Three previously undescribed alkaloids sophormodines A-C (1-3), along with three known analogues (4-6), were isolated and fully elucidated from the seeds of the Tibetan medicine plant Sophora moorcroftiana. Compounds 1 and 2 possess unprecedented 6/5/6/6 and 5/6/6/6 ring systems, respectively, while 3 is a C15N2-alkaloid featuring a unique 5/6/6/6-tetracyclic carbon skeleton with an unusual pyrrole-2-carboxaldehyde unit. These previously undescribed structures were elucidated by means of spectroscopic data analysis (including NMR and MS), and the absolute configurations were determined using single-crystal X-ray diffraction and ECD data. Moreover, a biosynthetic pathway for the formation of 1-3 is also proposed. In addition, the isolated alkaloids were evaluated for their antiviral activity against hepatitis B virus (HBV). Overall, this study provides insights into the potential therapeutic uses of the compounds found in the seeds of S. moorcroftiana, particularly in the treatment of HBV infections.

Hepatitis B and C infections are an underdiagnosed global health problem. Measurement of HBV DNA or HCV RNA levels using nucleic acid-based molecular diagnostic assays has been established as the standard of care for assessing diagnosis, guiding the treatment decision, and evaluating responses to antiviral therapy. In the present study, we examined the performance of the cobas 5800 System for HBV DNA and HCV RNA quantification in a large series of patients chronically infected. Specificity of the cobas HBV and HCV Tests on the 5800 System was high (99.1 % and 100 %, respectively). Linearity using the AcroMetrix panels was excellent. Repeatability and intermediate precision coefficients of variation were within 5 %. Of the 334 clinical specimens tested in parallel on the cobas 5800 and cobas 4800 Systems for HBV and the m2000 RealTime or Alinity m Systems for HCV, only 12 (3.6 %) yielded discrepant results that were at or near the limit of quantification of the cobas 5800 assays. The correlation between viral load results was extremely high, and only weak bias were observed across the entire range of concentrations tested without clinical impact in patients who are eligible for antiviral therapy. This comparison study demonstrated equivalent performance of the new cobas 5800 System compared with other molecular platforms widely used in clinical practice for HBV DNA and HCV RNA quantification. The cobas 5800 System can be confidently used in clinical practice. A few clinical specimens with low viral loads may be missed. Further studies are warranted to confirm or refute this finding.

To investigate the predictive value of serum hepatitis B virus (HBV) RNA on HBeAg seroconversion in treated chronic hepatitis B (CHB) patients.

Sixty-four HBeAg-positive CHB patients were selected. They were divided into HBeAg seroconversion group including 11 cases and HBeAg non-seroconversion group including 53 cases. HBV RNA levels and other laboratory results were measured at baseline and week 12, 24, 48, 72 during treatment in both groups. The predictive value of HBV RNA level for the seroconversion of HBeAg in patients treated for hepatitis B was analyzed.

Significant differences existed in serum HBV DNA and HBV RNA levels between the two groups at baseline while there was no significant difference in HBsAg. The correlation between HBV RNA and HBV DNA was significantly high ( r  = 0.707, P  < 0.05), while the correlation between HBV DNA and HBsAg ( r  = 0.474, P  < 0.05) or HBV RNA and HBsAg was poor ( r  = 0.372, P  < 0.05). Patients with younger age and higher HBV RNA levels at baseline and week 24 were less likely to have HBeAg seroconversion. HBV RNA was better than HBV DNA and HBsAg in predicting HBeAg seroconversion whether at baseline or week 12 and week 24. The area under the curve of HBV RNA level at 24th week was the highest, which was 0.942, and the cutoff value was 4.145 log 10 copies/ml.

HBV RNA level may be a suitable serum marker to predict whether HBeAg seroconversion can occur. CHB patients with serum HBV RNA level lower than 4.145 log 10 copies/ml at week 24 were more likely to achieve HBeAg seroconversion.

HBsAg and anti-HBs coexistence represents an unusual serological pattern in hepatitis B virus (HBV) infection. However, its natural course remains unclear. This study investigated the occurrence of this serological pattern in patients with HBV in acute and chronic phases and estimated the associated risks. Of the 215 adult patients diagnosed with acute-phase HBV, 19 (8.84 %) cases demonstrated HBsAg and anti-HBs coexistence. In the chronic phase, 54 new cases of HBsAg and anti-HBs coexistence were identified during a median follow-up of 14 months (interquartile range: 14-28) among 4593 HBsAg-positive patients. The average annual incidence of coexistence was 1.41 % ± 0.28 %. The cumulative risk of HBsAg and anti-HBs coexistence in chronic phase patients was higher in those aged ≥ 50 years (risk ratio [RR]: 1.79, 95 % confidence interval [CI]: 1.04-3.09, P = 0.035), with positive HBeAg (RR: 3.43, 95 % CI: 1.91-6.19, P < 0.001), baseline alanine transaminase abnormalities (RR: 3.62, 95 % CI: 1.93-6.79, P < 0.001), and higher HBV DNA levels (RR: 1.97, 95 % CI: 1.12-3.49, P = 0.017). The quasispecies heterogeneity of the "a" determinant mutation demonstrated no significant change during the occurrence of coexistence with HBsAg and anti-HBs in HBV infection. Therefore, HBsAg and anti-HBs coexistence may be the intermediate process in the natural history of HBV infection, unrelated to "a" determinant mutation but associated with the disease phase.

To identify risk factors associated with liver complications in patients with chronic hepatitis B infection in an unselected cohort of hepatitis B patients in southern Spain.

A prospective open-cohort study was conducted on 437 patients with uncomplicated chronic hepatitis B infection in two hospitals in Málaga, southern Spain. The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8±9.5 years; median: 11.4 years). The aim of this study was to evaluate the occurrence of the initial liver complication during follow-up, which is defined as the emergence of liver cancer or complications resulting from portal hypertension. Survival curves were obtained using a time-to-event method through Kaplan-Meier analysis. Multivariate Cox regression was conducted to estimate the hazard ratios of risk factors associated with complications after adjusting for multiple variables. The follow-up of the patients was carried out under conditions of usual clinical practice. Based on the weighted adjustment of these factors, we developed a Hepatitis B Complication Score (HBCS) from which it was possible to identify patients with low and high risk of complications during follow-up.

33 out of 437 patients (7.55%) experienced liver complications, 12 (36.3%) were secondary to portal hypertension, and 21 patients (63.7%) developed liver cancer. A Multivariate Cox regression identified the following independent risk factor: Age above 45 years: HR 7.10 (2.9-17.3); low platelet count: HR 4.88 (2.1-10.9); hepatitis C coinfection: HR 4.68 (2.0-10.9); Male gender: HR 4.64 (1.5-14.2); alkaline phosphatase above 147 UI/mL: HR 4.33 (2.0-8.9); and Child score above 5 points: HR 3.83 (1.7-8.4). The Risk of Complications Score (HBCS) was developed with a high predictive capacity AUROC 0.92 (0.87-0.97).

An HBCS score greater than 3.07 points identifies patients at high risk of developing complications and with an increased risk of liver and all-cause mortality.

The pathological characteristics of lymphocyte infiltration in the hepatic portal tracts of patients with primary biliary cholangitis (PBC) remain unclear. Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues associated with the exacerbation of autoimmune reactions. Here, we evaluate the role of TLSs in PBC and investigate their potential therapeutic value.

We recruited 75 patients with PBC and 53 control patients with liver biopsies who were followed more than 2 years. TLSs and their maturity were identified by the amount and spatial distribution of immune cells. Bulk RNA sequencing of liver was performed in PBC patients with different TLS maturity. The sphingosine-1-phosphate receptor (S1PRs) modulator FTY720 was administered to dnTGFβRII mice to assess the role of TLSs on cholangitis.

TLSs presented in 61.3% (46/75) of liver tissues from patients with PBC, including 26 patients with mature TLS (mTLS) and 20 patients with immature TLS (imTLS). The proportion of mTLS was higher in PBC compared with chronic hepatitis B and autoimmune hepatitis. PBC patients with mTLS exhibited the highest serum levels of biochemical indicators, immune globulin and proportions of liver cirrhosis. Gene sets for lymphocyte migration and chemokine signalling pathways were enriched in patients with PBC presenting with TLS. FTY720 inhibited TLS formation and relieved cholangitis and fibrosis in dnTGFβRII mice.

TLSs are characteristics of lymphocyte accumulation in the portal tracts of PBC, of which the maturity of TLSs correlates with the inflammation and fibrosis of PBC. Targeting TLSs formation is a potential treatment of PBC.

Aplastic anemia occurs with an incidence of 2-5: 1 million people worldwide. However, the frequency of newly diagnosed cases of bone marrow aplasia is greater, and some of these patients present to emergency departments initially. Description of Case: We present the case of a middle-aged man with pancytopenia. In this case, aplastic anemia associated with hepatitis B and syphilis was only the initial diagnosis. An indolent hematologic malignancy-hairy cell leukemia-was diagnosed as the real cause of the bone marrow failure in a clinic of hematology. Conclusions: This clinical case allows us to make a conclusion, albeit not definitively, about the contribution of hepatitis B and syphilis to the clinical manifestation of hairy cell leukemia. A detailed and consistent diagnostic plan is also required in patients presenting with pancytopenia. Failure to diagnose a hepatitis B infection in a patient with malignant hematologic disease would lead to fatal therapeutic errors.

Chronic Hepatitis B presents a significant health and socioeconomic burden. The risk of hepatocellular carcinoma remains elevated although treatments are available. Achieving an optimal treatment regimen necessitates a deep comprehension of the dynamic relationship between the virus and its host across disease states. This tutorial elucidates essential considerations for establishing a disease modeling platform to facilitate informed decision-making in hepatitis B treatment strategies. We review several published models of varying complexity and describe the context that motivated each model's structure and assumptions. Several of the models are made available in an interactive RShiny app to demonstrate the influence of model choice and sensitivity to the choice of parameter values.

Tenofovir disoproxil fumarate (TDF) is a third-generation nucleoside analogue commonly used as a first-line therapy for chronic hepatitis B virus (HBV) infection. However, it is associated with nephrotoxicity, which can occur through mechanisms such as mitochondrial deoxyribonucleic acid (DNA) depletion and damage to renal tubules. This nephrotoxic effect typically manifests as a mild increase in serum creatinine and a decrease in serum phosphate, usually within 4-12 months after starting treatment. Recent studies suggest that novel biomarkers, such as urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, may predict acute kidney injury (AKI) earlier and more accurately than traditional markers like serum creatinine. In line with this, we investigated NGAL and cystatin C levels in HBV patients receiving TDF therapy to assess their potential in monitoring kidney function.

The study included 350 cases in total. Each participant underwent a thorough assessment, including a detailed medical history, clinical examination, and routine blood tests, as outlined in the study's working proforma. Based on the above details, 226 cases fulfilling the inclusion criteria were enrolled for the second step of the study, where a 5 mL urine sample from each case was taken and sent to the pathology laboratory for estimation of cystatin C and NGAL by the ELISA method with the help of a kit.

The average age of the participants was 37.93 years, with 124 individuals falling within the 18-35-year age-group. After accounting for confounding factors, 87 cases were identified, predominantly young males, who exhibited elevated levels of both urinary NGAL and cystatin C.

In this cross-sectional study, after controlling for confounding factors, we observed that TDF treatment was linked to elevated levels of urinary NGAL and cystatin C in 87 (38.4%) of the cases. Notably, increased levels of these biomarkers were also found in the younger age-group (18-35 years). These findings suggest the need for further prospective studies with larger sample sizes to better understand the direct impact of TDF on kidney function in hepatitis B patients.

The prognostic impact of preoperative gamma-glutamyl transpeptidase to platelet ratio (GPR) levels in patients with solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) following radical resection has not been established.

To examine the clinical utility of GPR for prognosis prediction in solitary HBV-related HCC patients.

A total of 1167 solitary HBV-related HCC patients were retrospectively analyzed. GPR levels were compared with 908 non-HCC individuals. Overall survival (OS) and recurrence-free survival (RFS) were evaluated, and cox proportional hazard model analyses were performed to identify independent risk factors. Differences in characteristics were adjusted by propensity score matching (PSM). Subgroup and stratified survival analyses for HCC risks were performed, and a linear trend of the hazard ratio (HR) according to GPR levels was constructed.

GPR levels of patients with solitary HBV-related HCC were higher than those with hepatic hemangiomas, chronic hepatitis B and healthy control (adjusted P < 0.05). Variable bias was diminished after the PSM balance test. The low GPR group had improved OS (P < 0.001) and RFS (P < 0.001) in the PSM analysis and when combined with other variables. Multivariate cox analyses suggested that low GPR levels were associated with a better OS (HR = 0.5, 95%CI: 0.36-0.7, P < 0.001) and RFS (HR = 0.57, 95%CI: 0.44-0.73, P < 0.001). This same trend was confirmed in subgroup analyses. Prognostic nomograms were constructed and the calibration curves showed that GPR had good survival prediction. Moreover, stratified survival analyses found that GPR > 0.6 was associated with a worse OS and higher recurrence rate (P for trend < 0.001).

Preoperative GPR can serve as a noninvasive indicator to predict the prognosis of patients with solitary HBV-related HCC.

Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis.

Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011-14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma.

943 HBsAg-positive people with chronic hepatitis B were recruited to the PROLIFICA study. Of these 943, 58 (6%) fulfilled 2012 EASL treatment eligibility criteria at baseline, 35 (4%) were ineligible for treatment but received antiviral therapy, and 44 (5%) were immediately lost to follow-up. Thus, 806 (85%) participants were analysed for the primary outcome (486 [60%] were male and 320 [40%] were female). After a median follow-up of 6·11 years (IQR 5·34-6·80), 708 (88%) participants were confirmed to be alive at last surveillance, 71 (9%) were lost to follow-up and were censored, and 27 (3%) died, giving an all-cause mortality rate of 582 per 100 000 person-years (95% CI 399-849). Of the 27 people who died, five (19%) had liver-related deaths. Of 708 participants confirmed to be alive, 544 (77%) attended follow-up and were assessed for the secondary outcome. Disease progression occurred in 36 (7%) participants: five (1%) became newly eligible for antiviral therapy per EASL 2017 criteria without liver fibrosis progression; 18 (3%) had liver fibrosis progression alone; 13 (2%) had liver fibrosis progression and newly fulfilled the treatment criteria; and none had hepatic decompensation or developed hepatocellular carcinoma. In multivariable analysis adjusted for sex and age, only a baseline HBV DNA of 20 000 IU/mL or more, compared with the baseline HBV DNA of 2000 IU/mL or lower as the reference, was significantly associated with liver disease progression (odds ratio 5·39, 95% CI 1·37-21·23).

Among people with chronic hepatitis B who were ineligible for antiviral therapy in The Gambia, all-cause mortality and liver disease progression were low. The clinical benefit of expanding antiviral therapy in this subgroup of patients remains uncertain.

European Commission, Medical Research Council UK Research and Innovation, and Gilead Sciences.

Chronic hepatitis B virus (HBV) infection is a serious human health threat given its high morbidity and mortality. Timely and effective antiviral treatment can postpone liver disease progression and reduce the occurrence of HBV-related end-stage liver disease. At present, the antiviral treatment criteria are mainly based on alanine transaminase (ALT) levels, HBV DNA levels and HBV e antigen levels according to the American Association for the Study of Liver Diseases treatment guidelines. However, some chronic hepatitis B (CHB) patients not meeting the above criteria still experience liver disease progression without antiviral treatment. It is urgent to identify a more comprehensive tool to screen out more antiviral treatment candidates as soon as possible.

Considering the vital role of the immune response in the development of HBV infection and CHB cure, we collected data from 335 treatment-naïve CHB patients and comprehensively analysed their clinical and immune traits (including innate and adaptive responses). The immune parameters were obtained by flow cytometry. Finally, we established a model that can better distinguished CHB patients who need treatment through machine learning and LASSO regression of serological and immune parameters.

Through a series of analyses, we selected four important clinical parameters (ALT, HBV DNA, the Fibroscan value, and the A/G ratio) and four immune indicators (NKbright + NKp44+, NKbright + NKG2A+, NKT+GranzymeB+, and CD3 + CD107a + ) from more than 200 variables and then successfully established a mathematical model with high sensitivity and specificity to better screen out antiviral treatment candidates from all CHB patients.

Our results developed a refined model to better screen out antiviral treatment candidates from all CHB patients by combining common clinical parameters and important immune indicators, including innate and adaptive immunity. These findings provide more information for improving treatment guidelines and have potential implications for the timing of antiviral therapy to achieve better virus control and reduce the occurrence of end-stage liver disease.

Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.

Quantitative susceptibility mapping (QSM) is a post-processing technique that creates brain susceptibility maps reflecting metal burden through tissue magnetic susceptibility. We assessed topographic differences in magnetic susceptibility between participants with and without Wilson's disease (WD), correlating these findings with clinical severity, brain volume, and biofluid copper and iron indices.

A total of 43 patients with WD and 20 unaffected controls, were recruited. QSM images were derived from a 3T MRI scanner. Clinical severity was defined using the minimal Unified Wilson's Disease Rating Scale (M-UWDRS) and Montreal Cognitive Assessment scoring. Differences in magnetic susceptibilities between groups were evaluated using general linear regression models, adjusting for age and sex. Correlations between the susceptibilities and clinical scores were analyzed using Spearman's method.

In age- and sex-adjusted analyses, magnetic susceptibility values were increased in WD patients compared with controls, including caudate nucleus, putamen, globus pallidus, and substantia nigra (all p < 0.01). Putaminal susceptibility was greater with an initial neuropsychiatric presentation (n = 25) than with initial hepatic dysfunction (n = 18; p = 0.04). Susceptibility changes correlated negatively with regional brain volume in almost all topographic regions. Serum ferritin, but not serum copper or ceruloplasmin, correlated positively with magnetic susceptibility level in the caudate nucleus (p = 0.04), putamen (p = 0.04) and the hippocampus (p = 0.03). The dominance of magnetic susceptibility in cortical over subcortical regions correlated with M-UWDRS scores (p < 0.01).

The magnetic susceptibility changes could serve as a surrogate marker for patients with WD.

BACKGROUND: Hepatitis B virus (HBV) is one of the most widespread viruses worldwide and a major cause of hepatitis, cirrhosis, and hepatocellular carcinoma. Previous studies have revealed the impacts of HBV infection on fertility. An increasing number of infertile couples with chronic hepatitis B (CHB) virus infection choose assisted reproductive technology (ART) to meet their fertility needs. Despite the high prevalence of HBV, the effects of HBV infection on assisted reproduction treatment remain limited and contradictory. OBJECTIVE: The aim of this study was to provide a comprehensive overview of the effect of HBV infection on fertility and discuss its effects on pregnancy outcomes, vertical transmission, pregnancy complications, and viral activity during ART treatment. METHODS: We conducted a literature search in PubMed for studies on HBV infection and ART published from 1996 to 2022. RESULTS: HBV infection negatively affected fertility in both males and females. Existing research shows that HBV infection may increase the risk of pregnancy complications in couples undergoing assisted reproduction treatment. The impact of HBV infection on the pregnancy outcomes of ART is still controversial. Current evidence does not support that ART increases the risk of vertical transmission of HBV, while relevant studies are limited. With the development of ART, the risk of HBV reactivation (HBVr) is increasing, especially due to the wide application of immunosuppressive therapy. CONCLUSIONS: Regular HBV infection screening and HBVr risk stratification and management are essential to prevent HBVr during ART. The determination of optimal strategy and timing of prophylactic anti-HBV therapy during ART still needs further investigation.

To label entecavir (ETV) with radioiodine and evaluate its effect on inhibiting hepatitis B virus (HBV) secretion and replication in vitro as well as its biodistribution in BALB/c mice.

125I-ETV was synthesized via binding a vinyl tributyltin group to ETV and producing electrophilic iodination of the group. Its chemical properties were assessed using traditional methods. Upon intravenous injection of 125I-ETV into BALB/c mice, the radioactivity of the critical organs was detected. In vitro, the anti-HBV activity of 125I-ETV was investigated using HepG2.2.15 cell culture model. Confocal microscopy was used to analyze the cell apoptosis. Culture supernatant samples were used for measuring HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) by enzyme-linked immunosorbent assay. Intracellular HBV pregenomic RNA (pgRNA), DNA, and covalently closed circular DNA (cccDNA) were measured by real-time fluorescence quantitative PCR.

The radiochemical purity of 125I-ETV was greater than 95% after incubation in freshly serum within 48 h. The three highest radioactivities were in the stomach, intestine, and liver after intravenous injection at 0.5 h, 2 h, and 24 h. The confocal fluorescence imaging showed that 125I-ETV did not induce cell apoptosis after treatment for 96 h. 125I-ETV decreases HBsAg and HBeAg secretions as well as intracellular HBV pgRNA, DNA, and cccDNA copies in a dose-dependent manner. Moreover, the anti-HBV activity of 125I-ETV is greater than that of ETV.

The study outcome establishes 125I-ETV as a candidate for anti-HBV. However, it is still in need of further endorsement and optimization by animal model studies before using 125I-ETV to treat chronic HBV disease.

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.

Background: Liver cirrhosis presents significant challenges in the pediatric population due to a complex interplay of etiological factors, clinical manifestations, and limited therapeutic options. The leading contributors to cirrhosis among pediatric patients are chronic cholestasis, metabolic disorders present from birth, and long-term hepatitis. Materials and method: Our narrative review aimed to synthesize literature data on the etiology, clinical picture, diagnostic techniques, optimal management of complications, and timely transplantation. Results: The epidemiology of liver cirrhosis in pediatric patients is evolving. The introduction of a universal vaccination and effective long-term viral suppression in viral hepatitis have significantly decreased complications rates. Liver transplantation programs worldwide have also improved the management of cirrhosis complications. Conclusions: Early diagnosis, comprehensive management strategies, and advancements in treatment modalities are critical for improving outcomes. Understanding these differences is crucial in providing age-appropriate care and support for those affected by cirrhosis.

We aimed to evaluate the risk of hepatitis B virus reactivation in rheumatic patients using anti-tumor necrosis factor-alpha drugs and the awareness of physicians about hepatitis B virus reactivation.

Demographic characteristics, pre- and post-treatment hepatitis markers, and laboratory parameters of patients receiving anti-tumor necrosis factor-alpha therapy in our rheumatology clinic were retrospectively examined.

A total of 448 patients, 240 (53.6%) female and 208 (46.4%) male, were evaluated. Their mean age was 48.02±14.64 years. While HBsAg was examined in 443 (98.9%) patients before treatment, 7 (1.6%) patients were found to be HBsAg positive. While anti-HBc IgG was examined in 405 (90.4%) patients, it was positive in 69 (17%) patients. HBs Ag (total 446-99.6%) test was performed in three patients who were not tested for HBsAg before the treatment, and anti-HBc total (431-96.2% total) test was performed in 26 patients who were not tested for anti-HBc total. All HBsAg positive patients and 17 (24.6%) of those with previous hepatitis B received antiviral treatment. While the median follow-up period of the patients was 24 (6-60) months, no patient developed hepatitis B virus reactivation.

The screening rates and awareness of physicians providing anti-tumor necrosis factor-alpha therapy for hepatitis B virus infection were found to be higher compared to similar studies. Hepatitis B virus reactivation did not develop in any patient. Since the risk of hepatitis B virus reactivation is low, especially in patients with previous hepatitis B, it would be more appropriate to follow up the patients without giving antiviral prophylaxis.

Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium.

This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses.

We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001).

Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Chronic viral hepatitis B (CHB)-infected patients occasionally develop cirrhosis despite having persistent viral suppression with antiviral therapy. We aimed to identify risk factors for developing cirrhosis in hepatitis B virus (HBV)-suppressed patients.

We conducted a case-control study involving 120 noncirrhotic CHB-infected patients achieving viral suppression with antiviral treatment, with 40 cases developing cirrhosis and 80 age-, sex-, and Fibrosis-4 (FIB-4)-matched controls. Clinical and laboratory data at viral suppression, including body mass index (BMI), comorbidities, pretreatment HBV viral load, HBe antigen status, hepatitis C virus (HCV) and HIV coinfections, liver chemistries, and AST to Platelets Ratio Index (APRI) values, were retrospectively abstracted. Risk factors for cirrhosis post-HBV suppression were identified using Cox proportional hazard analysis.

Case and control groups had similar ages (51.4 ± 9.9 vs. 51.4 ± 10.2 years), proportions of males (80% vs. 80%), and FIB-4 values (1.32 vs. 1.31). The cirrhosis group showed significantly higher BMI (25.1 vs. 22.7, P = 0.01) and more diabetes prevalence (50.0% vs. 26.3%, P = 0.01), while other comorbidities and laboratory parameters were comparable (P > 0.05). By univariate analysis, BMI >23 kg/m2, diabetes, and APRI >0.7 were significantly associated with cirrhosis, with hazard ratios (HRs) (95%CI) of 2.99 (1.46-6.13), 2.31 (1.23-4.36), and 2.71 (1.05-6.99), P = 0.003, 0.010, and 0.039, respectively. In multivariate analyses adjusted for APRI, BMI>23 kg/m2 remained significantly associated with cirrhosis (aHR: 2.76, P = 0.006), while diabetes showed borderline significance (aHR: 1.99, P = 0.072).

In HBV-infected patients achieving viral suppression with therapy, a BMI >23 kg/m2 increases the risk of cirrhosis. Therefore, a comprehensive approach addressing metabolic factors is imperative for preventing disease progression in HBV-infected patients.

As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.

After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase.

All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed.

The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF.

The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Early assessment and accurate staging of liver fibrosis may be of great help for clinical diagnosis and treatment in patients with chronic hepatitis B (CHB). We aimed to identify serum markers and construct a machine learning (ML) model to reliably predict the stage of fibrosis in CHB patients. The clinical data of 618 CHB patients between February 2017 and September 2021 from Zhejiang Provincial People's Hospital were retrospectively analyzed, and these data as a training cohort to build the model. Six ML models were constructed based on logistic regression, support vector machine, Bayes, K-nearest neighbor, decision tree (DT) and random forest by using the maximum relevance minimum redundancy (mRMR) and gradient boosting decision tree (GBDT) dimensionality reduction selected features on the training cohort. Then, the resampling method was used to select the optimal ML model. In addition, a total of 571 patients from another hospital were used as an external validation cohort to verify the performance of the model. The DT model constructed based on five serological biomarkers included HBV-DNA, platelet, thrombin time, international normalized ratio and albumin, with the area under curve (AUC) values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the training cohort were 0.898, 0.891, 0.907 and 0.944, respectively. The AUC values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the external validation cohort were 0.906, 0.876, 0.931 and 0.933, respectively. The simulated risk classification based on the cutoff value showed that the classification performance of the DT model in distinguishing hepatic fibrosis stages can be accurately matched with pathological diagnosis results. ML model of five serum markers allows for accurate diagnosis of hepatic fibrosis stages, and beneficial for the clinical monitoring and treatment of CHB patients.

(1) Background: HBV-DNA is an essential clinical indicator of primary hepatocellular carcinoma (HCC) prognosis. Our study aimed to investigate the prognostic implication of a low load of HBV-DNA in HCC patients who underwent local treatment. Additionally, we developed and validated a nomogram to predict the recurrence of patients with low (20-100 IU/mL) viral loads (L-VL). (2) Methods: A total of 475 HBV-HCC patients were enrolled, including 403 L-VL patients and 72 patients with very low (<20 IU/mL) viral loads (VL-VL). L-VL HCC patients were randomly divided into a training set (N = 282) and a validation set (N = 121) at a ratio of 7:3. Utilizing the Lasso-Cox regression analysis, we identified independent risk factors for constructing a nomogram. (3) Results: L-VL patients had significantly shorter RFS than VL-VL patients (38.2 m vs. 23.4 m, p = 0.024). The content of the nomogram included gender, BCLC stage, Glob, and MLR. The C-index (0.682 vs. 0.609); 1-, 3-, and 5-year AUCs (0.729, 0.784, and 0.783, vs. 0.631, 0.634, the 0.665); calibration curves; and decision curve analysis (DCA) curves of the training and validation cohorts proved the excellent predictive performance of the nomogram. There was a statistically significant difference in RFS between the low-, immediate-, and high-risk groups both in the training and validation cohorts (p < 0.001); (4) Conclusions: Patients with L-VL had a worse prognosis. The nomogram developed and validated in this study has the advantage of predicting patients with L-VL.

Clinical management of patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) relies on the viral load (VL). The Cobas 5800 system (Roche Diagnostics) can determine VLs in 200 and 500 μL samples, but the performance of each protocol has not been compared. We evaluated the performance of both protocols for the HBV and HCV tests.

Precision and linearity were verified using commercial panels. Probit analyses were used to determine limits of detection (LoDs). The results obtained with 336 samples were compared using the 200 and 500 μL protocols. Data from 6,737 retrospective HBV and 768 HCV samples were compared to estimate the effects of the different LoDs on the diagnostic results of the protocols. Correlations between protocols were tested with Spearman's rank correlation coefficients (rho).

The precision and linearity of both protocols were verified. The LoDs for the 200 and 500 μL protocols were 6.5 and 2.7 IU/mL for HBV and 29.7 and 8.2 IU/mL for HCV, respectively. The agreement between the protocols ranged from 0.8 to 1.0. The results obtained with the HBV and HCV tests showed a strong correlation (rho=0.994). Only 0.4% of HBV and 0.4% of HCV test results were affected by the LoDs of the 200 μL protocol.

The Cobas 5800 200 and 500 μL protocols for the HBV DNA and HCV RNA tests demonstrated excellent performance. These findings establish the 200 μL protocol as a new option for low-volume samples, especially for pediatric and difficult-to-bleed patients.

To analyze the evolution of glomerular filtration rate (GFR) and the presence of renal tubular dysfunction during the treatment of chronic hepatitis B virus (HBV) infection with tenofovir disoproxil fumarate (TDF) and to determine the risk factors involved.

Retrospective cohort observational study of adults with chronic hepatitis B. Exclusion: hepatitis C virus-HBV coinfection, diabetes, baseline GFR less than 60 ml/min. Measurements of serum and urinary creatinine and phosphate; urinary albumin, retinol-binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) were performed. Univariate and multivariate analyses tracked factors associated with worsening GFR.

A total of 120 individuals were included: 35% NAÏVE (G1); 49.2% HBV using TDF (G2); 15.8% HBV-HIV using TDF (G3); 63.3% men; 60.8% white; 30% hypertensive. Average age was 50.5 years (SD ± 12.9 years). Reactive HBeAg predominated in G3 ( P  < 0.001) and cirrhosis in G2 ( P  < 0.036). NGAL was elevated in 5.3% of cases (G1 = 3.2%; G2 = 8.7%; G3 = 0%; P  = 0.582), RBP in 6.7% (G1, G3 = 0%; G2 = 13.6%; P  = 0.012), urinary phosphate/creatinine ratio in 16.2% (G1 = 15.2%; G2 = 14.5%; G3 = 23.5%; P  = 0.842) and urinary albumin/creatinine ratio in 12.9% (G1 = 12.2%; G2 = 10.7%; G3 = 21.1%; P  = 0.494). Worsening of renal function occurred in 22.5% of the population (G1 = 11.9%; G2 = 28.8%; G3 = 26.3%; P  = 0.122), independently associated only with systemic arterial hypertension [adjusted odds ratio (AOR) = 4.14; P  = 0.008], but not to TDF (AOR = 2.66; P  = 0.110) or male sex (AOR = 2.39; P  = 0.135). However, the concomitance of these variables generated a high estimated risk for this outcome (51%).

Renal tubular dysfunction was uncommon according to NGAL, RBP or urinary phosphate/creatinine ratio. TDF was not an independent factor for worsening renal function, significantly associated only with systemic arterial hypertension. However, in hypertensive men, the use of TDF should be monitored.

Hepatitis Delta virus (HDV) infection is a major cause of liver-related morbidity and mortality in patients infected with HBV, with a global HDV prevalence uncertain. In France, 2 to 5 % of HBs antigen (HBsAg) carriers present anti-HDV antibodies (anti-HDV). The EASL recommends testing for anti-HDV in all HBsAg-positive patients. Since January 2022, we have systematically carried out anti-HDV serology when a positive HBsAg is discovered (new HBsAg carriers).

We evaluated the benefit of anti-HDV reflex testing after one year of practice by comparing anti-HDV and HBsAg serology data over the last six years, among the new HBsAg carriers and all the HBsAg carriers.

HBsAg and anti-HDV were screened using the Abbott Architect HBsAg quanti kit and the DIA.PRO HDVAb kit. Serological, demographic, virological, and clinical data were analyzed.

Implementing anti-HDV reflex testing leads to more than a 2-fold increase in diagnoses of HDV infection among all HBsAg carriers. If the anti-HDV positive rate remains stable among the new HBsAg carriers, a significant increase in the anti-HDV positive rate from 6.8 % to 10.3 % was observed considering all HBsAg carriers. Interestingly, the discovery of anti-HDV carriage increased from 3.9 % to 6.5 % in 2022, allowing earlier identification of HBV-HDV-infected patients and a fast referral to hepatologists for adequate clinical management and, in some cases, the introduction of bulevirtide-based therapy.

Our preliminary results at one year seem promising and evaluating the cost-effectiveness of reflex tests in real life with feedback would be helpful.

The objective of this review is to determine the costs and benefits of non-invasive liver tests vs liver biopsy in patients with chronic liver diseases.

Hepatic diseases can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the past, liver biopsy was the only option for diagnosing fibrosis degree. Liver biopsy is an invasive procedure that depends on the sample size to be able to deliver an accurate diagnosis. In recent years, non-invasive liver tests have been increasingly used to estimate liver fibrosis degree; however, there is a lack of economic assessments of technology implementation outcomes.

This review will include partial (cost studies) and complete economic evaluation studies on hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic fatty liver disease that compare non-invasive liver tests with liver biopsies. Studies published in English, French, Spanish, German, Italian, or Portuguese will be included. No date limits will be applied to the search.

This review will identify published and unpublished studies. Published studies will be identified using MEDLINE (PubMed), Cochrane Library (CENTRAL), Embase, Web of Science, Scopus, and LILACS. Sources of unpublished studies and gray literature will include sources from health technology assessment agencies, clinical practice guidelines, regulatory approvals, advisories and warnings, and clinical trial registries, as well as Google Scholar. Two independent reviewers will screen and assess studies, and extract and critically appraise the data. Data extracted from the included studies will be analyzed and summarized to address the review objective using narrative text, and the JBI dominance ranking matrix.

PROSPERO CRD42023404278.

Hepatitis B virus (HBV) is a frequent cause of chronic hepatitis worldwide, with an estimated 5.6 million children under 5 years being infected. In Romania, there are no available epidemiology reports on large cohorts in children. We aimed to assess the profile of pediatric chronic HBV infection in southern Romania. We conducted an observational retrospective study on 506 HBV-infected children. Based on alaninaminotransferase (ALT), HBV serology and viremia, we identified four states of the disease. We correlated age, gender, household HBV infection, coinfection with other viruses and laboratory parameters. Most patients were in a positive HBV envelope antigen (HBeAg) immune-active state (65.4%). Age at diagnosis was significantly lower for those with household infection (p < 0.05). ALT values were not significantly different between positive or negative HBeAg patients in the immune-active state (p = 0.780). ALT values were higher in patients with hepatitis D virus (HDV)-associated infection (p < 0.001). Children with a household HBV infection had a high viraemia more frequently when compared to those with no infected relative (79.3% vs. 67.4%) (p < 0.001), but the ALT values were not significantly different (p = 0.21). Most of the patients are in an immune-active state (high ALT, high viremia). The percentages of HBV- and HDV-associated infections are high, but lower than the reported prevalence in Romania in the general population.

Hepatitis B and C are common causes of end-stage liver disease and etiologies of liver transplantation. It is important to prevent recurrence in cases of hepatitis B. Nucleos(t)ide analogs are the mainstay of HBV treatment before (in patients with decompensated cirrhosis) and after liver transplantation. After the introduction of direct-acting antivirals, the treatment of HCV has become considerably easy. In patients with advanced HCV-related cirrhosis, it is better to do transplantation first and treat them after liver transplantation. The sustained virological response rates have improved from 8 to 50% in the interferon era to 90% in the direct-acting antivirals era. In the current review, we discuss the treatment of HBV and HCV before and after liver transplantation.

Psoriatic arthritis (PsA) is a complex inflammatory disease characterized by musculoskeletal and non-musculoskeletal manifestations. It is a distinct disease entity at the interface between rheumatology and dermatology, making it challenging to manage. The diverse clinical presentation and severity of PsA require a multidisciplinary approach for optimal care. Early diagnosis and management are necessary to improving quality of life for patients. In Saudi Arabia, there is currently no unified national consensus on the best practices for managing PsA. This lack of consensus leads to debate and uncertainty in the treatment of the disease, resulting in over or under prescribing of biological agents. To address this issue, a multidisciplinary work group was formed by the Saudi Ministry of Health. This group, consisting of dermatologists, rheumatologists, and pharmacists, aimed to develop evidence-based consensus recommendations for he use and monitoring of biological therapy in PsA management. The work group conducted five consensus workshops between December 2021 to March 2022. Using the nominal group technique, they discussed various aspects of PsA management, including eligibility criteria for biological treatment, monitoring of disease activity, treatment goals, screening, precautions, and management of PsA with biologic therapies. The group also considered special considerations for patients with comorbidities, pregnant and lactating women, as well as pediatric and adolescent populations. The resulting consensus document provides recommendations that are applicable to the Saudi setting, taking into account international guidelines and the specific needs of PsA patients in the country. The consensus document will be regularly updated to incorporate new data and therapeutic agents as they become available. Key Points • In Saudi Arabia, there is a lack of unified national consensus on the optimal management of PsA, therefore, this article aims to provide up-to-date evidence-based consensus recommendations for the optimal use and monitoring of biologic therapy in the management of PsA in Saudi Arabia. • The consensus development process was undertaken by a multidisciplinary work group of 13 experts, including two dermatologists, six rheumatologists, and five pharmacists. • There is more than one disease activity tool used in PsA disease, depending on the disease domain - peripheral arthritis Disease Activity Index in Psoriatic Arthritis (DAPSA) or Minimal Disease Activity (MDA), axial PsA Ankylosing Spondylitis Disease Activity Score (ASDAS), and dactylitis and enthesitis MDA. • The main goal of therapy in all patients with PsA is to achieve the target of remission, or alternatively, low disease activity in all disease domains and improve quality of life (QoL).