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*

BACKGROUND: The hepatitis B virus (HBV) vaccine has been efficiently used for decades. However, hepatocellular carcinoma caused by HBV is still prevalent globally. We previously reported that interferon (IFN)-induced tripartite motif-containing 25 (TRIM25) inhibited HBV replication by increasing the IFN expression, and this study aimed to further clarify the anti-HBV mechanism of TRIM25. METHODS: The TRIM25-mediated degradation of hepatitis B virus X (HBx) protein was determined by detecting the expression of HBx in TRIM25-overexpressed or knocked-out HepG2 or HepG2-NTCP cells via Western blotting. Co-immunoprecipitation was performed to confirm the interaction between TRIM25 and HBx, and colocalization of TRIM25 and HBx was identified via immunofluorescence; HBV e-antigen and HBV surface antigen were qualified by using an enzyme-linked immunosorbent assay (ELISA) kit from Kehua Biotech. TRIM25 mRNA, pregenomic RNA (pgRNA), and HBV DNA were detected by quantitative real-time polymerase chain reaction. The retinoic acid-inducible gene I (RIG-I) and pgRNA interaction was verified by RNA-binding protein immunoprecipitation assay. RESULTS: We found that TRIM25 promoted HBx degradation, and confirmed that TRIM25 could enhance the K90-site ubiquitination of HBx as well as promote HBx degradation by the proteasome pathway. Interestingly, apart from the Really Interesting New Gene (RING) domain, the SPRY domain of TRIM25 was also indispensable for HBx degradation. In addition, we found that the expression of TRIM25 increased the recognition of HBV pgRNA by interacting with RIG-I, which further increased the IFN production, and SPRY, but not the RING domain is critical in this process. CONCLUSIONS The study found that TRIM25 interacted with HBx and promoted HBx-K90-site ubiquitination, which led to HBx degradation. On the other hand, TRIM25 may function as an adaptor, which enhanced the recognition of pgRNA by RIG-I, thereby further promoting IFN production. Our study can contribute to a better understanding of host-virus interaction.
Humans ; Hepatitis B virus ; DEAD Box Protein 58/metabolism* ; RNA ; Liver Neoplasms ; Virus Replication ; Tripartite Motif Proteins/genetics* ; Transcription Factors ; Ubiquitin-Protein Ligases/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

Objective: To investigate the association of circulating sPD-1 level and PD-1 gene polymorphisms with HBV infection and HBV infection-associated hepatocellular carcinoma. Methods: A case-control study was conducted. A total of 237 chronic HBV infection cases and 138 HBV infection-associated hepatocellular carcinoma in the Department of Infectious Diseases of the First Hospital of Shanxi Medical University from 2018 to 2021 were selected as the case group. About 250 individuals who visited a hospital physical examination center for routine physical examination during the same period were selected as the control group. Plasma sPD-1 levels were measured by using an ELISA kit and genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The association of sPD-1 levels and PD-1 polymorphisms with HBV infection as well as HBV infection-associated hepatocellular carcinoma was analyzed by using logistic regression models after adjusting for age, sex, alcohol consumption, smoking, ALT and AST levels. The sPD-1 level and PD-1 polymorphisms were independent variables, and HBV infection was the dependent variable. Results: The age of 237 chronic HBV infections, 138 HBV infection-related liver cancer case subjects and 250 control subjects in the study was (49.1±10.8), (51.9±12.7) and (50.7±11.9) years, respectively. Multivariate logistic regression model analysis showed that with a 1 pg/ml increase in sPD-1 level, the OR (95%CI) values for the risk of incident HBV infection cases and HBV hepatocellular carcinoma cases were 1.92 (1.68-2.19) and 2.02 (1.69-2.40). For rs2227981, compared with the CC genotype, the TT genotype had a lower risk of HBV infection and liver cancer associated with HBV infection, with OR (95%CI) values of 0.45 (0.22-0.91) and 0.35 (0.14-0.91). For rs2227982, compared with the CC genotype, the CT and TT genotypes also had a lower risk of HBV infection [OR (95%CI) values of 0.72 (0.53-0.97) and 0.57 (0.35-0.93)] and HBV infection-related liver cancer [OR (95%CI) values of 0.64 (0.45-0.92) and 0.52 (0.29-0.93)]. Conclusions: Plasma sPD-1 levels and PD-1 gene polymorphisms are associated with HBV infection and HBV infection-associated hepatocellular carcinoma.
Humans ; Carcinoma, Hepatocellular/genetics* ; Case-Control Studies ; Genetic Predisposition to Disease ; Genotype ; Hepatitis B virus/genetics* ; Liver Neoplasms/genetics* ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Programmed Cell Death 1 Receptor/genetics* ; Adult ; Middle Aged

Objective: This article investigated the clinical characteristics and distribution of drug resistance mutation sites in HBV RT region of hepatitis B infected patients. Methods: Retrospective analysis was made on 1 948 patients with HBV infection, who had been tested for NAs resistance mutation and had a medical history of NAs in the Laboratory Department of the Fifth Medical Center of the PLA General Hospital from January 2020 to December 2021. Basic clinical information and drug resistance related mutation information were recorded. Meanwhile, the serological index data of hepatitis B were collected. Drug resistance gene mutant group and non-mutated group were grouped according to whether the drug resistance genes had a mutation in HBV RT region, and the clinical characteristics and genotype distribution of the two groups were statistically analyzed. The pattern of drug resistance gene mutation, number of mutation sites, drug resistance type and mutation of NAs resistance-related sites were analyzed in 917 patients with drug resistance gene mutation in HBV RT region. χ² Inspection was used for counting data. Meanwhile, two independent samples t-test and Wilcoxon rank sum test were used for measurement data. Results: Among the 1 948 patients with chronic HBV infection, 917 patients had drug resistance gene mutation in RT region (47.07%). The proportion of patients with acute hepatitis B and CHB in HBV RT resistance gene mutant group was lower than that in the non-mutated group, while the proportion of patients with HBV-related cirrhosis was higher than that in the non-mutated group, these differences were statistically significant. Compared with the non-mutated group in HBV RT region, the age, the positive rates of HBeAg and HBV DNA, and HBV DNA load of these patients were increased in drug resistance gene mutant group, these differences were statistically significant. Genotypes of patients in both groups were dominated by C, followed by B and D. The proportion of patients with genotype C in HBV RT drug resistance gene mutant group was higher than that of non-mutated group, the difference was statistically significant. There were 53 gene mutation patterns in 917 patients with drug resistance gene mutation in HBV RT region, and the main pattern was rtL180M+rtM204V+rtS202G (9.70%). The mutation sites were dominated by 3 (20.74%). There were 5 types of drug resistance, LAM+Ldt (21.25%) was the most. Among the 18 sites that were clearly associated with LAM, ADV, ETV and Ldt resistance in the HBV RT region, 14 sites were mutated, and the most common mutation sites were rtL180M, rtM204V, rtM204 and rtS202G. what's more, the proportion of patients with NAs drug resistance was LAM>Ldt>ETV>ADV. Conclusion: In order to prevent adverse consequences of this study such as disease recurrence or disease progression caused by HBV drug resistance, HBV infected patients, who have long-term use of NAs antiviral therapy, should monitor the level of HBV DNA and drug resistance genes in HBV RT region in order to optimize the treatment plan in time or guide individualized treatment.
Humans ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic ; Antiviral Agents/therapeutic use* ; DNA, Viral/therapeutic use* ; Retrospective Studies ; Mutation ; Drug Resistance, Viral/genetics* ; Lamivudine/therapeutic use*

Objective: To understand the distribution of genotypes and sub-genotypes of HBV in different ethnic groups in China. Methods: The HBsAg positive samples were selected by stratified multi-stage cluster sampling from the sample base of national HBV sero-epidemiological survey in 2020 for the amplification of S gene of HBV by nested PCR. A phylogeny tree was constructed to determine the genotypes and sub-genotypes of HBV. The distribution of genotypes and sub-genotypes of HBV were analyzed comprehensively by using laboratory data and demographic data. Results: A total of 1 539 positive samples from 15 ethnic groups were successfully amplified and analyzed, and 5 genotypes (B, C, D, I and C/D) were detected. The proportion of genotype B was higher in ethnic group of Han (74.52%, 623/836), Zhuang (49.28%, 34/69), Yi (53.19%, 25/47), Miao (94.12%, 32/34), Buyi (81.48%, 22/27). The proportions of genotype C were higher in ethnic groups of Yao (70.91%, 39/55). Genotype D was the predominant genotype in Uygur (83.78%, 31/37). Genotype C/D were detected in Tibetan (92.35%,326/353). In this study, 11 cases of genotype I were detected, 8 of which were distributed in Zhuang nationality. Except for Tibetan, sub-genotype B2 accounted for more than 80.00% in genotype B in all ethnic groups. The proportions of sub-genotype C2 were higher in 8 ethnic groups, i.e. Han, Tibetan, Yi, Uygur, Mongolian, Manchu, Hui and Miao. The proportions of sub-genotype C5 were higher in ethnic groups of Zhuang (55.56%, 15/27) and Yao (84.62%, 33/39). For genotype D, sub-genotype D3 was detected in Yi ethnic group and sub-genotype D1 was detected in both Uygur and Kazak. The proportions of sub-genotype C/D1 and C/D2 in Tibetan were 43.06% (152/353) and 49.29% (174/353). For all the 11 cases of genotype I infection, only sub-genotype I1 was detected. Conclusions: Five genotypes and 15 sub-genotypes of HBV were found in 15 ethnic groups. There were significant differences in the distribution of genotypes and sub-genotypes of HBV among different ethnic groups.
Humans ; Asian People ; China/epidemiology* ; Ethnicity ; Genotype ; Gerbillinae ; Hepatitis B virus/genetics* ; Hepatitis B/virology*

Objective: To understand the infection status and epidemiological characteristics of hepatitis C in people aged 1-69 years in Henan Province in 2020. Methods: The estimated sample size was 5 827. From August to December 2020, multistage sampling was used to select 8 counties (districts) in Henan, and two survey sites were selected in each county (district), and a questionnaire survey was conducted in local people aged 1-69 years, blood samples were collected from them for anti-HCV, HCV RNA and genotype detections. Results: A total of 5 165 people aged 1-69 years completed the questionnaire survey. Men accounted for 44.76% (2 312/5 165), women accounted for 55.24% (2 853/5 165). In the people aged 1-69 years, the overall prevalence rates of anti-HCV and HCV RNA were 0.69% (95%CI: 0.68%-0.70%) and 0.20% (95%CI: 0.19%-0.21%) respectively. The prevalence rates of anti-HCV and HCV RNA were 0.48% (95%CI: 0.46%-0.50%), 0.09% (95%CI: 0.08%-0.10%) in men and 0.86% (95%CI: 0.85%-0.87%), 0.30% (95%CI: 0.28%-0.32%) in women. The prevalence rates of anti-HCV and HCV RNA increased with age. The prevalence rates of anti-HCV and HCV RNA were 0.87% (95%CI: 0.86%-0.88%), 0.28% (95%CI: 0.26%-0.30%) in urban residents and 0.53% (95%CI: 0.51%-0.55%), 0.14% (95%CI: 0.13%-0.15%) in rural residents. The genotyping results of 10 HCV RNA positive samples ware genotype 1b (4/10), genotype 2 (3/10), genotype 1b/3 (1/10), genotype 1b/3/6 (1/10) and genotype 2/6 (1/10). Conclusions: The prevalence of hepatitis C was low in Henan in 2020. It is necessary to strengthen hepatitis C surveillance in people aged 40 years and above. The major HCV genotypes were 1b and 2, and mixed genotype infection existed.
Female ; Humans ; Male ; Coinfection ; Genotype ; Hepacivirus/genetics* ; Hepatitis C/epidemiology* ; Hepatitis C Antibodies/genetics* ; Prevalence ; RNA, Viral/genetics* ; Surveys and Questionnaires ; Infant ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged

Humans ; Lymphoma, Large B-Cell, Diffuse/genetics* ; Herpesvirus 4, Human/genetics* ; Mutation ; Epstein-Barr Virus Infections/pathology* ; Hepatitis A Virus Cellular Receptor 2/genetics*

Hepatitis E is a viral hepatitis that the hepatitis E virus (HEV) causes. In the early 1980s, the hepatitis E virus was first discovered and identified, and it is one of the important pathogens that cause acute viral hepatitis globally. HEV infection is usually self-limiting, but in some groups of populations, such as pregnant women, patients with chronic liver disease, and the elderly, the prognosis is poor and may result in acute or subacute liver failure or even death. In addition, HEV infection can occur in chronically immunocompromised populations. At present, some regions and countries are not paying enough attention to hepatitis E prevention, diagnosis, and treatment, which suggests that we should study the epidemiology of HEV infection.
Humans ; Female ; Pregnancy ; Aged ; Hepatitis E/epidemiology* ; Hepatitis E virus/genetics* ; Prognosis ; Liver Failure ; Pregnancy Complications, Infectious

Hepatitis type E virus (HEV) is a significant infectious zoonotic disease that causes hepatitis E. The disease is primarily transmitted via the fecal-oral route through contaminated water or food and is transmissible between species and genera. The causative agent for the disease is the hepatitis type E virus, which is a member of the Hepadnaviridae family and a single-stranded RNA virus. Its 7.2 kb genome mainly contains three open reading frames (ORFs): ORF1 encodes a non-structural polyprotein that mediates viral replication and transcription; ORF2 encodes a capsid protein and free antigen that induce neutralizing antibodies; ORF3 partially overlaps with ORF2 and encodes a small multifunctional protein involved in virion formation and release. HEV has a unique dual life cycle: it is excreted into feces in the form of naked virions but circulates in the blood in the form of "quasi-enveloped" particles. The two kinds of virus particles adsorb and penetrate the host cell in distinct ways, then internalize and decapsulate to replicate the genome, thereby producing more virion and releasing it outside the cell to mediate the virus's spread. This paper reviews the morphological characteristics, genome structure, encoded proteins, and function of HEV virus-like particles in order to provide a theoretical basis for basic research and comprehensive disease prevention and control.
Humans ; Hepatitis E virus/genetics* ; Hepatitis E