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*

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

BACKGROUND: Hepatitis B surface antigen (HBsAg) clearance is vital for a functional cure of hepatitis B virus (HBV) infection. However, the incidence and predictors of HBsAg seroclearance in patients co-infected with HBV and human immunodeficiency virus (HIV) remain largely unknown in Guangdong, China. METHODS: Between 2009 and 2019, patients co-infected with HBV/HIV undergoing antiretroviral therapy (ART) in Guangzhou Eighth People's Hospital affiliated to Guangzhou Medical University were retrospectively reviewed with the endpoint on December 31, 2020. The incidence and risk factors for HBsAg seroclearance were evaluated using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: A total of 1550 HBV/HIV co-infected patients were included in the study, with the median age of 42 years and 86.0% (1333/1550) males. Further, 98.3% (1524/1550) received ART containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC). HBV DNA was examined in 1283 cases at the last follow-up. Over the median 4.7 years of follow-up, 8.1% (126/1550) patients achieved HBsAg seroclearance, among whom 50.8% (64/126) obtained hepatitis B surface antibody, 28.1% (137/488) acquired hepatitis B e antigen seroconversion, and 95.9% (1231/1283) undetectable HBV DNA. Compared with patients who maintained HBsAg positive, cases achieving HBsAg seroclearance showed no differences in age, gender, CD4 + T cell count, alanine aminotransferase (ALT) level, or fibrosis status; however, they presented lower HBV DNA levels, lower HBsAg levels, and higher rates of HBV genotype B at the baseline. Multivariate analysis showed that baseline HBsAg <1500 cutoff index (COI) (adjusted hazard ratio [aHR], 2.74, 95% confidence interval [95% CI]: 1.48-5.09), ALT elevation >2 × upper limit of normal during the first six months after receiving ART (aHR, 2.96, 95% CI: 1.53-5.77), and HBV genotype B (aHR, 3.73, 95% CI: 1.46-9.59) were independent predictors for HBsAg seroclearance (all P <0.01). CONCLUSIONS Long-term TDF-containing ART has high anti-HBV efficacy including relatively high overall HBsAg seroclearance in HBV/HIV co-infected patients. Lower baseline HBsAg levels, HBV genotype B, and elevated ALT levels during the first six months of ART are potential predictors of HBsAg seroclearance.
Male ; Humans ; Adult ; Hepatitis B Surface Antigens ; Hepatitis B virus/genetics* ; HIV Infections/drug therapy* ; HIV ; DNA, Viral ; Incidence ; Coinfection/drug therapy* ; Retrospective Studies ; Tenofovir/therapeutic use* ; Lamivudine/therapeutic use* ; Hepatitis B, Chronic/drug therapy*

The infection of Hepatitis B virus (HBV) can result in severe consequences, including chronic hepatitis, liver fibrosis, cirrhosis, and even liver cancer. Effective antiviral treatment has the potential to slow down the progression of the disease. HBV serum biomarkers play a crucial role in the dynamic management of chronic hepatitis B (CHB) patients. However, the conventional hepatitis B virus markers, such as hepatitis B serologic testing and HBV DNA, are insufficient to meet the clinical requirements. This review provided a comprehensive overview of the current research on the quantification of HBsAg and anti-HBc, HBV RNA and HBV core-associated antigen, which summarized the crucial role these markers play in the administration of antiviral medications, predicting the efficacy of treatment and anticipating the likelihood of virologic rebound following drug cessation, as well as assessing disease progression in CHB patients.
Humans ; Hepatitis B virus/genetics* ; Clinical Relevance ; Hepatitis B, Chronic/drug therapy* ; Hepatitis B Core Antigens/therapeutic use* ; Biomarkers ; Liver Cirrhosis/drug therapy* ; Antiviral Agents/therapeutic use* ; Hepatitis B Surface Antigens/therapeutic use* ; DNA, Viral/therapeutic use* ; Hepatitis B e Antigens/therapeutic use* ; Hepatitis B/drug therapy*

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*

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

Hepatitis B virus (HBV) infection remains to be the major cause of chronic liver diseases in China. Since the nucleos(t)ide analogues and pegylated interferon-alpha do not directly target the covalently closed circular DNA (cccDNA) in the nuclei of HBV-infected hepatocytes, those standard-of-care medications cannot efficiently cure the infected hepatocytes and rarely achieve the functional cure of chronic hepatitis B (CHB). Therefore, new antiviral drugs targeting distinct steps of HBV replication and immunotherapeutics reinvigorating antiviral immune responses are urgently needed for the functional cure of CHB. Based on the extensive discussion of the biological and clinical significance of new virologic biomarkers and distinct mechanism of drug candidates currently in clinical development, we propose that the selection of virologic and immunological biomarkers for evaluation of therapeutic efficacy as well as setting the therapeutic endpoints in the clinical trials should be based on the mode of action of investigational drugs. In addition, due to the complexity of CHB pathogenesis, selection of specific subpopulation of CHB patients for the clinical trials of drugs with a specific mode of action should also be considered.
Antiviral Agents/therapeutic use* ; Biomarkers ; DNA, Circular ; DNA, Viral ; Hepatitis B/drug therapy* ; Hepatitis B Surface Antigens ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic ; Humans ; Virus Replication

OBJECTIVES: Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure in China, with a high mortality. Early rapid reduction of HBV-DNA load can improve the survival rate of HBV-ACLF patients. At present, the commonly used drugs are nucleoside (acid) analogues, such as entecavir (ETV), tenofovir, and so on. The newly listed tenofovir alafenamide fumarate (TAF) has attracted great attention of clinicians because of its stronger antiviral effect, higher transaminase normalization rate, better bone and kidney safety, and zero drug resistance. However, there are few clinical research data on the efficacy and safety of TAF in the treatment of Chinese HBV-ACLF patients, and there is a lack of pharmacoeconomic evaluation. This study aims to compare the efficacy, safety, and cost-effectiveness between TAF and ETV in patients with HBV-ACLF. METHODS: The data were collected from 196 HBV-ACLF patients (80 patients in the TAF group and 116 patients in the ETV group) who were hospitalized in Xiangya Hospital, Central South University from May 2020 to March 2021. Biochemistry and virology were detected before and after treatment (at baseline, Week 2, 4, and 12). Clinical features, disease prognosis, and cost-effectiveness were compared between the 2 groups. According to the baseline, HBV-ACLF patients were divided into 4 stages including pre-liver failure stage, early stage, medium stage, and end stage. And the liver transplantation rate and mortality was also compared. Pharmacoeconomic evaluation was taken using cost-effectiveness analysis and cost minimization analysis．. RESULTS: After 4 weeks of treatment, there were no significant differences in the efficacy (liver function, viral load) between the 2 groups (all P>0.05). The TAF group showed lower creatinine [(80.35±18.77) μmol/L vs (105.59±82.32) μmol/L, P<0.05] and higher estimated glomerular filtration rate (eGFR) levels [(95.65±23.21) mL/(min·1.73 m²) vs (82.68±26.32) mL/(min·1.73 m²), P<0.05] than the ETV group. After 12 weeks of treatment, the analysis of overall the liver transplantation rate and mortality between the 2 groups showed similar conclusion. However, the TAF group had a lower the liver transplantation rate and mortality than the ETV group in patients with pre-liver failure (0vs13.89%, P<0.05). No evident distinction was found in the liver transplantation rate and mortality during the early, medium, or end stages of liver failure (13.04% vs 17.65%, 37.50% vs 37.04%, and 54.55% vs 68.42%, respectively). Ratio of cost to effectiveness in the ETV group was higher than that in the TAF group. CONCLUSIONS TAF is not more efficient than ETV group in improving liver function and reducing viral load for HBV-ACLF patients and they also show similar safety. However, TAF has a greater advantage over ETV not only in preserving renal function, but also in reducing the liver transplantation rate and mortality in patients with pre-liver failure. TAF can provide economic benefit to patients with HBV-ACLF.
Acute-On-Chronic Liver Failure/drug therapy* ; Alanine/therapeutic use* ; Antiviral Agents/therapeutic use* ; Guanine/analogs & derivatives* ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Humans ; Tenofovir/analogs & derivatives* ; Treatment Outcome