According to functional pathway analysis, the DEproteins-DEmRNAs were primarily linked to signaling pathways, amino acid metabolism, and cellular function. Furthermore, the viability and significance of the ceRNA regulatory networks, LOC105377730/miR-4726-5p/FHL2 and hsa_circ_0001098/miR-2110/IGF2BP1, were randomly chosen and confirmed. Our work provides a valuable asset in terms of understanding regulatory activities at the RNA level, and might reveal fresh information about the fundamental mechanism and potential therapeutic targets of HBV-induced HCC.

Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in hepatitis B virus (HBV)-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and hepatocellular carcinoma (HCC). This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.

To unravel the still unexplored HBV-replicative kinetics in anti-HBc-positive/HBsAg-negative people-with-HIV (PWH) suspending tenofovir disoproxil-fumarate/tenofovir-alafenamide (TDF/TAF).

A total of 101 anti-HBc-positive/HBsAg-negative PWH switching to TDF/TAF-sparing therapy were included. Serum HBV-DNA and HBV-RNA were quantified by droplet-digital-PCR at switching (T0), within 12 months (T1) and 12-24 months postswitch (T2).

At T0, 33.7% had cryptic HBV-DNA (undetected by commercial assays, median [interquartile range (IQR)]: 2 [1-5] IU/mL) and 22% were positive to HBV-RNA alone (median [IQR]: 4 [3-4] IU/mL), indicating an active HBV-reservoir despite HBsAg-negativity and TDF/TAF-pressure. Notably, anti-HBs-titer <100 mIU/mL independently correlated with cryptic HBV-DNA at T0 (OR [95% CI]: 2.6 [1.02-6.5], P = 0.04). After TDF/TAF-withdrawal, the rate of PWH achieving HBV-DNA >10 IU/mL increased from 12.9% at T1 to 42.6% at T2 (P < 0.0001). Likewise, a rise from 2 to 11% was observed for HBV-DNA >100 IU/mL (P = 0.02); median (IQR) HBV-DNA: 579 (425-770) IU/mL. Notably, HBV-DNA >10 IU/mL at T2 occurred in 70% of PWH with cryptic HBV-DNA, in 38.5% with HBV-RNA alone and in 25% negative to both HBV-markers at T0 (P = 0.01). Cryptic HBV-DNA at T0 and lower nadir CD4+ T-cell-count independently predicted HBV-DNA >10 IU/mL at T2 (OR [95% CI]: 8.2 [1.7-40.6], P = 0.01; OR [95% CI]: 8.1 [1.3-52.1], P = 0.03). Lastly, persistent HBV-DNA positivity was independently associated with a reduced CD4+ T-cell recovery at T2 (OR [95% CI]: 0.07 [0.01-0.77], P = 0.03).

This study underlines the importance to regularly monitor anti-HBc-positive/HBsAg-negative PWH undergoing TDF/TAF-sparing regimen and the role of highly-sensitive HBV markers in optimizing their management.

In Poland, a national hepatitis B (HBV) immunization program was introduced for neonates in 1996, and between 2000 and 2011, those born from 1986 to 1995 were vaccinated. Little is known about vaccination rates among adults born before 1986. This study aimed to determine the frequency of anti-HBs seropositivity rates related to vaccination and past HBV infection in older Poles.

The HBV serological status was analyzed in 5781 (96.6%) of the PolSenior2 population-based cohort (60+) by assessing serum seropositivity for HBs antigen, anti-HBs, and anti-HBc antibodies. The survey was performed in 2018-2019 and included medical and socio-economic questionnaires, anthropometric measurements, and comprehensive geriatric assessment.

Serological status implying past hepatitis B and serological profile consistent with anti-HBV vaccination corresponded to 15.2% (95% CI: 13.4-17.0) and 25.2% (95% CI: 23.4-27.0) prevalences, respectively. Female gender, living in a town or city, having better education, and suffering from coronary artery disease, or depression independently increased the rate of past hepatitis B. On the other hand, being 'white collar' and self-reliant, having the ability to use the Internet, and past surgical procedures in the last 5-year period were factors associated with a higher vaccination rate.

More than 15% of older adults in Poland present serological profiles suggesting past hepatitis B, and one-fourth anti-HBV vaccination. Being functionally independent, 'white collar', using the Internet, and having past surgical procedures are factors associated with a higher chance of being vaccinated. Nevertheless, a large group of older adults should be prophylactically vaccinated due to increased exposure to medical procedures.

Hepatitis B virus (HBV) infection remains a major health challenge in Nigeria, with high prevalence rates among pregnant women. The prevalence of overt and occult hepatitis B infection (HBIOV and HBIOC) among pregnant women was investigated to understand the burden and associated risk factors in this population.

A cross-sectional study was conducted among 200 pregnant women. Socio-demographic and clinical data were collected, and blood samples were screened for hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV-DNA) using Enzyme-Linked Immunosorbent Assay (ELISA) and real time Polymerase Chain Reaction max Eco 48 system. Data were analyzed using GraphPad Prism software (v6) and Statistical Package for the Social Sciences (IBM SPSS 23.0). A significance level of P ≤ 0.05 was considered statistically significant.

The overall prevalence of hepatitis B infection was 6.0% (12/200), comprising 2.5% HBIOC and 3.5% HBIOV. The participants, aged 19 to 43 years, were predominantly married (89.5%) and urban-dwelling (69.0%), with diverse educational levels and occupations. There were no statistically significant differences in demographic factors such as age, marital status, or education between HBIOC and HBIOV groups. However, significant associations were observed between HBV infection and risk factors including blood transfusion (p = 0.01), cigarette exposure (p = 0.03), and alcohol consumption (p = 0.01). Viral load was significantly higher in the HBIov group [4.84 log IU/mL (IQR: 4.00-9.14)] compared to the HBIoc group [2.30 log IU/mL (IQR: 2.19-3.00)] (p = 0.001).

The findings reveal a 6.0% prevalence of hepatitis B infection among pregnant women, with 3.5% overt and 2.5% occult infections. The results emphasize the need for HBV DNA testing in screening protocols to detect occult and overt HB infections and address key risk factors to improve antenatal care and prevention strategies.

Occult hepatitis B virus (HBV) infection (OBI) is a significant challenge for HBV prevention and control. We investigated the prevalence and surface (S) gene mutations of OBI among blood donors in Huzhou City, eastern China. The hepatitis B surface antigen (HBsAg) was routinely screened among 44,256 blood donors. HBV-DNA was detected using the Roche cobas®system. Serum samples that were HBsAg negative and HBV-DNA positive were selected, and the HBV S gene was amplified and sequenced. HBV genotype and S gene mutations were analyzed. The OBI rate in these blood donors was 0.070 % (31/44,256). Among the blood donors with OBI, only two cases (2/31, 6.5 %) were anti-HBc negative. The S gene sequences of 28 samples were successfully obtained, and we found that HBV genotype C (21/28, 70 %) was predominant among blood donors with OBI. Most S gene mutations were associated with OBI, and the high frequency mutations included N40S, G44E, Q51R/P, T113A/S,T118K/M, P120Q/S/T, and Y161F/S. Notably, amino acid substitutions at some sites differed from those reported previously, such as Y72F, G102V, P127L, Q129P, and S143T. Additionally, six novel mutations (S31I/N/R, P46L, S58C, C76Y, Y200F/C, and I208T) that may be associated with OBI were found. OBI was detected in a certain proportion of blood donors in Huzhou City. S gene mutations play an important role in OBI development. Further research is required to explore the functions of novel S gene mutants in OBI pathogenesis. The findings of this study may provide important insights to prevent HBV transmission through blood transfusions.

The pathological and physiological characteristics between HBsAg-positive HBV infection and occult hepatitis B infection (OBI) are currently unclear. This study aimed to explore the immune microenvironment in the peripheral circulation of OBI patients through integration of proteomic and metabolomic sequencing, and to identify molecular biomarkers for clinical diagnosis of HBsAg-positive HBV and OBI.

This research involved collection of plasma from 20 patients with OBI (negative for HBsAg but positive for HBV DNA, with HBV DNA levels < 200 IU/mL), 20 patients with HBsAg-positive HBV infection, and 10 healthy individuals. Mass spectrometry-based detection was used to analyze the proteome, while nuclear magnetic resonance spectroscopy was employed to study the metabolomic phenotypes. Differential molecule analysis, pathway enrichment and functional annotation, as well as weighted correlation network analysis (WGCNA), were conducted to uncover the characteristics of HBV-related liver disease. Prognostic biomarkers were identified using machine learning algorithms, and their validity was confirmed in a larger cohort using enzyme linked immunosorbent assay (ELISA).

HBsAg-positive HBV individuals showed higher ALT levels (p=0.010) when compared to OBI patients. The influence of HBV infection on metabolic functions and inflammation was evident through the analysis of distinct metabolic pathways in HBsAg-positive HBV and OBI groups. Tissue tracing demonstrated a connection between Kupffer cells and HBsAg-positive HBV infection, as well as between hepatocytes and OBI. Immune profiling revealed the correlation between CD4 Tem cells, memory B cells and OBI, enabling a rapid response to infection reactivation through cytokine secretion and antibody production. A machine learning-constructed and significantly expressed molecule-based diagnostic model effectively differentiated HBsAg-positive and OBI groups (AUC values > 0.8). ELISA assay confirmed the elevation of FGB and FGG in OBI samples, suggesting their potential as biomarkers for distinguishing OBI from HBsAg-positive infection.

The immune microenvironment and metabolic status of HBsAg-positive HBV patients and OBI patients vary significantly. The machine learning-based diagnostic model described herein displayed impressive classification accuracy, presenting a non-invasive means of differentiating between OBI and HBsAg-positive HBV infections.

Recent advances in studies exploring the roles of extracellular vesicles (EVs) in viral transmission and replication have illuminated hepatotropic viruses, such as hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). While previous investigations have uncovered these viruses' ability to exploit cellular EV pathways for replication and transmission, most have focused on the impacts of exosomal pathways. With an improved understanding of EVs, four main subtypes, including exosomes, microvesicles, large oncosomes, and apoptotic bodies, have been categorized based on size and biogenic pathways. However, there remains a noticeable gap in comprehensive reviews summarizing recent findings and outlining future perspectives for EV studies related to hepatotropic viruses. This review aims to consolidate insights into EV pathways utilized by hepatotropic viruses, offering guidance for the future research direction in this field. By comprehending the diverse range of hepatotropic virus-associated EVs and their role in cellular communication during productive viral infections, this review may offer valuable insights for targeting therapeutics and devising strategies to combat virulent hepatotropic virus infections and the associated incidence of liver cancer.

Active vaccination has been utilized to prevent de novo hepatitis B virus infection (DNHB) in anti-HBc (+) grafts after liver transplantation. However, the long-term efficacy of active vaccination and graft/patient outcomes of anti-HBc (+) grafts have yet to be comprehensively investigated.

Among 204 pediatric patients enrolled in the study, 82 recipients received anti-HBc (+) grafts. For DNHB prevention, active vaccination was repeatedly administered prior to transplant. Antiviral therapy was given to patients with pretransplant anti-HBs <1000 IU/ml (nonrobust response) for 2 years and discontinued when post-transplant patients achieved anti-HBs >1000 IU/ml, while antiviral therapy was not given in patients with an anti-HBs titer over 1000 IU/ml. The primary outcome was to investigate the long-term efficacy of active vaccination, while the secondary outcomes included the graft and patient survival rates.

Among the 82 anti-HBc (+) transplant patients, 68% of recipients achieved a robust immune response, thus not requiring antiviral therapy. Two patients (2.4%) developed DNHB infection, one of which was due to an escape mutant. With a median follow-up of 150 months, the overall 10-year patient and graft survival rates were significantly worse in recipients of anti-HBc (+) grafts than those of anti-HBc (-) grafts (85.2 vs 93.4%, P =0.026; 85.1 vs 93.4%, P =0.034, respectively). Additionally, the 10-year patient and graft outcomes of the anti-HBc (+) graft recipients were significantly worse than those of the anti-HBc (-) graft recipients after excluding early mortality and nongraft mortality values (90.8 vs 96.6%, P =0.036; 93.0 vs 98.3%, P =0.011, respectively).

Our long-term follow-up study demonstrates that active vaccination is a simple, cost-effective strategy against DNHB infection in anti-HBc (+) graft patients, whereby the need for life-long antiviral therapy is removed. Notably, both the anti-HBc (+) grafts and patients exhibited inferior long-term survival rates, although the exact mechanisms remain unclear.

The prevalence of chronic hepatitis B virus (HBV) poses a significant threat to the lives of 257 million individuals globally, potentially resulting in severe outcomes such as liver cirrhosis or hepatocellular carcinoma. Among the existing preventive measures, yeast-derived vaccines have proven to be the most efficacious approach in combatting hepatitis B. Nonetheless, as scientific inquiries focus more on occult HBV infection (OBI) in vaccinated persons and the lingering risk of vertical transmission affecting 10-30 % of babies born to HBsAg-positive mothers, there is a growing apprehension regarding the inability of HBV vaccines to ensure complete immunity. This study aims to offer a more comprehensive understanding of the implications of widespread HBV vaccination initiatives on OBI while tackling the primary limitations associated with current vaccine formulations.

The exploration was conducted on PubMed, Scopus, and Web of Science databases to pinpoint research on OBI within vaccinated cohorts. A sum of 76 suitable studies was recognized.

Multiple studies have documented the occurrence of OBI in fully vaccinated individuals, including both the general population and high-risk groups, such as newborns born to HBsAg-positive mothers. Factors contributing to vaccine failures include low-level anti-HBs antibodies, high maternal viral loads in mother-to-child transmission cases, as well as the presence of vaccine escape mutants and heterologous HBV genotypes. However, further research is needed to precisely understand the impact of active immunization on the emergence of OBI in vaccinated populations. Nonetheless, it is apparent that the advancement of more effective HBV vaccines could potentially lead to the extinction of HBV.

Based on current knowledge, hepatocellular carcinoma (HCC) is a condition with numerous etiologies and risk factors. However, the pathogenesis of HCC remains unclear.

To investigate the roles of senegenin and O-GlcNAcylation in the growth and metastasis of HCC.

The levels of O-linked N-acetylglucosamine transferase (OGT) and O-GlcNAcylation in HCC cells and tissues were detected using western blot analysis. The effects of senegenin and O-GlcNAcylation on the proliferation of HCC cells were investigated in vitro using cell counting kit-8 and clonogenic assays. The potential effects of senegenin and O-GlcNAcylation on HCC metastasis were examined using the transwell migration assay. O-GlcNAcylation levels were altered via drug treatment and lentiviral infection, and western blot analysis was used to detect proteins involved in various pathways.

Western blot analysis revealed that OGT and O-GlcNAcylation levels were significantly elevated in HCC tissues and cells. O-GlcNAcylation levels in HCC cells were significantly altered by drug treatment and lentiviral infection. An increase in the glycosylation level was linked to enhanced proliferation, invasiveness, clonogenicity, and metastatic potential of cancer cells. O-GlcNAcylation induced by senegenin was found to slow the proliferation and migration of HCC cells. The levels of proteins involved in nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, which are associated with endoplasmic reticulum stress, were altered.

Senegenin lowers O-GlcNAcylation levels, decreases OGT expression, and inhibits cancer cell growth and metastasis by regulating proteins involved in NF-κB and JNK pathways.

HBV-associated hepatocellular carcinoma (HCC) represents the prevalent form of HCC, with HBx protein being a crucial oncoprotein. Numerous members of the protein tyrosine phosphatase nonreceptor (PTPN) family have been confirmed to be significantly associated with the occurrence and progression of malignant tumors. Our group previously identified the involvement of PTPN13 in HCC. However, the roles of other PTPNs in HCC require further investigation. In this study, we found that PTPN18 expression was significantly downregulated within HCC tissues compared with adjacent nontumor and reference liver tissues. Functionally, PTPN18 exerted inhibitory effects on the proliferation, migration, invasion, and sphere-forming capability of HCC cells while concurrently promoting apoptotic processes. Through phospho-protein microarray screening followed by subsequent validation experiments, we identified that PTPN18 could activate the p53 signaling pathway and suppress the AKT/FOXO1 signaling cascade in HCC cells. Moreover, the HBx protein mediated the repression of PTPN18 expression by upregulating miR-128-3p. Collectively, our study unveiled the role of PTPN18 as a tumor suppressor in HBV-related HCC. Implications: Our findings revealed that PTPN18 might be a potential diagnostic and therapeutic target for HBV-related HCC.

Routine screening for viral infections at blood donation is important to avoid transfusion-transmitted infections. It also offers an opportunity to detect an asymptomatic infection.

To study changes in serology positivity for viral infections (B and C hepatitis, HTLV-1/2, and HIV) at blood donation in a blood bank from Southern Brazil, comparing two periods of 5 years: the period from 2013 to 2017 with the period from 2018 to 2022. In addition, data on the donor fidelity rate during the studied period were sought.

Retrospective study using data from 2013 to 2022 from a single blood center electronic database from Curitiba, Southern Brazil.

A significant drop in positive serology for all studied viruses was observed: highest in HIV (OR=0.39; 95% CI=0.27-0.57) and lowest in total anti HBc (0.56; 95 CI=0.50-0.63). Anti HBc serology became more commonly seen in women in the period of 2018-2022 when compared to men. No changes in the distribution of positive serology according to donors' ages were observed. Loyalty rates had a median of 70%, with the lowest being 60% in 2013, while the highest was 73% in 2018 and 2022.

A significant reduction in discarded blood bags due to viral serology was observed when the period of 2013-2017 was compared to 2018-2022 on this blood bank; the highest reduction was observed in HIV serology and the lowest in HBc serology, which became more common in women in the second period. High rates of donor fidelity were observed during the period studied.

Recent studies from both India and outside India have shown a change in the etiological profile of hepatocellular carcinoma (HCC). We aimed to analyze the etiological spectrum and changing trends of HCC etiology in India using a systematic review of current literature and meta-analysis.

Electronic databases of PubMed/Medline, Scopus, and Embase were searched from inception to July 2023 for studies reporting the data on the etiology of HCC from India. The pooled proportions with 95% confidence interval were calculated using summative statistics.

A total of 60 studies (n = 12,327) were included in the final analysis. The pooled proportions of HCC cases with at least one positive and negative viral marker were 56.0 (49.5-62.6) and 43.1% (36.5-49.8), respectively. The pooled proportion of HCC cases with positive hepatitis B virus (HBV) markers was 41.0 (35.8-46.1), while those with positive markers for hepatitis C virus were 20.3 (17.0-23.6). The pooled proportion of cases with HCC with significant alcohol intake was 19.0% (15.6-22.4), and those related to nonalcoholic fatty liver disease (NAFLD) were 16.9% (12.1-21.7). Around 7.9% (5.8-10.0) of the cases had HCC with multiple etiologies. Subgroup analysis showed a significant variation with the location of the study based on zone. Meta-regression analysis based on publication year (1990-2023) showed a significant reduction in the proportion of cases with HBV and an increase in cases with NAFLD. In contrast, the proportion of cases with hepatitis C virus and alcohol did not change significantly.

Viral hepatitis is the most common etiology of HCC in India, predominantly HBV. The proportions of cases with HCC related to NAFLD are increasing, and those related to HBV are declining.

Liver damage can progress through different stages, resulting in cirrhosis or hepatocellular carcinoma (HCC), conditions that are often associated with viral infections. Globally, 42% and 21% of cirrhosis cases correlate with HBV and HCV, respectively. In the Americas, the prevalence ranges from 1% to 44%. The WHO has the goal to eliminate viral hepatitis, but it is important to consider occult HBV infection (OBI), a clinical condition characterized by the presence of HBV genomes despite negative surface antigen tests. This review aims to provide an overview of recent data on OBI, focusing on its role in the development of hepatic diseases and its significance in the WHO Viral Hepatitis Elimination Plan. Specific HBV gene mutations have been linked to HCC and other liver diseases. Factors related to the interactions between OBI and mutated viral proteins, which induce endoplasmic reticulum stress and oxidative DNA damage, and the potential role of HBV integration sites (such as the TERT promoter) have been identified in HCC/OBI patients. Health initiatives for OBI research in Latin American countries are crucial to achieving the WHO's goal of eradicating viral hepatitis by 2030, given the difficulty in diagnosing OBI and its unclear association with hepatic diseases.

The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).

We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC.

Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031).

For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.

Transgender women sex workers (TWSWs) and men sex workers (MSWs) are especially vulnerable to acquiring hepatitis B virus (HBV) infection. We aimed to describe HBV prevalence (hepatitis B surface antigen [HBsAg] and core antibody [HBcAb]) and associated risk factors for HBV exposure (HBcAb), to assess vaccination status and risk factors for no prior vaccination, and to compare HBV prevalence and vaccination status between TWSWs and MSWs.

The SexCohort study was advertised to TWSWs and MSWs through several communication channels. At cohort entry through 2 community-based organizations in Barcelona, the study population was screened for HBV and other sexually transmitted infections, and an epidemiological questionnaire was administered (n = 271).

Overall, 93.0% of participants were migrants, mostly from South and Central American countries. HBsAg prevalence was 1.9% (TWSWs, 2.4%; vs MSWs, 0.9%; P = .42), and previous exposure to HBV was 31.8% (TWSWs, 38.5%; vs MSWs, 20.8%; P = .002). Over 5 years of sex work (adjusted odds ratio [aOR], 9.35), prior exposure to Treponema pallidum (aOR, 3.49), and treatment with anxiolytic drugs (aOR, 3.23) were associated with HBV exposure. Overall, 33.7% of participants exhibited immunity from vaccination (TWSWs, 30.8%; vs MSWs, 38.61%; P < .001), while 34.4% were candidates to HBV vaccination (TWSWs, 30.8%; vs MSWs, 40.6%; P < .001). Never having been on pre-exposure prophylaxis for HIV (odds ratio [OR], 4.23) and non-Spanish origin (OR, 5.00) were associated with no prior HBV vaccination.

There is a need to reinforce screening and vaccination programs aimed at TWSWs and MSWs as integrated services offered at the community centers commonly accessed by these populations.

Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCVposMCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCVposMCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCVposMCV. The prevalence of HBsAg seroclearance was 48% within 123 HCVposMCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCVposMCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCVposMCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCVposMCV in male CHC patients.

Although a combination of immunoprophylaxis and antiviral therapy can effectively prevent mother-to-child transmission (MTCT) of hepatitis B virus (HBV), a considerable number of infants born to highly viremic mothers still develop occult HBV infection (OBI). To uncover the virological factor and risk predictor for OBI in infants, we found that the diversity and complexity of maternal HBV quasispecies in the case group were lower than those in the control group. Mutations with significant differences between the two groups were most enriched in the NTCPbd and PreC regions. Genetic distance at the amino-acid level of the PreC region, especially the combination of three amino-acid mutations in the PreC region, could strongly predict the risk of OBI in infants. HBV quasispecies in OBI infants were highly complex, and the non-synonymous substitutions were mainly found in the RT and HBsAg regions. The sK47E (rtQ55R) and sP49L mutations in OBI infants might contribute to OBI through inhibiting the production of HBV DNA and HBsAg, respectively. This study found the potential virological factors and risk predictors for OBI in infants born to highly viremic mothers, which might be helpful for controlling OBI in infants.

The current World Health Organization (WHO) Hepatitis Elimination Strategy suffers from lack of a target for diagnosing or expunging occult HBV infection. A sizable segment of the global population has an undetected HBV infection, particularly the high-risk populations and those residing in countries like India with intermediate endemicity. There is growing proof that people with hidden HBV infection can infect others, and that these infections are linked to serious chronic hepatic complications, especially hepatocellular carcinoma. Given the current diagnostic infrastructure in low-resource settings, the WHO 2030 objective of obliterating hepatitis B appears to be undeniably challenging to accomplish. Given the molecular basis of occult HBV infection strongly linked to intrahepatic persistence, patients may inexplicably harbour HBV genomes for a prolonged duration without displaying any pronounced clinical or biochemical signs of liver disease, and present histological signs of moderate degree necro-inflammation, diffuse fibrosis, and hence the international strategy to eradicate viral hepatitis warrants inclusion of occult HBV infection.

To investigate the clinical implication of quantitative polymerase chain reaction (PCR)-based high-sensitivity detection of hepatitis B virus (HBV)-DNA levels in patients with HBV-related liver cirrhosis (LC).

From January 2020 to December 2022, 100 fasting serum samples were collected and retrospectively analyzed from patients with treated HBV-related LC attending the Suzhou Hospital of Integrated Traditional Chinese and Western Medicine and Suzhou Guangci Cancer Hospital. Patients were divided into a negative group (HBV-DNA < 20 IU/mL) and a positive group (HBV-DNA ≥ 20 IU/mL) according to their high-sensitivity HBV-DNA test results. The clinical characteristics and serological indicators of the two groups were compared, mainly including gender, age, liver function [total protein (TP), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL)], lipids [total cholesterol (TC) and triglycerides (TG)], platelets (PLT), five serum liver fibrosis markers [cholyglycine (CG), hyaluronic acid (HA), laminin (LN), precollagen type III (PCIII), and type IV collagen (IV-C)], serum gastrointestinal tumor markers [α-fetoprotein (AFP) and carcinoembryonic antigen (CEA)], and hepatitis B surface antigen (HBsAg). The differences between the two groups in terms of liver function Child-Pugh grades and the incidence of hepatocellular carcinoma (HCC) were also compared.

There were 39 patients in the positive group, including 29 males and 10 females, and 61 patients in the negative group, including 38 males and 23 females, with no statistically significant differences in gender and age distribution between the two groups (P > 0.05). The levels of serological indicators (TP, ALB, AST, GGT, ALP, TBIL, DBIL, IBIL, TC, TG, PLT, CG, HA, LN, PCIII, IV-C, AFP, CEA, and HBsAg) in both groups showed no significant differences (P > 0.05), but the ALT level in the positive group was higher than that in the negative group (P < 0.0001). The positive group had worse Child-Pugh grades and higher HCC incidence compared to the negative group (P < 0.0001, P = 0.028).

Patients with HBV-related LC and HBV-DNA ≥ 20 IU/mL have higher serum ALT levels, worse liver function Child-Pugh grades, and higher HCC incidence than those with HBV-DNA < 20 IU/mL. High-sensitivity HBV-DNA quantification can reflect the deterioration of liver function in patients with HBV-related LC to some extent.

Occult HBV infection (OBI) remains a potential threat for blood safety. The prevalence of OBI was investigated in a blood donation center of Chinese PLA General Hospital to improve HBV blood safety. 229446 samples from blood donors were screened by two different enzyme-linked immunosorbent assay (ELISA) kits. 78 samples were HBV DNA positive among 212134 ELISA nonreactive donor samples. The prevalence of OBI was 0.04% (76/212134). Ten samples of OBI were permitted by the donors' content for further research, and all of these were below 200IU/mL, and six of these were below 20IU/mL(6/10,60%). Genotype B and genotype C was 20% (2/10) and 80% (8/10), respectively. 16 amino acid mutations were detected in the S region of OBI, included three mutations in MHR region of S. The prevalence of OBI is rare in this donation center. These mutations we found may contribute to the multifactorial occurrence of OBI.

Occult hepatitis B infection (OBI) is a globally prevalent infection, with its frequency being influenced by the prevalence of hepatitis B virus (HBV) infection in a particular geographic region, including Africa. OBI can be transmitted through blood transfusions and organ transplants and has been linked to the development of hepatocellular carcinoma (HCC). The associated HBV genotype influences the infection.

To highlight the genetic diversity and prevalence of OBI in Africa.

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and involved a comprehensive search on PubMed, Google Scholar, Science Direct, and African Journals Online for published studies on the prevalence and genetic diversity of OBI in Africa.

The synthesis included 83 articles, revealing that the prevalence of OBI varied between countries and population groups, with the highest prevalence being 90.9% in patients with hepatitis C virus infection and 38% in blood donors, indicating an increased risk of HBV transmission through blood transfusions. Cases of OBI reactivation have been reported following chemotherapy. Genotype D is the predominant, followed by genotypes A and E.

This review highlights the prevalence of OBI in Africa, which varies across countries and population groups. The study also demonstrates that genotype D is the most prevalent.