Natural History Of Chronic Hepatitis Research Articles

Natural History of Chronic Hepatitis B Infection Among Chinese Children and Young Adults: A Single-Center Experience.

There are limited data on the natural history of chronic hepatitis B virus (HBV) infection in Asian American children. The aim of the present study was to describe a single-center experience of chronic HBV infection in Chinese American patients in New York City. A retrospective chart review was conducted for patients with chronic HBV infection who had pediatric visits from 2006 to 2017. Clinical and laboratory data were collected to characterize the status of HBV infection and its disease course both cross-sectionally and longitudinally. Available maternal charts were reviewed. Of the total 353 patients, 72 patients (20%) were US-born. Positive hepatitis B envelope antigen (HBeAg) was documented in 208 patients (58%). Three phases of chronic HBV infection were categorized for 329 patients: immune-tolerant 112 (34%), HBeAg-positive immune-active 47 (14%), and inactive carrier 82 (25%). The remaining 88 patients (27%) did not fit into a particular category with 26 of 88 patients meeting the criteria for inactive carrier except for mildly elevated alanine aminotransferase. Age and liver enzyme levels were significantly different between HBeAg-positive and HBeAg-negative groups (P < 0.05). Among 179 patients followed for ≥5 years, the spontaneous seroconversion rate was 38%. In eight patients with linked maternal data, all children completed the HBV vaccine series and seven of eight received hepatitis B immunoglobulin. All mothers were HBeAg-positive with high HBV DNA and had no anti-viral therapy during pregnancy. Both immune-tolerant and inactive carrier phases were common for chronic HBV infection with a spontaneous seroconversion rate of 38%. All US-born patients were born in the era of implemented universal immune-prophylaxis.

A perspective of the relationship of serum HBV DNA and HBsAg apportioned by the same hepatic parenchyma cell volume with inflammation in the natural history of chronic hepatitis B.

This study aimed to investigate the dynamic changes of serum HBV DNA and hepatitis B surface antigen (HBsAg) titers apportioned by the same hepatic parenchyma cell volume (HPCV) at different liver histological inflammation grades in the natural history of chronic hepatitis B (CHB). The serum HBV DNA and HBsAg titers were detected by real-time polymerase chain reaction and electrochemiluminescence, separately, in CHB patients without any treatment. The serum HBV DNA levels and HBsAg titers apportioned by the same HPCV were figured out based on sphere geometry theory. In addition, the differences of HBV DNA levels and HBsAg titers apportioned by the same HPCV in different liver inflammation grades were further assessed based on statistical analysis. There was no difference of serum HBV DNA levels or HBsAg titers before apportioned by the same HPCV in liver inflammation grades 1-4, but significant differences were observed after apportion in CHB patients (HBV DNA: P=0.101; HBsAg: P=0.211 & HBV DNA apportioned by HPCV: P<0.001; HBsAg apportioned by HPCV: P<0.001). No correlation was observed between HBV DNA levels and liver inflammation grades (r=0.083, P=0.186), or between HBsAg titers and liver inflammation grades (r=0.083, P=0.078). A significant correlation was observed between HBV DNA levels apportioned by HPCV and liver inflammation grades (r=0.249, P<0.001), and obvious correlation of HBsAg titers apportioned by HPCV and liver inflammation grades was also found in CHB patients (r=0.554, P<0.001). These results suggest that the levels of serum HBV DNA and HBsAg apportioned by the same HPCV are correlated with the severity of liver histological inflammation grade in the natural history of CHB.

Long-term prognosis with or without nucleot(s)ide analogue therapy in hepatitis B virus-related decompensated cirrhosis.

The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non-liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. HBV DNA ≥20,000IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non-liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non-liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC.

Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity

HBeAg seroconversion during the natural history of chronic hepatitis B (CHB) is associated with a strong drop in serum HBV DNA levels and a reduction of intrahepatic covalently closed circular DNA (cccDNA) content. Of particular interest is the transition to HBeAg-negative chronic infection (ENCI). ENCI, previously known as inactive carrier state, is characterized by very low or negative viremia and the absence of liver disease. The molecular mechanisms responsible for the transition to ENCI and for the control of viral replication in ENCI are still poorly understood. To identify which step(s) in the viral life cycle are controlled during the transition to ENCI, we quantified cccDNA, pre-genomic RNA (pgRNA), total HBV RNA and DNA replicative intermediates in 68 biopsies from patients in different phases of CHB. HBeAg seroconversion is associated with a reduction of cccDNA amounts as well as transcriptional activity. Silencing of cccDNA is particularly pronounced in ENCI, where there was ~46 times less pgRNA per cccDNA compared to HBeAg-negative CHB. Furthermore, a subgroup of patients with HBeAg-negative CHB can be characterized by reduced replication efficiency downstream of pgRNA. The reduction in serum viral load during the transition to ENCI seems to primarily result from strong inhibition of the transcriptional activity of cccDNA which can be maintained in the absence of liver disease. During the natural course of chronic hepatitis B virus infections, the immune response can gain control of viral replication. Quantification of viral DNA and RNA in liver biopsies of patients in different stages of chronic hepatitis B allowed us to identify the steps in the viral life cycle that are affected during the transition from active to inactive disease. Therapeutic targeting of these steps might induce sustained inhibition of viral transcription.

Chronic hepatitis B in children, report of a single-centre longitudinal study on 152 children.

The aims of this prospective study were as follows: (1) to describe the natural history of chronic hepatitis B virus (HBV) infection in a large cohort of untreated children followed at a single centre and (2) to evaluate whether or not the new European Association for the Study of Liver (EASL) classification for the phases of HBV infection in adults can be used for children. All children who presented at the Liver Unit of our hospital from 1 January 1987 to 31 December 2019 and were diagnosed with chronic HBV infection were enrolled. The final sample consisted of 152 children. The median duration of the follow-up was 83months (range 7-232). At baseline, 125 patients (82.2%) were HBeAg positive (85.3% abnormal alanine aminotransferase (ALT) levels), and 24 (15.8%) were HBeAg-negative (93.3% abnormal ALT). At the end of the observation period, 62 of the HBeAg-positive patients (40.7%) achieved HBeAg seroconversion (median age 9.45years, range 0.8-19) and 2 (1.4%) achieved HBsAg seroconversion. Elevated ALT serum levels at baseline (P=.011), lower baseline HBV DNA levels (P<.001) and Asian ethnicity (P=.0001) were identified as predisposing factors towards HBeAg seroconversion. EASL criteria could not be applied to 43.3% and 43.5% of the children at baseline and at end of observation, respectively, that were grouped into an undetermined phenotype category. According to the results of the present study, the new EASL guidelines for adults with HBV infection cannot be applied in a satisfactory manner in children.

Use of hepatitis B virus core-related antigen to evaluate natural history of chronic hepatitis B.

Hepatitis B core-related antigen (HBcrAg) has been shown to correlate with various viral markers in chronic hepatitis B, but its role in defining natural history is not well studied. We aimed to investigate the use of HBcrAg to define different phases of chronic hepatitis B. Stored residual serum samples from longitudinal cohorts of chronic hepatitis B patients in Hong Kong and Japan were studied. Viral markers were measured in three serial serum samples for each patient. Patients were divided into six groups for analysis: hepatitis B e antigen (HBeAg)-positive chronic infection (EPI), HBeAg-positive chronic hepatitis (EPH), HBeAg seroconversion (ES), HBeAg-negative chronic hepatitis (ENH), HBeAg-negative chronic infection (ENI), and HBsAg seroclearance (SS). In total, 166 patients followed up for 100 (76-113) months were included. HBcrAg was correlated with hepatitis B virus DNA and HBsAg levels in both HBeAg-positive and HBeAg-negative patients. HBcrAg cut-off of ≥6.0 log U/mL could best differentiate HBeAg-positive from HBeAg-negative patients (area under receiver operating characteristic curve of 0.99, P<0.001). HBcrAg could not differentiate patients in EPI and EPH phases, but HBcrAg declined dramatically at HBeAg seroconversion. In HBeAg-negative patients, HBcrAg ≥4.0 log U/mL could best differentiate ENH from ENI (area under receiver operating characteristic curve of 0.81; P<0.001), with high specificity (81.6%) but only moderate sensitivity (65.7%) at baseline. Undetectable HBcrAg was found in 17%, 63%, and 89% patients in ENH, ENI, and SS groups at the last visit, respectively. HBcrAg provides useful information to stage the natural history of chronic hepatitis B, particularly identifying HBeAg-positive patients and HBeAg-negative patients with active disease.

2957 Retrospective Review of Patients With Chronic Hepatitis B in Las Vegas, Nevada

INTRODUCTION: The estimated annual incidence of clearance of Hepatitis B surface antigen (HBsAg) is 1–2% in Asian populations. The spontaneous seroclearance of HBsAg in patients with chronic Hepatitis B infection in the Western world is seldomly reported. HBsAg loss is a relatively rare outcome in the natural history of chronic Hepatitis B. Aim of this study was to assess the incidence of spontaneous seroconversion of Hepatitis B surface antigen and the natural development of immunity to HBV virus as evidenced by development of Hepatitis B surface antibody (HBsAb) in a US-based outpatient population. METHODS: Electronic medical records from January 2010 to May 2019 at a large outpatient community-based Gastroenterology practice were retrospectively reviewed. Seroconversion of HBsAg and appearance of HBsAb were recorded. Serologic markers for Hepatitis B infection, AST, ALT, and alpha fetoprotein levels were also recorded. RESULTS: A total of 263 charts were reviewed. One hundred seventy nine (179/263; 68%) of these patients had a positive HBsAg upon referral. Fifty five had a history of Hep B treatment; 124 (124/179; 69%) were treatment-naïve. Forty six (46/179; 26%) had chronic active Hepatitis B, and seventy three (73/179; 40%) were lost to follow up. Five (5/179; 2.7%) patients seroconverted to negative HBsAg. Four of these patients subsequently developed immunity as evidenced by the appearance of HBsAb (4/179; 2.2%). Sixty seven (67/263; 25.5%) of all referred patients had immunity to Hepatitis B through natural infection. Thirteen (13/263; 4.9%) patients had incomplete serologies; 4 (4/263; 1.5%) patients were caught in the “window period” with both negative HBsAg and HBsAb. All four patients who had a documented loss of HBsAg were male, Asians (Filipino), aged 48-65 years. The average time from referral to HBsAg clearance was 8-9 years. None of the 4 patients had a positive Hepatitis delta agent, concomitant infection with Hepatitis C, or elevated AFP. CONCLUSION: Chronic HBV infection poses a significant socio-economic burden specially among immigrant communities from endemic geographic regions. Continued adherence to CDC guidelines for HBV screening should be encouraged among high risk patient populations. Further race/ethnicity and community based studies on the natural history of chronic HBV infection will further increase knowledge of disease prevention and cure.

The present situation and prospect of research on HBeAg-negative mouse model

Hepatitis B virus (HBV) infection is one of the important causes of global liver disease. There are about 250 million patients infected with hepatitis B virus in the world. Chronic HBV infection will lead to liver fibrosis, liver cirrhosis (LC) and even hepatocellular carcinoma (HCC). HBV is a partially double-stranded circular 3.2 kb DNA virus containing four overlapping open reading frames that encode HBsAg, HBeAg, HBcAg, HBV polymerase and HBx protein, respectively. Once HBV particles interacting with sodium taurocholate cotransporting polypeptide (NTCP) on the cell membrane, the nucleocapsid is released into cytoplasm. Subsequently, relaxed circular DNA (rcDNA) is converted to covalently closed circular DNA (cccDNA) in the nucleus, then forms stable minichromosome in the existence of histone and nonhistone proteins. The nucleocapsid can either assemble with viral envelope and released as mature HBV particles or transport back to the nucleus to refill the cccDNA pool. HBV cccDNA serves as a template for viral mRNA synthesis. Persistence of cccDNA is the major course that HBV is hard to eliminate and relapses after drug withdrawal. Though current approved drugs have made huge progress in suppressing viral replication, completely eliminating HBV remains a challenge. The natural history of chronic hepatitis B (CHB) may go through four phases, including the immune tolerant, the immune clearance, the inactive or non-replicative and the re-activation or immune escape phases. During the first two phases the patient is hepatitis B e antigen (HBeAg) positive. On the contrary, during the last two phases the patient is HBeAg-negative. Most infected patients that are HBeAg-negative is usually associated with HBV gene dual mutations of ntA1762T/G1764A and mutation of ntG1896A leading to reduce or HBeAg-negative in basic core promoter (BCP) and PreC region, respectively. The prevalence of HBeAg-negative patients is likely to vary across geographic areas. In recent years, HBeAg-negative patients are increasing globally. Compared with HBeAg-positive patients, HBeAg-negative patients have the following clinic characteristics: More complex course of disease, lower sustained response rate to antiviral drugs and more likely to develop into end-stage liver disease. The mechanism research and drug treatment on HBeAg-negative infection are seriously hampered by the absence of ideal animal model: Simple and efficient transduction method, long-term cccDNA, and model animal with normal immunological function. So far, there have been numerous studies on mouse models of CHB, but few reports about HBeAg-negative mouse models. It is of great significance to study disease mechanisms and develop therapeutic drugs of HBeAg-negative CHB infection using HBeAg-negative CHB mouse model with cccDNA and normal immunological function. In this paper, we have briefly reviewed the research status and application prospect of the model.

European mitochondrial haplogroups predict liver-related outcomes in patients coinfected with HIV and HCV: a retrospective study

BackgroundMitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients.MethodsWe carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk.ResultsThe study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values.ConclusionsEuropean mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

Serum IL-6 level may differentiate immune inactive phase from other phases in patients with chronic hepatitis B virus infection

Abstract Background and Aims Previous studies have found that serum level of IL-6 was increased in HBV-infected patients. Here we evaluate the impact of IL-6 levels according to the natural history of chronic hepatitis B(CHB) infection. Method Patients(n=71) with hepatitis B virus(HBV) were enrolled between September 2016 and Feb. 2018. Treatment-naïve chronic HBV carries were recruited. IFN-γ, TNF-α, IL-2, IL-6, and IL-17A were measured by a cytometric bead assay according to manufacturer’s instructions. Soluble PD-1 and soluble CD14 were made by the enzyme linked immunosorbent assay (ELISA) technique. The assay procedures were followed according to the manufacturer’s instructions. We studied patients with immune inactive phase (HBV DNA&amp;lt; 1,000 copies/ml, anti-HBe + and normal ALT, n=22), immune tolerant phase (HBV DNA &amp;gt; 10,000 copies/ml, HBeAg + and normal ALT, n=36), and immune active phase (elevated ALT and HBV DNA&amp;gt;10,000 copies/ml, n=13). Results Serum IL-6 levels in patients with immune inactive phase were significantly lower than patients with immune tolerant and immune active phases (267.3±245.6 pg/mL vs. 620.2±207.8 pg/mL and 1,815±803.2) (p&amp;lt;0.001). Serum TNF-α levels in patients with immune inactive phase was slightly lower than patients with immune tolerant and immune active phases (3.36±4.40 pg/mL vs. 8.74±12.91 pg/mL and 111.9±377.4) (p=0.079). However, other cytokines (serum IL-2, IL-17A, IFN-γ), soluble CD 14, and soluble PD-1 levels might not be significantly related to the natural history of CHB phase. Conclusion These results demonstrate the potential to apply serum IL-6 as a biomarker for differentiating immune inactive phase from other phases in patients with chronic HBV infection.

Immune response pattern varies with the natural history of chronic hepatitis B.

BACKGROUNDChronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG).AIMTo investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B.METHODSThe frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.RESULTSThe ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.CONCLUSIONOur findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.

Serum HBV RNA quantification: useful for monitoring natural history of chronic hepatitis B infection

BackgroundAs an alternative biomarker of intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B virus (HBV) RNA may evolve during long-lasting virus-host interactions during chronic hepatitis B viral infection. The distribution pattern of serum HBV RNA levels in the natural course of chronic HBV infection remains unclear. The aim of this study was to evaluate the levels of HBV RNA during the natural course of CHB and the role in distinguishing the natural history of HBV infection.MethodsA total of 291 treatment-naïve chronic HBV carriers were enrolled. Based on the clinical, biochemical, serological, and histological data as well as HBV DNA levels, patients were classified into the following four categories: the immune-tolerant phase (IT,n = 35), HBeAg-positive immune-active phase (EPIA,n = 121), inactive chronic hepatitis B(ICH,n = 77) and HBeAg-negative immune reactive hepatitis (ENH,n = 58). The parameters and distribution patterns of serum HBV RNA were evaluated in relation to viral replication status, immune phase, disease category and Child-Pugh class. The relationships between serum HBV RNA and other serum hepatitis B viral markers were also analyzed.ResultsSerum HBV RNA levels were significantly lower in the HBeAg-negative patients compared to those in the HBeAg-positive patients, with the lowest levels seen in inactive carriers. In HBeAg-negative patients, serum HBV RNA levels increased if there is reactivation to active hepatitis and showed obvious superiority for the combination of serum HBV DNA (cutoff>3.39 Log copies/mL) and HBsAg (cutoff>2.74 Log IU/mL) in discriminating between ‘HBeAg-negative immune reactive’ phase and inactive chronic hepatitis B phases of HBeAg-negative chronic HBV infection. Serum HBV RNA levels were positively correlated with serum HBV DNA and HBsAg levels in all chronic HBV-infected patients. A stratified analysis revealed that a correlation between serum HBV RNA and HBV DNA or HBsAg was present in HBeAg-positive patients; however, in HBeAg-negative patients, serum HBV RNA was positively correlated with HBV DNA only.ConclusionDuring the natural course of chronic HBV infection, serum HBV RNA levels vary. Serum HBV RNA can act as a biomarker to predict the natural history of disease in chronic hepatitis B patients. In treatment-naïve HBeAg-negative chronic HBV-infected individuals, serum HBV RNA shows superiority in differentiating the ‘HBeAg-negative reactive’ phase.

Infection par le virus de l’hépatite B : histoire naturelle, manifestations cliniques et principes thérapeutiques

Chronic hepatitis B infection remains a major public-health problem, with approximately 260 million world-wide cases of infection. Recent advances in the understanding of the natural history of chronic hepatitis B infection have led to progress in the care of infected patients. Sustained viral suppression is now possible for a majority of treated patients and is associated with a decrease in the morbidity and mortality attributable to cirrhosis and hepatocellular carcinoma. Complete cure is however not yet possible, due to the long-term persistence of viral DNA in hepatocytes of treated patients. Assessing the risk of viral reactivation in patients receiving immunosuppressive therapy is an increasingly frequent situation in clinical practice and its management is guided by both the patient's serological status and the potency of the immunosuppressive regimen. This review aims to present the clinical and biological presentations of chronic hepatitis B infection, the modalities of antiviral treatment, and how to assess the risk of viral reactivation in patients receiving immunosuppressive therapy.

HBcAg-induced upregulated 4-1BB ligand on B cells contributes to B-cell hyperactivation during chronic hepatitis B infection.

During the natural history of chronic hepatitis B infection (CHB), the function of B cells is still obscure. Several limited studies have suggested that B cells are highly active in patients with CHB. In the present study, we reported that the 4-1BB ligand (4-1BBL) expression on B cells was significantly higher in patients with CHB than that in healthy subjects, meanwhile, the patients with CHB had higher serological IgG levels. Further, after being stimulated with sCD40L or hepatitis B core antigen (HBcAg), B cells had higher levels of 4-1BBL. After being cocultured with 4-1BBL+ B cells, the expressions of CD69 and 4-1BB on CD4+ T cells were significantly higher than that cocultured with 4-1BB- B cells. Cytokines including interleukin (IL)-2, IL-4, and IL-6 were significantly higher in the supernatant from 4-1BBL+ B cells coculture group than those from coculture group of 4-1BBL- B cell group, respectively; while IFN-γ and TNF-α in cocultured supernatant of 4-1BBL+ B cell group were significantly lower. Consistently, the total IgG levels in culture supernatant were significantly higher in 4-1BBL+ B cell group. Thus, hyperactive status of B cells in patients with CHB could be partially derived from the higher 4-1BBL expression on B cells triggered by HBcAg. 4-1BBL signaling pathway is involved in B cells activation, and further regulates B cell-T cell interaction by modulating the cytokines secretion, which might be critical in B cells dysfunction during CHB infection.

Serological and virological markers of nigerian patients with hepatitis B infection.

The natural history of chronic hepatitis B virus (HBV) infection and the spectrum of diseases attributable to chronic hepatitis B are diverse. It is estimated that 15%-25% of chronic carriers will die from complications of progressive disease such as liver cirrhosis, hepatocellular carcinoma, and hepatic decompensation. The main aim of this study is to evaluate the serological and virological profile of patients with hepatitis B infection to enhance the evaluation of the natural history of viral hepatitis in an endemic population. Characteristics of hepatitis B surface antigen (HBsAg) patients (2010-2016) were extracted from the database of a reference laboratory in Lagos. These included serological tests for hepatitis B antigens (HBeAg, HBsAg), antibodies (anti-HBcIgM, anti-HBeAb) (DIA.PRO), and HBV DNA (Roche Diagnostics). SPSS version 20.0 was used for data analysis. Of the 1,983 patients, 1,252 were male and 731 female. HBeAg was detected in 8.0% (128/1,605) of the subjects, anti-HBe was positive in 90.0% (1,257/1,396), while HBcore subclass IgM antibody was detected in 12.6% (116/930). Detectable HBV DNA was identified in 1,781 (89%), with viral load exceeding 2,001 IU/mL in 712 (35.9%) subjects. HBV viral loads >200,000 IU/mL were more frequently detected in HBeAg-positive compared with HBeAg-negative subjects (65.7% vs 4.9%, P < 0.0001). We have demonstrated the predominance of low replicative phase HBV infection and highlighted the importance of HBeAg-negative infections that may require antiviral therapy. HBeAg-positive infections occurred significantly in younger adults with new or acute infections. Our findings have implications for patient evaluation and planning of hepatitis treatment programs.

Risk factors of transmission and natural history of chronic hepatitis B infection in Iranian patients.

To investigate routes of transmission, demographic characteristics, and frequency of different phases of chronic hepatitis B (CHB) in 2000 Iranian patients. Knowledge about the most frequent risk factors of CHB and its different phases is very important for optimal prevention and management policy making. In this cross-sectional study, 2000 HBsAg positive patients who were referred to Taleghani Hospital from 2011 through 2018 were enrolled. ELISA method was employed to detect serological markers of CHB. Taking into account the HBV DNA and ALT levels and HBeAg status, the patients were classified in four groups, according to AASLD 2017 guideline. Male and female patients had nearly equal frequencies in our study and 82.5 % of them aged more than 20 years. A great number of our patients (95%) were HBeAg negative and the most frequent risk factors of HBV infection were positive periodontal and family history (40.3% and 24.9%, respectively). The majority of our patients were inactive carriers (63.35%), while s mall number of them were in the immune tolerant group (2.15 %). Immune tolerance phase group had the minimum number of members in our study and most of them were above 20 years old. This can be due to the mass vaccination of neonates since 1993. Most of CHB patients were in inactive carrier group. Although it is recommended not to treat these patients, performing periodic liver function tests and disease severity assessment is warranted, especially in patients above 40 years old.

On-Treatment Improvement of MELD Score Reduces Death and Hepatic Events in Patients With Hepatitis B-Related Cirrhosis

Antiviral treatment modifies the natural history of chronic hepatitis B (CHB)-related cirrhosis as reflected by improving Model for End-Stage Liver Disease (MELD) score over time. We evaluated the impact of on-treatment change of MELD score on clinical outcomes in patients with CHB-related cirrhosis. Cirrhotic CHB patients who received entecavir and/or tenofovir disoproxil fumarate for at least 6 months in Hong Kong between 2005 and 2016 were identified. The primary outcome was all-cause mortality; secondary outcomes were hepatocellular carcinoma (HCC), and hepatic events including ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, hepatic encephalopathy, and liver transplantation. We identified 1743 cirrhotic CHB patients. Their mean MELD score decreased from 12.3 ± 5.5 at baseline to 11.0 ± 4.7 at month 6. At a median (interquartile range) follow-up of 3.9 (1.9-6.0) years, 290 (16.6%) patients died; 201 (11.5%) developed HCC. Among 1140 patients without prior hepatic events, 150 (13.2%) developed hepatic events. Among 464 patients with baseline MELD score ≥15, the 6-year cumulative mortality was 72.8, 36.7, and 23.1% for unchanged or increased MELD score, 1-5 point improvement in MELD score, and >5 point improvement in MELD score at month 6, respectively (log-rank test, P < 0.001); the corresponding 6-year cumulative incidence of hepatic events was 52.7, 30.5, and 23.9% in the three subgroups (Gray's test, P = 0.004). Patients with MELD score <15 at month 6 had lower risk of mortality and hepatic events (all P < 0.001). On-treatment improvement of MELD score correlates with reduced risk of mortality and hepatic events in cirrhotic CHB patients.

A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B.

Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome-wide association study (GWAS)-identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with the full spectrum of hepatitis B virus (HBV) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated. To determine whether STAT4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this effect. STAT4 rs7574865 was genotyped in 1085 subjects (830 with CHB and 255 healthy controls). STAT4 expression in liver, PBMCs and NK cells, STAT4 phosphorylation and secretion of interferon-gamma (IFN-γ) according to STAT4 genetic variation was examined. STAT4 rs7574865 genotype was independently associated with hepatic inflammation (OR: 1.42, 95% CI: 1.07-2.06, P=0.02) and advanced fibrosis (OR: 1.83, 95% CI: 1.19-2.83, P=0.006). The minor allele frequency of rs7574865 was significantly lower than that in healthy controls. rs7574865 GG risk carriers expressed lower levels of STAT4 in liver, PBMCs and in NK cells, while NK cells from patients with the risk genotype had impaired STAT4 phosphorylation following stimulation with IL-12/IL-18 and a reduction in secretion of IFN-γ. Genetic susceptibility to HBV persistence, hepatic inflammation and fibrosis in Caucasians associates with STAT4 rs7574865 variant. Downstream effects on NK cell function through STAT4 phosphorylation-dependent IFN-γ production likely contribute to these effects.

Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend.

The natural history of chronic hepatitis B (CHB) is complex and may run through different immune phases that may overlap. In particulars, the immune-tolerant phase is the most interesting and not as well understood as we thought. The concept of true immune tolerance have been under challenged from immunology points of view. The major international guidelines have not yet reached a consensus on the definition of the immune-tolerant phase. While positive hepatitis B e antigen (HBeAg), high serum hepatitis B virus (HBV) DNA and normal serum alanine aminotransferase (ALT) levels are the three key features of this phase, some guidelines also put age into consideration. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest European Association for the Study of the Liver (EASL) published in April 2017. While current guidelines advise against starting antiviral treatment for immune-tolerant CHB patients, some new data suggest treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.

Differentially Expressed Intrahepatic Genes Contribute to Control of Hepatitis B Virus Replication in the Inactive Carrier Phase.

The natural history of chronic hepatitis B virus (HBV) infection was divided into 4 phases. Patients in the inactive carrier (IC) status and immune tolerant (IT) phase had normal alanine aminotransferase levels but huge different viral loads. The mechanism underlying low viral replication status in IC phase is unknown. We determined the intrahepatic transcriptomes of 83 chronic hepatitis B patients by microarray analysis of liver biopsies, and screened the effect of differentially regulated genes on HBV replication using specific small interfering RNAs in vitro. The gene profile distinguishing active chronic hepatitis from IT and IC was predominantly composed of immune-related genes. The liver transcriptomes between the IT and IC phase were largely similar, and 109 expressed genes were significantly different. By performing systematic screening, 5 candidate genes including EVA1A, which were expressed at a relative higher level in IC phase than IT, were identified to regulate HBV replication and gene expression in cellular models. The immune-related pathways were up-regulated in the active chronic hepatitis phase but not in the IT and IC phase. A number of intrahepatic genes highly expressed in the IC phase may participate in the control of HBV replication and determine the inactive status of HBV infection.