Hepatitis B Research Articles

Plasma Interleukin-35 Levels Predict the Prognosis in Patients with HBV-Related Acute-on-Chronic Liver Failure

This study aimed to investigate the impact of IL-35 on the prognosis of patients with HBV-ACLF. We recruited 69 patients with HBV-ACLF, 20 patients with chronic hepatitis B (CHB), 17 patients with liver cirrhosis (LC), and 20 healthy controls (HCs) from a regional infectious disease treatment center in China. Plasma levels of IL-35 at baseline were detected using ELISA. Plasma IL-35 levels in the HBV-ACLF group were the highest among all four groups. Furthermore, survivors exhibited significantly higher IL-35 levels than non-survivors (p < 0.001). IL-35 levels correlated with MELD (r = −0.678, p < 0.001), COSSH-ACLF IIs (r = −0.581, p < 0.001), alpha-fetoprotein (AFP) (r = 0.433, p < 0.001), creatinine (Cr) (r =−0.396, p = 0.001), and lactate (r =−0.38, p =0.001). The combination of plasma IL-35 and MELD score had the highest mortality prediction efficiency, with an area under the curve (AUC) of 0.895 (95% CI: 0.812–0.978, p < 0.001), a sensitivity of 80.6%, and a specificity of 93.9%. Additionally, the Kaplan–Meier analysis revealed that lower levels of IL-35 (≤191.5pg/mL) were associated with poorer survival rates in HBV-ACLF patients (p < 0.001). Our results demonstrated that IL-35 could be an effective predictive marker for the prognosis of HBV-ACLF and improve the predictive performance when combined with the MELD score.

Natural History and Prognosis of Chronic Hepatitis B Patients in the Indeterminate Phase.

In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes. We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow-up) and those who received treatment, following standard AASLD 2018 guidance. The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients (n = 104). For HBeAg-negative indeterminate phase patients (n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg-positive indeterminate phase patients (n = 140), it was 40.4%, 52.0%, and 55.0% (p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan-Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients (n = 294) is higher than that among treated patients (n = 76), (p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031-0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044-0.496, p = 0.002). The indeterminate phase patients had a high-risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.

Virological and Immunological Characteristics of HBeAg-Positive Chronic Hepatitis B Patients With Low HBsAg Levels.

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. Invitro 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. Invitro 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.

A Machine Learning Model to Predict De Novo Hepatocellular Carcinoma Beyond Year 5 of Antiviral Therapy in Patients With Chronic Hepatitis B.

This study aims to develop and validate a machine learning (ML) model predicting hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients after the first 5 years of entecavir (ETV) or tenofovir (TFV) therapy. CHB patients treated with ETV/TFV for > 5 years and not diagnosed with HCC during the first 5 years of therapy were selected from two hospitals. We used 36 variables, including baseline characteristics (age, sex, cirrhosis, and type of antiviral agent) and laboratory values (at baseline, at 5 years, and changes between 5 years) for model development. Five machine learning algorithms were applied to the training dataset and internally validated using a test dataset. External validation was performed. In years 5-15, a total of 279/5908 (4.7%) and 25/562 (4.5%) patients developed HCC in the derivation and external validation cohorts, respectively. In the training dataset (n = 4726), logistic regression showed the highest area under the receiver operating curve (AUC) of 0.803 and a balanced accuracy of 0.735, outperforming other ML algorithms. An ensemble model combining logistic regression and random forest performed best (AUC, 0.811 and balanced accuracy, 0.754). The results from the test dataset (n = 1182) verified the good performance of the ensemble model (AUC, 0.784 and balanced accuracy, 0.712). External validation confirmed the predictive accuracy of our ensemble model (AUC, 0.862 and balanced accuracy, 0.771). A web-based calculator was developed (http://ai-wm.khu.ac.kr/HCC/). The proposed ML model excellently predicted HCC risk beyond year 5 of ETV/TFV therapy and, therefore, could facilitate individualised HCC surveillance based on risk stratification.

All-cause and cause-specific mortality in patients with chronic hepatitis B and concurrent steatotic liver disease.

Steatotic liver disease (SLD) is prevalent among patients with chronic hepatitis B (CHB). However, the effects of metabolic dysfunction-associated SLD (MASLD) on the long-term survival of such patients remain unknown. Accordingly, this study investigated the mortality risks in patients with CHB and concurrent SLD. Consecutive patients with CHB and concurrent SLD were retrospectively recruited at National Taiwan University Hospital. MASLD was defined by the presence of cardiometabolic risk factors (CMRF). The cumulative incidences of all-cause and cause-specific mortality were compared. A total of 8,718 patients with CHB and concurrent SLD were included from 2006 to 2021. At baseline, the MASLD group (n=6,562) was older and had a lower proportion of hepatitis B e antigen positivity and lower hepatitis B virus DNA levels compared with the non-MASLD group (n=2,156). After a median follow-up period of 9.1 years, the MASLD group exhibited a higher risk of all-cause mortality compared with the non-MASLD group (adjusted hazard ratio [aHR]: 1.79, 95% confidence interval [CI]: 1.24-2.58, p=0.002). Furthermore, cumulative CMRF dose-dependently elevated the risks of all-cause, liver-related, and cardiovascular mortality (all p<0.05). During the follow-up period, new-onset diabetes mellitus, hypertension, and significant weight gain further increased the risks of all-cause and liver-related mortality (all p<0.05). However, patients with SLD had a lower mortality risk than non-SLD patients after propensity score matching (HR: 0.62, 95% CI: 0.53 - 0.74, p<0.001). Among patients with CHB and SLD, metabolic burden dose-dependently increases the all-cause, liver-related, and cardiovascular mortality risks. Patients with SLD have a lower mortality risk than those without SLD. Identifying these metabolic dysfunctions is crucial for stratifying the level of risk in daily care. Concurrent steatotic liver disease (SLD) is prevalent among patients with chronic hepatitis B (CHB); however, the effects of the associated cardiometabolic risk factors on all-cause and cause-specific mortality remain unknown. This study demonstrated that cumulative metabolic burden dose-dependently increased the risks of all-cause, liver-related, and cardiovascular mortality in patients with CHB and SLD. Moreover, new-onset diabetes mellitus, hypertension, and weight gain during the follow-up period further exacerbated these risks. However, patients with SLD had a lower risk of mortality than those without SLD. Thus, routine screening and monitoring of metabolic dysfunctions constitute a key element of daily care for patients with CHB.

Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies

In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.

Investigational RNA Interference Agents for Hepatitis B.

Functional cure of chronic hepatitis B (CHB)-defined as sustained seroclearance of hepatitis B surface antigen (HBsAg) with unquantifiable hepatitis B virus (HBV) DNA at 24 weeks off treatment, is an optimal treatment endpoint. Nonetheless, it cannot be consistently attained by current treatment modalities. RNA interference (RNAi) is a novel treatment strategy using small-interfering RNA (siRNA) or antisense oligonucleotide (ASO) to target HBV post-transcriptional RNA, in turn suppressing viral protein production and replication. Hence, RNAi has indirect effects in promoting host immune reconstitution against HBV. Multiple RNAi therapeutics have entered phase II/III clinical trials, demonstrating potent, dose-dependent, and sustainable effects in suppressing HBsAg. Incidences of HBsAg seroclearance, particularly with the use of ASO, have also been documented. The combination of RNAi with other antivirals/immunomodulators (e.g. pegylated interferon), have shown promising results in potentiating RNAi effects and enhancing treatment durability. Further research will be required to establish predictors of response, optimal treatment protocols, and long-term outcomes in patients on RNAi. RNAi therapeutics have shown promising results and will likely be the keystone of future HBV treatment.

Design of multi-epitope-based therapeutic vaccine candidates from HBc and HBx proteins of hepatitis B virus using reverse vaccinology and immunoinformatics approaches.

The major problem in cases of chronic hepatitis B (CHB) is the failure of the patient's immune response to eliminate the covalently closed circular DNA (cccDNA) minichromosome of hepatitis B virus (HBV). Epigenetic regulation involving the HBV core protein (HBc) and HBV X protein (HBx) influences the transcription and stability of the cccDNA minichromosome. The HBc and/or HBx-based therapeutic vaccines that have been developed cannot accommodate differences between HBV genotypes. This research aims to design a therapeutic vaccine candidate based on the multi-epitope of HBc and HBx using reverse vaccinology (RV) and immunoinformatics approach. HBc and HBx sequences from 10 HBV genotypes were obtained from the NCBI Entrez Protein database. Epitopes were predicted from consensus sequences, which consisted of 13,610 HBc sequences and 12,333 HBx sequences. The study identified four cytotoxic T lymphocyte epitopes, two helper T lymphocyte epitopes, and five linear B lymphocyte that met the inclusion criteria. The vaccine candidate designed using cholera toxin subunit B and pan HLA DR-binding epitope adjuvants was predicted to be safe, antigenic, stable, and has a global population coverage of 99.43%. Molecular docking and molecular dynamics simulations demonstrated that the vaccine candidate could stably bind to B cell receptor, cytotoxic T cell receptor, and TLR4 for 100 ns. Immune response simulation indicated that it can induce antibody production and the proliferation of B and T cells. It can be concluded that RV and immunoinformatics successfully facilitated the design of a multi-epitope therapeutic vaccine candidate for CHB.

STING modulates HBV-related acute-on-chronic liver failure by mediating autophagy and macrophage polarization

Background & AimsHBV-related acute-on-chronic liver failure (HBV-ACLF) is a severe acute liver injury secondary to HBV-related chronic liver disease (with or without cirrhosis) and is characterized by a high short-term mortality rate. Presently, there is a paucity of experimental models that specifically focus on HBV-ACLF based on chronic hepatitis B. Therefore, this study aimed to establish an experimental mouse model of HBV-ACLF using chronic hepatitis B (CHB) as a basis and investigate the impact of STING activation on the disease. MethodsTo simulate HBV-ACLF conditions, a model was constructed by combining chronic HBV replication (caudal vein high-pressure hydrodynamic injection of pAAV/HBV1.2 plasmid) and acute hepatic insult (intraperitoneal injection of Acetaminophen (APAP)). Then, model mice were administered either a STING agonist or STING inhibitor. Liver injury, STING pathway, autophagy flux, and macrophage polarization were assessed to elucidate the potential role of STING. ResultsThe mouse model developed chronic hepatitis B and acute liver injury, partially reflecting features of clinical HBV-ACLF based on CHB. STING activation, autophagy, and macrophage polarization were found to be involved in the disease process. During the early stage (6 h) of the STING agonist treatment group, the STING pathway was activated, autophagy flux was up-regulated, and liver inflammation and injury were alleviated. Contrastingly, at the late stage of STING agonist treatment (24 h, 48 h), macrophages were polarized to the M1 phenotype, exacerbating liver inflammatory infiltration and injury. However, treatment with a STING covalent inhibitor reversed these effects. ConclusionsSting-induced autophagy exerts a protective effect on liver injury during the early stage. However, in later stages, STING may aggravate liver injury by shifting liver macrophage polarization to the M1 phenotype, thereby enhancing the inflammatory response.

Exploring Disease Manifestations and Influencing Factors in Acute and Chronic Hepatitis B

Scope and Aims: The investigation of disease manifestations and influencing factors in both acute hepatitis B (AHB) and chronic hepatitis B (CHB) remains limited, with varying results. This study aimed to explore the factors influencing AHB and CHB and their disease manifestations within a Ghanaian population, with the goal of developing a control strategy. Methods: A retrospective study was conducted on 569 admitted hepatitis B cases. Demographic data and disease manifestations were compared between AHB and CHB patients. Logistic regression and correlation analyses were employed to identify the factors influencing the progression of the disease. Results: Significant differences were observed between AHB and CHB patients in terms of median age and hospitalization duration. Variations in age, gender, education level, and occupational distributions were statistically significant (P &lt; 0.05) between the two groups. Symptoms such as fever, nausea, polydipsia, palpitation, anicteric presentation, anorexia, and itching were less common in CHB patients (P &lt; 0.05), while abdominal pain, jaundice, and enlarged liver were more frequent (P &lt; 0.05). CHB patients exhibited significantly higher levels of aspartate aminotransferase, viral load, bilirubin, prothrombin time, partial thromboplastin time, HBeAg, albumin, abdominal ultrasound findings, and globin (P &lt; 0.05), while HBsAg and liver function test levels were significantly lower (P &lt; 0.05) in CHB patients compared to AHB patients. Logistic regression identified age, gender, occupation, education level, and hospitalization duration as significant influencing factors. Conclusion: Males and the adult population represented a higher proportion of CHB patients, with a significant association between CHB and elevated clinical and laboratory characteristics. Age, gender, occupation, education level, and hospitalization duration were established as key influencing factors in the progression of hepatitis B.

Role of Air Pollution in Development of Hepatocellular Carcinoma Among Chronic Hepatitis B Patients Treated With Nucleotide/Nucleoside Analogues.

To investigate the association between air pollution and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues. We enrolled 1298 CHB patients treated with nucleotide/nucleoside analogues and analysed the incidence and risk factors for HCC. Daily estimates of air pollutants were estimated since the previous year from the enrolment date. The annual incidence of HCC was 2.1/100 person-years after a follow-up period of over 4840.5 person-years. Factors with the strongest association with HCC development were liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 3.00/1.55-5.81; p = 0.001), male sex (2.98/1.51-5.90; p = 0.02), body mass index (1.11/1.04-1.18; p = 0.002) and age (1.06/1.04-1.09; p < 0.001). Among patients with cirrhosis, the factors associated with HCC development were male sex (HR/95% CI: 2.10/1.00-4.25; p = 0.04) and NO2 (per one-unit increment, parts per billion; 1.07/1.01-1.13; p = 0.01). Moreover, patients with the highest quartile of annual NO2 exposure had more than a three-fold risk of HCC than those with the lowest quartile of annual exposure (HR/95% CI: 3.26/1.34-7.93; p = 0.01). Among patients without cirrhosis, the strongest factors associated with HCC development were male sex (HR/95% CI: 5.86/1.79-19.23; p = 0.004), age (1.12/1.07-1.17; p < 0.001) and platelet count (0.99/0.98-1.00; p = 0.04). Air pollution influences HCC development in CHB patients who receive nucleotide/nucleoside analogue therapy. Long-term NO2 exposure might accelerate HCC development in CHB patients with cirrhosis receiving nucleotide/nucleoside analogue treatment.

Non-Invasive Test for Assessment of Liver Fibrosis in Chronic Hepatitis B

Chronic hepatitis B (CHB) is a high-risk condition that requires continuous monitoring and appropriate management during the natural course of the disease. In particular, the assessment of liver fibrosis is crucial for determining the optimal timing of antiviral therapy, evaluating the treatment response, and predicting the occurrence and prognosis of hepatocellular carcinoma (HCC) in the management of CHB. Although a liver biopsy is the gold standard for diagnosing liver inflammation, steatosis, and fibrosis, there has been a growing trend in the use of non-invasive tests, such as serum biomarkers, transient elastography, and shear wave elastography in CHB patients. This review provides a summary of the key research findings on the use of serum biomarkers and transient elastography in assessing liver fibrosis, monitoring the disease progression, and predicting the prognosis of CHB patients, with an emphasis on their clinical applicability.

The Discovery and Preclinical Profile of ALG-000184, a Prodrug of the Potent Hepatitis B Virus Capsid Assembly Modulator ALG-001075.

Chronic hepatitis B (CHB) represents a significant unmet medical need with few options beyond lifelong treatment with nucleoside analogues, which rarely leads to a functional cure. Novel agents that reduce levels of HBV DNA, RNA and other viral antigens could lead to better treatment outcomes. The capsid assembly modulator (CAM) class of compounds represents an important modality for chronic suppression and to improve functional cure rates, either alone or in combination. GLP-26 is a potent CAM, which in this work was optimized for potency, safety, and other drug-like properties leading to ALG-001075. ALG-001075 was further advanced through clinical development as the highly soluble prodrug ALG-000184. ALG-000184 is currently being explored in multiple clinical trials in HBV-infected subjects where unprecedented reductions in HBV DNA, RNA and other viral antigens have been observed, making ALG-000184 a promising candidate to become a cornerstone for future chronic suppressive and combination treatment regimens for CHB.

Mechanisms of HCC and cirrhosis development in concurrent steatotic liver disease and chronic hepatitis B.

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 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 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.

Predicting Immune Flares in Untreated Chronic Hepatitis B Patients Using Novel Risk Factors and the FLARE-B Score.

Risk factors of chronic hepatitis B (CHB) immune flares are poorly understood. The primary aim of this study was to discover predictors of the CHB flare in non-cirrhotic, untreated CHB patients and develop a simple risk-stratifying score to predict the CHB flare. The secondary aim was to compare different machine learning methods for prediction. A retrospective cohort of untreated, non-cirrhotic CHB patients with normal baseline ALT was followed up over time until an immune flare as defined by ALT twice the upper limit of normal. Statistical learning and machine learning algorithms were used to develop predictive models using baseline variables. Bootstrap validation was used to internally validate the models. Of 405 patients (median age 44y; 41% male, 10% HBeAg positive), 67 (17%) experienced an immune flare by 5 years (annual incidence 4.0%). Predictors of flare included raised serum globulin, younger age, HBeAg positive status, higher viral load and raised liver stiffness. A simple predictive model "FLARE-B" had optimism-adjusted 1, 3 and 5-year AUCs of 0.813, 0.728 and 0.702, respectively. The random survival forest algorithm had the highest optimism-adjusted AUCs of 0.861, 0.766 and 0.725, respectively. New, novel predictors of the CHB flare include a raised serum globulin and possibly raised liver stiffness and the absence of liver steatosis. FLARE-B can be used to risk-stratify individuals and potentially guide personalized management strategies such as monitoring schedules and proactive antiviral treatment in high-risk patients.

Prospect of emerging treatments for HBV functional cure.

Functional cure, defined as sustained hepatitis B surface antigen (HBsAg) seroclearance with unquantifiable hepatitis B virus (HBV) DNA at 24 weeks off treatment, is a favorable treatment endpoint in chronic hepatitis B (CHB). Nonetheless, functional cure is rarely attained with the current treatment modalities of nucleos(t)ide analogues (NUCs) and pegylated interferon alpha (Peg-IFNα). Multiple novel virus-targeting agents and immunomodulators are under development for HBV with functional cure as the treatment goal. Among virus-targeting agents, antisense oligonucleotides (ASOs) and small-interfering RNA (siRNAs) are the most advanced in the developmental pipeline, and can induce potent and sustainable HBsAg suppression. The other virus-targeting agents have varying effects on HBsAg and HBV DNA, depending on the drug mechanism. In contrast, immunomodulators have modest effects on HBsAg and have limited roles in monotherapy. Multiple combination regimens incorporating RNA interference agents with immunomodulators have been studied through many ongoing clinical trials. These combination strategies demonstrate synergistic effects in inducing functional cure, and will likely be the future direction of development. Despite the promising results, research is warranted to optimize treatment protocols and to establish criteria for NUC withdrawal after novel therapies. Functional cure is now an attainable target in CHB, and the emerging novel therapeutics will revolutionize CHB management.

HBeAg-positive CHB patients with indeterminate phase associated with a high risk of significant fibrosis

BackgroundThe risk of liver fibrosis in HBeAg-positive chronic hepatitis B (CHB) patients with indeterminate phase is not well characterized. We aimed to compare the presence of liver fibrosis in HBeAg-positive CHB patients between indeterminate phase and immune-tolerant phase.MethodsThis multi-center, retrospective cohort study included 719 treatment-naïve HBeAg-positive CHB patients with normal alanine aminotransferase (ALT). Patients with HBV DNA > 106 IU/mL were categorized into immune-tolerant phase, whereas those with HBV DNA ≤ 106 IU/mL were classified into indeterminate phase. Significant liver fibrosis and cirrhosis were determined by APRI, FIB-4, transient elastography, or liver biopsy.ResultsThe median age of patients was 33.0 years and 59.8% of patients were male. 81.5% and 18.5% of patients were in the immune-tolerant phase and indeterminate phase, respectively. The APRI (0.33 vs. 0.27, P < 0.001), FIB-4 (1.07 vs. 0.72, P < 0.001), and liver stiffness values (7.80 kPa vs. 5.65 kPa, P = 0.011) were higher in patients with indeterminate phase than those with immune-tolerant phase. Patients in the indeterminate phase had significantly higher proportions of significant fibrosis (27.1% vs. 11.3%, P < 0.001) and cirrhosis (14.3% vs. 3.2%, P < 0.001) compared to those in the immune-tolerant phase. In the multivariate analysis, indeterminate phase (OR 2.138, 95% CI 1.253, 3.649, P = 0.005) was associated with a higher risk of significant fibrosis, especially for patients aged ≥ 30 years.ConclusionHBeAg-positive CHB patients in the indeterminate phase had more severe liver fibrosis compared to those in the immune-tolerant phase.

Effect of dyslipidemia on HBsAg clearance in nucleos(t)ide analogues-experienced chronic hepatitis B patients treated with peginterferon alfa

BackgroundWhile previous reports have shown that hepatitis B virus (HBV) infection affects lipid metabolism and vice versa, the impact of dyslipidemia on the functional cure of HBV infection following peginterferon alfa (PegIFNα) therapy remains unknown. Hence, this study aimed to investigate the effect of dyslipidemia on hepatitis B surface antigen (HBsAg) clearance and develop a nomogram model for predicting patients for whom PegIFNα therapy is indicated.MethodsA total of 160 nucleos(t)ide analogues (NAs)- experienced chronic hepatitis B (CHB) patients treated with PegIFNα (180 µg/week) were enrolled in this study. The relationship between serum lipid and HBsAg clearance was analysed. Univariate and multivariate COX analyses were used to construct and plot the nomogram model. The area under the receiver operating characteristic curve (AUC) and calibration curve were used to evaluate the discrimination and calibration of the model, respectively.ResultsAfter 48 weeks of PegIFNα therapy, a total of 33 patients in the cohort achieved HBsAg clearance. Univariate and multivariate COX analyses indicated that dyslipidemia was significantly associated with HBsAg clearance and was an independent predictor of HBsAg clearance (HR = 0.243, P = 0.001). Kaplan-Meier survival analyses show that cumulative HBsAg clearance was significantly higher in the normolipidemic group than in the dyslipidemia group (log-rank test, P = 0.007). During the treatment, triglyceride showed an increasing trend, while the levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, apolipoprotein A1 and apolipoprotein B decreased. Dyslipidemia and other indicators independently associated with HBsAg clearance were used to construct the nomogram model. The AUC of the model at 36-week and 48-week were 0.879 and 0.856, and the model demonstrated good discrimination and calibration.ConclusionDyslipidemia can affect the antiviral efficacy of PegIFNα in NAs-experienced CHB patients. Our findings suggest that the nomogram model constructed using serum lipid has good predictive power and may help physicians to identify the superior patients for PegIFNα therapy.

Evaluation of genotype characteristics and drug resistance mutations in patients with chronic hepatitis B

Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.

TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism

ObjectiveAchieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical...