Chronic hepatitis B virus (HBV) infection is a global public health concern. Existing antiviral drugs, including nucleos(t)ide analogs and interferon-α, can suppress HBV replication and improve the prognosis. However, the persistence of covalently closed circular DNA (cccDNA), the integration of HBV-DNA into the host genome, and compromised immune responses impede the successful treatment of hepatitis B. While achieving a functional cure of HBV remains elusive with the current treatment methods, this is the goal of new therapeutic approaches. Therefore, developing novel antiviral drugs is necessary for achieving a functional or complete cure for chronic hepatitis B. In recent years, substantial progress has been made in drug discovery and development for HBV infection. Direct-acting antiviral agents such as entry inhibitors, capsid assembly modulators, subviral particle release inhibitors, cccDNA silencers, and RNA interference molecules have entered clinical trials. In addition, several immunomodulatory agents, including toll-like receptor agonists, therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also making their way toward clinical use. In this review, we summarize the recent progress and limitations of chronic hepatitis B treatment and discuss perspectives on approaches to achieving functional cure. Although it will take some time for these new antiviral drugs to be widely used in clinical practice, combination therapy may become a preferable treatment option in the future.
Humans ; Antiviral Agents/therapeutic use* ; Hepatitis B, Chronic/drug therapy* ; Hepatitis B virus/genetics*

The resolution of the hepatitis C issue has raised expectations for a chronic hepatitis B cure, driving the industry to expand investment in research and development efforts to strengthen functional cure strategies. These strategies have a wide variety of types, and the published research findings are heterogeneous. The theoretical analysis of these strategies is of great significance for determining prioritized research orientations as well as sensibly allocating research and development resources. However, due to a paucity of necessary conceptual models, current theoretical analysis has not been able to unify various therapeutic strategies into a proper theoretical framework. In view of the fact that the decrease in the quantity of cccDNA is an inevitable core event accompanied by the process of functional cure, this paper intends to analyze several chronic hepatitis B cure strategies using cccDNA dynamics as a framework. Furthermore, there are currently few studies on the dynamics of the cccDNA field, hoping that this article can promote recognition and research in this field.
Humans ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Antiviral Agents/therapeutic use* ; Virus Replication ; DNA, Circular/therapeutic use* ; DNA, Viral/genetics* ; Hepatitis B/drug therapy*

Objective:b> To compare the clinical and pathological features of children with chronic viral hepatitis B combined with metabolic-associated fatty liver disease (CHB-MAFLD) and chronic viral hepatitis B alone (CHB alone), and to further explore the effect of MAFLD on the progression of hepatic fibrosis in CHB. Methods:b> 701 initially treated CHB children confirmed by liver biopsy admitted to the Fifth Medical Center of the PLA General Hospital from January 2010 to December 2021 were collected continuously. They were divided into CHB-MAFLD and CHB-alone groups according to whether they were combined with MAFLD. A retrospective case-control study was conducted. CHB-MAFLD was used as the case group, and 1:2 propensity score matching was performed with the CHB alone group according to age and gender, including 56 cases in the CHB-MAFLD group and 112 cases in the CHB alone group. The body mass index (BMI), metabolic complications, laboratory indicators, and pathological characteristics of liver tissue were compared between the two groups. The related factors affecting liver disease progression in CHB were analyzed by a binary logistic regression model. The measurement data between groups were compared using the t-test and rank sum test. The χ (2) test was used for the comparison of categorical data between groups. Results:b> Alanine aminotransferase (ALT, P = 0.032) and aspartate aminotransferase (AST, P = 0.003) levels were lower in the CHB-MAFLD group than those in the CHB alone group, while BMI (P < 0.001), triglyceride (TG, P < 0.001), total cholesterol (P = 0.016) and the incidence of metabolic syndrome (P < 0.001) were higher in the CHB alone group. There were no statistically significant differences in HBsAg quantification or HBV DNA load between the two groups (P > 0.05). Histologically, the proportion of significant liver fibrosis (S2-S4) was higher in the CHB-MAFLD group than that in the CHB alone group (67.9% vs. 49.1%, χ (2) = 5.311, P = 0.021). Multivariate regression results showed that BMI (OR = 1.258, 95% CI: 1.145 ~ 1.381, P = 0.001) and TG (OR = 12.334, 95% CI: 3.973 ~ 38.286, P < 0.001) were the risk factors for hepatic steatosis occurrence in children with CHB. MAFLD (OR = 4.104, 95% CI: 1.703 ~ 9.889, P = 0.002), liver inflammation (OR = 3.557, 95% CI: 1.553 ~ 8.144, P = 0.003), and γ-glutamyl transferase (OR = 1.019, 95% CI: 1.001 to 1.038, P = 0.038) were independent risk factors for significant hepatic fibrosis in children with CH. Conclusion:b> MAFLD occurrence is related to metabolic factors in children with CHB. Additionally, the combination of MAFLD may promote liver fibrosis progression in CHB patients.
Humans ; Child ; Hepatitis B, Chronic/pathology* ; Retrospective Studies ; Case-Control Studies ; Hepatitis B virus/genetics* ; Liver Cirrhosis/pathology* ; Non-alcoholic Fatty Liver Disease/complications* ; Risk Factors

Humans ; Hepatitis B Surface Antigens ; Hepatitis B/drug therapy* ; Hepatitis B virus/genetics* ; Antiviral Agents/therapeutic use* ; Hepatitis B, Chronic/diagnosis* ; DNA, Viral

Objective:b> To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods:b> Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t-test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results:b> 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion:b> Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.
Humans ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Antiviral Agents/adverse effects* ; Esophageal and Gastric Varices/complications* ; Liver Cirrhosis/complications* ; Treatment Outcome ; Gastrointestinal Hemorrhage/complications* ; Hepatitis B/drug therapy*

Objective:b> To understand ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China. Methods:b> Patients with chronic HBV infection:demographic, virologic, hematologic, blood biochemistry, and antiviral treatment data were extracted from the China Registry of Hepatitis B (CR-HepB) database between 2012 and 2022 for descriptive statistics and change trend analysis. Multiple group comparisons were conducted using the Kruskal Wallis H test, while counting data was compared between groups using χ (2) test. Results:b> A total of 180 012 patients with chronic HBV infection were included, with a median age of 40 years old, and a male proportion accounting for 60.2%. The HBeAg positive rate was 43.3%. Over time, the median age of new patients each year increased from 39 to 47 years, while the HBeAg positive rate decreased from 51.3% to 32.8%. The initial diagnosis of patients was mainly CHB (71.4%), followed by hepatitis B cirrhosis (11.8%), inactive HBsAg carrier status (10.6%), and chronic HBV carrier status (6.2%). Among the newly registered patients every year from 2012 to 2022, the proportion of hepatitis B cirrhosis remained stable, but after 2019, the proportion of CHB increased and the proportion of other diagnoses decreased. The proportion of patients with cirrhosis increased with age in different age groups, with 3.5%, 19.3%, and 30.4% in the < 40, 40-69, and≥70 age groups, respectively. The proportion of women in patients with cirrhosis also increased with age, from 16.1% in those < 30 years old to 44.3% in those≥80 years old. From 2012 to 2022, the proportion of patients receiving first-line nucleos(t)ide analog antiviral treatment increased year by year, from 51.0% in 2012-2013 to 99.8% in 2022. Conclusion:b> The CR-HepB registration data reflect the changes in clinical characteristics and antiviral treatment patterns in patients with chronic HBV infection in China over the past ten years and can thus provide a reference to promote hepatitis B diagnosis and treatment practice, as well as scientific research.
Humans ; Male ; Female ; Adult ; Aged, 80 and over ; Antiviral Agents/therapeutic use* ; Hepatitis B, Chronic/epidemiology* ; Hepatitis B e Antigens ; Hepatitis B/drug therapy* ; Hepatitis B Surface Antigens ; Hepatitis A ; Liver Cirrhosis/drug therapy* ; China/epidemiology* ; Registries ; Hepatitis B virus/genetics* ; DNA, Viral

OBJECTIVES: Long-term hepatitis B virus (HBV) infection can cause recurrent inflammation in the liver, and then develop into liver fibrosis, cirrhosis, and liver cancer. The hepatic pathological change is one of the important criteria for guiding antiviral therapy in patients with chronic hepatitis B (CHB). Due to the limitations of liver biopsy, it is necessary to find valuable non-invasive indicators to evaluate the hepatic pathological changes in CHB patients and guide the antiviral therapy. This study aims to analyze the clinical characteristics of different pathological changes in CHB patients, and to explore the factors influnencing the degree of liver inflammation and fibrosis in CHB patients with normal alanine aminotransferase (ALT). METHODS: This retrospective study was conducted on 310 CHB patients. Liver biopsy was performed in all these patients. The clinical data of the patients were collected. The liver biopsy pathological results were used as the gold standard to analyze the relationship between clinical indicators and liver pathological changes. Then CHB patients with normal ALT were screened, and the independent factors influencing the degree of liver inflammation and fibrosis were explored. RESULTS: Among the 310 patients with CHB, there were 249 (80.3%) patients with significant liver inflammation [liver inflammation grade (G) ≥2] and 119 (38.4%) patients with significant liver fibrosis [liver fibrosis stage (S) ≥2]. The results of univariate analysis of total samples showed that the ALT, γ-glutamyl transferase, alkaline phosphatase, and HBV DNA were related to the significant liver pathological changes. Among the 132 CHB patients with normal ALT, the patients with liver pathology G/S≥2, G≥2, and S≥2 were 80.3% (106/132), 68.2% (90/132), and 43.2% (57/132), respectively. The results showed that the independent influencing factor of significant liver inflammation was HBV DNA>2 000 U/mL (OR=3.592, 95% CI 1.534 to 8.409), and the independent influencing factors of significant liver fibrosis were elevated alkaline phosphatase level (OR=1.022, 95% CI 1.002 to 1.043), decreased platelet count (OR=0.990, 95% CI 0.982 to 0.998), and positive in hepatitis B e antigen (HBeAg) (OR=14.845, 95% CI 4.898 to 44.995). According to the multivariate analysis, a diagnostic model for significant liver fibrosis in CHB patients with normal ALT was established, and the area under the receiver operating characteristic curve was 0.844 (95% CI 0.779 to 0.910). CONCLUSIONS The liver pathological changes should be evaluated in combination with different clinical indicators. A considerable number of CHB patients with normal ALT still have significant liver pathological changes, which need to be identified and treated with antiviral therapy in time. Among them, HBV DNA>2 000 U/mL suggests the significant liver inflammation, and the diagnostic model for significant liver fibrosis based on alkaline phosphatase, platelet count, and HBeAg can help to evaluate the degree of liver fibrosis.
Humans ; Hepatitis B, Chronic/complications* ; Hepatitis B e Antigens/therapeutic use* ; Alkaline Phosphatase ; DNA, Viral ; Retrospective Studies ; Fibrosis ; Hepatitis B virus/genetics* ; Liver Cirrhosis/etiology* ; Inflammation/drug therapy* ; Antiviral Agents/therapeutic use* ; Alanine Transaminase

This study aims to clarify host factors of IFN treatment in the treatment of chronic hepatitis B (CHB) patients by screening the differentially expressed genes of IFN pathway CHB patients with different response to interferon (IFN) therapy. Three cases were randomly selected in IFN-responding CHB patients (Rs), non-responding CHB patients (NRs) and healthy participants, respectively. The human type I IFN response RT ² profiler PCR array was used to detect the expression levels of IFN-related genes in peripheral blood monocytes (PBMCs) from healthy participants and CHB patients before and after Peg-IFN-α 2a treatment. The results showed that more differentially expressed genes appeared in Rs group than NRs group after IFN treatment. Comparing with healthy participants, IFNG, IL7R, IRF1, and IRF8 were downregulated in both Rs and NRs group before IFN treatment; CXCL10, IFIT1, and IFITM1 were upregulated in the Rs; IL13RA1 and IFI35 were upregulated in the NRs, while IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1, and ADAR were downregulated. The expression of IL15, IFI35 and IFI44 was downregulated by 4.09 ( t = 10.58, P < 0.001), 5.59 ( t = 3.37, P = 0.028) and 10.83 ( t = 2.8, P = 0.049) fold in the Rs group compared with the NRs group, respectively. In conclusion, IFN-response-related gene array is able to evaluate IFN treatment response by detecting IFN-related genes levels in PBMC. High expression of CXCL10, IFIT1 and IFITM1 before treatment may suggest satisfied IFN efficacy, while high expression of IL13RA1, IL15, IFI35 and IFI44 molecules and low expression of IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1 and ADAR molecules may be associated with poor IFN efficacy.
Humans ; Healthy Volunteers ; Hepatitis B, Chronic/genetics* ; Immunotherapy ; Interleukin-15 ; Leukocytes, Mononuclear ; Nuclear Proteins ; Oligonucleotide Array Sequence Analysis/methods* ; Interferons/therapeutic use* ; Treatment Outcome

Objective:b> To investigate the potential function and related mechanism of microRNA-223 (miRNA-223) in the podocyte pyroptosis of hepatitis B virus (HBV)-associated glomerulonephritis induced by HBV X protein (HBx). Methods:b> HBx-overexpressing lentivirus was transfected into human renal podocytes to mimic the pathogenesis of HBV-GN. Real-time fluorescence quantitative PCR and Western blotting experiments were used to detect the mRNA and protein expression of pyroptosis-related proteins [nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1], and inflammatory factors (interleukin-1β and interleukin-18), respectively.TUNEL staining and flow cytometry were used to detect the number of pyroptosis cells. Immunofluorescence staining was used to detect the expression of podocytes biomarkers desmin and nephrin; Hoechst 33342 staining was used to observe the morphological and quantitative changes of podocyte nuclei. Enzyme-linked immunosorbent assay was used to measure caspase-1 activity. The dual luciferase reporter gene assay was used to verify the downstream target of miRNA-223. Podocytes were divided into the following nine groups: control group (no special treatment), empty plasmid group (transfected with empty plasmid), HBx overexpression group (transfected with HBx overexpression lentivirus), HBx overexpression+miRNA-223 mimic group (transfected with HBx overexpression lentivirus and miRNA-223 mimic), HBx overexpression+miRNA-223 inhibitor group (transfected with HBx overexpression lentivirus and miRNA-223 inhibitor), HBx overexpression+miRNA-223 mimic+NLRP3 group (transfected with HBx overexpression lentivirus, miRNA-223 mimic and NLRP3 overexpression plasmid), HBx overexpression+miRNA-223 mimic+ NLRP3 siRNA group (transfected with HBx overexpression lentivirus, miRNA-223 mimic and NLRP3 siRNA), HBx overexpression+miRNA-223 inhibitor+NLRP3 group (transfected with HBx overexpression lentivirus, miRNA-223 inhibitor and NLRP3 overexpression plasmid), HBx overexpression+miRNA-223 inhibitor+NLRP3 siRNA group (transfected with HBx overexpression lentivirus, miRNA-223 inhibitor and NLRP3 siRNA). Results:b> miRNA-223 was down-regulated in HBx overexpression group compared with the control group (P < 0.05). TUNEL and immunofluorescence staining showed that NLRP3 knockdown attenuated podocyte injury and pyroptosis induced by HBx overexpression (P < 0.05). Dual luciferase reporter gene assay demonstrated that NLRP3 was one of the downstream targets of miRNA-223. Rescue experiments revealed that NLRP3 overexpression weakened the protective effect of miRNA-223 in podocyte injury (P < 0.05). The addition of miRNA-223 mimic and NLRP3 siRNA decreased the expression of NLRP3 inflammasome and cytokines, and reduced the number of pyroptosis cells induced by HBx overexpression (all P < 0.05); The addition of miRNA-223 inhibitor and NLRP3 overexpression plasmid significantly increased the expression of NLRP3 inflammasome and cytokines, caspase-1 activity, and the number of pyroptosis cells (all P < 0.05). Conclusion:b> HBx may promote podocyte pyroptosis of HBV-GN via downregulating miRNA-223 targeting NLRP3 inflammasome, suggesting that miRNA-223 is expected to be a potential target for the treatment of HBV-GN.
Humans ; Inflammasomes/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Pyroptosis ; Podocytes/metabolism* ; Hepatitis B virus/genetics* ; Caspase 1/metabolism* ; Cytokines/metabolism* ; Carrier Proteins/metabolism* ; MicroRNAs/genetics* ; Glomerulonephritis/metabolism* ; RNA, Small Interfering

Objective:b> To investigate the demographic characteristics and clinical influencing factors which associates with the occurrence probability of persistent or intermittent hypoviremia (LLV) in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs). Methods:b> A single-center retrospective analysis was performed on patients with CHB who received outpatient NAs therapy for≥48 ± 2 weeks. According to the serum hepatitis B virus (HBV) DNA load at 48±2 weeks treatment, the study groups were divided into LLV (HBV DNA < 20 IU/ml and < 2 000 IU/ml) and MVR group (sustained virological response, HBV DNA < 20 IU/ml). Demographic characteristics and clinical data at the start of NAs treatment (considered as baseline) were retrospectively collected for both patient groups. The differences in the reduction of HBV DNA load during treatment was compared between the two groups. Correlation and multivariate analysis were further conducted to analyze the associated factors influencing the LLV occurrence. Statistical analysis was performed using the independent samples t-test, c2 test, Spearman analysis, multivariate logistic regression analysis, or area under the receiver operating characteristic curve. Results:b> A total of 509 cases were enrolled, with 189 and 320 in the LLV and MVR groups, respectively. Compared to patients with MVR group at baseline: (1) the demographics characteristics of patients showed that LLV group was younger in age (39.1 years, P = 0.027), had a stronger family history (60.3%, P = 0.001), 61.9% received ETV treatment, and higher proportion of compensated cirrhosis (20.6%, P = 0.025) at baseline; (2) the serum virological characteristics of patients showed that LLV group had higher HBV DNA load, qHBsAg level, qHBeAg level, HBeAg positive rate, and the proportion of genotype C HBV infection but decreased HBV DNA during treatment (P < 0.001) at baseline; (3) the biochemical characteristics of patients showed that LLV group had lower serum ALT levels (P = 0.007) at baseline; (4) the noninvasive fibrosis markers of patients showed that LLV group were characterized by high aspartate aminotransferase platelet ratio index (APRI) (P = 0.02) and FIB-4 (P = 0.027) at baseline. HBV DNA, qHBsAg and qHBeAg were positively correlated with LLV occurrence (r = 0.559, 0.344, 0.435, respectively), while age and HBV DNA reduction were negatively correlated (r = -0.098, -0.876, respectively). Logistic regression analysis showed that ETV treatment history, high HBV DNA load at baseline, high qHBsAg level, high qHBeAg level, HBeAg positive, low ALT and HBV DNA level were independent risk factors for patients with CHB who developed LLV with NAs treatment. Multivariate prediction model had a good predictive value for LLV occurrence [AUC 0.922 (95%CI: 0.897 ~ 0.946)]. Conclusion:b> In this study, 37.1% of CHB patients treated with first-line NAs has LLV. The formation of LLV is influenced by various factors. HBeAg positivity, genotype C HBV infection, high baseline HBV DNA load, high qHBsAg level, high qHBeAg level, high APRI or FIB-4 value, low baseline ALT level, reduced HBV DNA during treatment, concomitant family history, metabolic liver disease history, and age < 40 years old are potential risk factors for developing LLV in patients with CHB during the therapeutic process.
Humans ; Adult ; Hepatitis B, Chronic/complications* ; Retrospective Studies ; Cross-Sectional Studies ; Hepatitis B e Antigens ; DNA, Viral ; Antiviral Agents/therapeutic use* ; Hepatitis B virus/genetics* ; Demography