New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection:Increase of entecavir dosage

Chronic hepatitis B virus(HBV)infection(CHB)is a public health concern worldwide.Current therapies utilizing nucleos(t)ide analogs(NA)have not resulted in a complete cure for CHB.Furthermore,patients on long-term NA treatment often develop low-level viremia(LLV).Persistent LLV,in addition to causing the progression of liver disease or hepatocellular carcinoma,may shed light on the current plight of NA therapy.Here,we review the literature on LLV,NA treatment,and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent.For LLV patients,three therapeutic options are available,switching to another antiviral monotherapy,interferon-αswitching therapy,and continuing monotherapy.In real-world clinical practice,entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV,which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies.The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety,and has great potential in inhibiting HBV replication,in all of the NAs.In the particular section of the drug approval package published by the United States Food and Drug Administration,entecavir doses 2.5-20 mg/d do not increase adverse events,and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy.The literature survey led us to two suggestions:(1)Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA>2×106 IU/mL is feasible and would provide better prognosis;and(2)Further research is needed to assess the long-term toxic effects of higher entecavir doses(2.5 and 5.0 mg/d),which may prove beneficial in treating patients with prior NA treatment,partial virological response,or LLV state.

Baseline hepatocyte ballooning is a risk factor for adverse events in patients with chronic hepatitis B complicated with nonalcoholic fatty liver disease

BACKGROUND Although many studies have investigated the impact of chronic hepatitis B virus(HBV)infection and nonalcoholic fatty liver disease(NAFLD)on liver disease,few have investigated the relationship between nonalcoholic steatohepatitis(NASH)defined by liver pathology and the prognosis of chronic HBV infection.Most patients were followed up for a short time.This study aimed to further explore the impact of NAFLD and the pathological changes confirmed by liver pathology in patients with chronic HBV infection.AIM To study the effect of NAFLD confirmed using liver pathology on the outcomes of long-term serious adverse events[cirrhosis,hepatocellular carcinoma(HCC),and death]in patients with chronic hepatitis B(CHB)virus infection.METHODS We enrolled patients with chronic hepatitis B virus(HBV)infection who underwent liver biopsy at the Third People’s Hospital of Zhenjaing Affiliated Jiangsu University between January 2005 and September 2020.Baseline clinical and pathological data on liver pathology and clinical data at the end of follow-up were collected.Propensity score matching(PSM)was used to balance baseline parameters,Kaplan-Meier(K-M)survival analysis was used to evaluate the risk of clinical events,and Cox regression was used to analyze the risk factors of events.RESULTS Overall,456 patients with chronic HBV infection were included in the study,of whom 152(33.3%)had histologically confirmed NAFLD.The median follow-up time of the entire cohort was 70.5 mo.Thirty-four patients developed cirrhosis,which was diagnosed using ultrasound during the follow-up period.K-M survival analysis showed that NAFLD was not significantly associated with the risk of cirrhosis(log-rank test,P>0.05).Patients with CHB with fibrosis at baseline were more prone to cirrhosis(log-rank test,P=0.046).After PSM,multivariate analysis showed that diabetes mellitus,ballooning deformation(BD),and platelet(PLT)were independent risk factors for cirrhosis diagnosed using ultrasound(P<0.05).A total of 10 patients(2.2%)developed HCC,and six of these patients were in the combined NAFLD group.K-M survival analysis showed that the cumulative risk of HCC in the NAFLD group was significantly higher(log-rank test,P<0.05).Hepatocyte ballooning,and severe liver fibrosis were also associated with an increased risk of HCC(log-rank test,all P<0.05).Cox multivariate analysis revealed that hepatocyte ballooning,liver fibrosis,and diabetes mellitus were independent risk factors for HCC.CONCLUSION There was no significant correlation between chronic HBV infection and the risk of cirrhosis in patients with NAFLD.Diabetes mellitus,BD,and PLT were independent risk factors for liver cirrhosis.Patients with chronic HBV infection and NASH have an increased risk of HCC.BD,liver fibrosis,and diabetes mellitus are independent risk factors for HCC.

Plasmacytoid Dendritic Cell Function and Cytokine Network Profiles in Patients with Acute or Chronic Hepatitis B Virus Infection

Background： Plasmacytoid dendritic cells （pDCs） and cytokines play an important role in occurrence and recovery of hepatitis B virus （HBV） infection. The aim of this study was to explore the frequency and function ofpDC and serum cytokine network profiles in patients with acute or chronic HBV infection. Methods： The healthy individuals （HI group）, hepatitis B envelope antigen （HBeAg）-positive chronic HBV patients in immune tolerance （IT） phase （IT group）, HBeAg-positive chronic HBV patients （CHB group）, and acute HBV patients （AHB group） were enrolled in this study. The frequency of cluster of differentiation antigen 86 （CD86） ＋ pDC and the counts of CD86 molecular expressed on surface ofpDC were tested by flow cytometer. The quantitative determinations ofcytokines, including Fins-like tyrosine kinase 3 ligand （FIt-3L）, interferon （1FN）-α2, IFN-γ, interleukin （IL）-17A, IL-6, IL-10, transforming growth factor （TGF）-β1 and TGF-β2, were performed using Luminex multiplex technology. Results： In this study, there were 13 patients in HI group, 30 in IT group, 50 in CHB group, and 32 in AHB group. Compared with HI group, HBV infected group （including all patients in IT, CHB and AHB groups） had significantly higher counts of CD86 molecular expressed on the surface ofpDC （4596.5 ± 896.5 vs. 7097.7 ± 3124.6; P 〈 0.001）. The counts of CD86 molecular expressed on the surface of pDC in CriB group （7739.2 ±4125.4） was significantly higher than that of IT group （6393.4 ± 1653.6, P=0.043）. Compared with IT group, the profile of cytokines of FIt-3L, IFN-γ, and IL-17A was decreased, IFN-α2 was significantly increased （P =0.012） in CH B group. The contents of IL-10, TGF-{31, and TGF-132 in AHB group were significantly increased compared with IT and CHB groups （all P 〈 0.05）. Conclusions： This study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-α2 might involve triggering the immune response from IT to hepatitis active phase in H BV infection. Acute patients mainly presented as down-regulation of the immune response by enhanced IL-10 and TGF-β.

Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure

AIM: To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure (ACLF) patients with chronic hepatitis B virus (HBV) infection as the single etiology. METHODS: Full length and caspase cleaved cytokeratin 18 (detected as M65 and M30 antigens) represent circulating indicators of necrosis and apoptosis. M65 and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls (n = 33), patients with chronic hepatitis B (CHB, n = 55) and patients with ACLF (n = 81). According to the 3-mo survival period, ACLF patients were defined as having spontaneous recovery (n = 33) and non-spontaneous recovery which included deceased patients and those who required liver transplantation (n = 48). RESULTS: Both biomarker levels significantly increased gradually as liver disease progressed (for M65: P < 0.001 for all; for M30: control vs CHB, P = 0.072; others: P < 0.001 for all). In contrast, the M30/M65 ratio was significantly higher in controls compared with CHB patients (P = 0.010) or ACLF patients (P < 0.001). In addition, the area under receiver operating characteristic curve (AUC) analysis demonstrated that both biomarkers had diagnostic value (AUC >= 0.80) in identifying ACLF from CHB patients. Interestingly, it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients (P = 0.032). The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores at the 3-mo survival period, the AUC of the M30/M65 ratio was 0.66 with a sensitivity of 52.9% and the highest specificity of 92.6% (MELD:AUC = 0.71; sensitivity, 79.4%; specificity, 63.0%; Child-Pugh: AUC = 0.77; sensitivity, 61.8%; specificity, 88.9%). CONCLUSION: M65 and M30 are strongly associated with liver disease severity. The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in patients with HBV-related ACLF. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Hepatitis B virus DNA is more powerful than HBeAg in predicting peripheral T-lymphocyte subpopulations in chronic HBV-infected individuals with normal liver function tests

AIM:To investigate the peripheral T-lymphocyte subpopulation profile,and its correlations with hepatitis B virus(HBV) replication level in chronic HBV-infected(CHI) individuals with normal liver function tests(LFTs) . METHODS:Frequencies of T-lymphocyte subpopu-lations in peripheral blood were measured by flow cytometry in 216 CHI individuals. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time PCR. Information of age at HBV infection,and maternal HBV infection status was collected. ANOVA linear trend test and linear regression were used in statistical analysis. RESULTS:CHI individuals had significantly decreased relative frequencies of CD3+,CD4+ subpopulationsand CD4+/CD8+ ratio,and increased CD8+ subset percentage compared with uninfected individuals(all P < 0.001) . There was a significant linear relationship between the load of HBV DNA and the parameters of T-lymphocyte subpopulations(ANOVA linear trend test P < 0.01) . The parameters were also significantly worse among individuals whose mothers were known to be HBV carriers,and those having gained infection before the age of 8 years. In multiple regressions,after adjustment for age at HBV infection and status of maternal HBV infection,log copies of HBV DNA maintained its highly significant predictive coefficient on T-lymphocyte subpopulations,whereas the effect of HBeAg was not significant. CONCLUSION:HBV DNA correlates with modification in the relative T-lymphocyte subpopulation frequencies. High viral load is more powerful than HBeAg in predicting the impaired balance of T-cell subsets.

B cell dysfunction in chronic hepatitis B virus infection

Chronic hepatitis B(CHB)remains a global health problem.The persistence of hepatitis B surface antigen(HBsAg)in the blood for longer than 6 months after the initial infection is a sign of CHB.The therapeutic goal for the functional cure of CHB is the generation of antibodies against HBsAg.However,the adaptive immune response of patients with CHB cannot generate an efficient antiviral response.Many previous studies have evaluated T cell function and T cell therapy specifically designed to counter hepatitis B virus(HBV)infection.As one of the major components of adaptive immunity,B cells also display dysfunctions in anti-HBsAg antibody(HBsAb)production and antigen presentation.Patients with CHB have amplification of CD19^(+)CD10^(-)CD27^(-)CD21^(-)atypical memory B cell subsets and CD19^(+)CD24^(hi)CD38^(hi) regulatory B cells.Currently,no reviews have summarized specific B cell responses during CHB infection.Thus,in this study,we summarized B cell dysfunction during CHB progression and the potential mechanisms behind these dysfunctions to further our understanding of the mechanisms of adaptive immune response of B cells in the process of CHB development and help provide new methods and ideas for the treatment of CHB.

Serum and ascites levels of macrophage migration inhibitory factor, TNF-α and IL-6 in patients with chronic virus hepatitis B and hepatitis cirrhosis

Objective: To study the potential role of macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the development of chronic virus hepatitis B (CH) and hepatitis cirrhosis (HC). Methods: The serum concentrations of MIF, TNF-α and IL-6 in 18 patients with chronic virus hepatitis B and in 14 patients with hepatitis cirrhosis without as- citic fluid, and the serum and ascites cytokine con- centrations in 22 HC patients with ascitic fluid were detected by enzyme linked immunity sorbed assay. Results: The cytokine concentrations of the patients were significantly higher than those of the controls. The serum levels of MIF, TNF-α and IL-6 of the 22 patients with ascitic fluid were higer than those of 14 HC patients without ascites. In the 18 patients with CH, the serum cytokine concentrations were the low- est. The serum cytokine concentrations of the 22 HC patients with ascites were significantly higher than those of the 14 HC patients without ascites (P< 0. 01). Their serum cytokine concentrations were sig- nificantly higher than those in the 18 patients with CH (P<0. 01). The concentration of IL-6 in ascites was the highest among all the groups. The serum le- vels of MIF, TNF-α and IL-6 are correlated with al- anine aminotransferase (ALT) in the patients with CH, but not in those with HC with or without asci- tes. Conclusions: These results indicated that MIF, TNF- α and IL-6 may participate in the pathological process of CH and cirrhosis, that IL-6 seems to play an important role in ascites formation, and that se- rum levels of MIF, TNF-α and IL-6 appear to reflect the severity of tissue injury in HBV disease.

Management of chronic hepatitis B infection: Current treatment guidelines, challenges, and new developments

Chronic hepatitis B(CHB)virus infection is a global public health problem,affecting more than 400 million people worldwide.The clinical spectrum is wide,ranging from a subclinical inactive carrier state,to progressive chronic hepatitis,cirrhosis,decompensation,and hepatocellular carcinoma.However,complications of hepatitis B virus(HBV)-related chronic liver disease may be reduced by viral suppression.Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon,entecavir,or tenofovir,but the optimal treatment for an individualpatient is controversial.The indications for treatment are contentious,and increasing evidence suggests that HBV genotyping,as well as serial on-treatment measurements of hepatitis B surface antigen and HBV DNA kinetics should be used to predict antiviral treatment response.The likelihood of achieving a sustained virological response is also increased by extending treatment duration,and using combination therapy.Hence the paradigm for treatment of CHB is constantly evolving.This article summarizes the different indications for treatment,and systematically reviews the evidence for the efficacy of various antiviral agents.It further discusses the shortcomings of current guidelines,use of rescue therapy in drug-resistant strains of HBV,and highlights the promising clinical trials for emerging therapies in the pipeline.This concise overview presents an updated practical approach to guide the clinical management of CHB.

Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

AIM: To investigate peripheral T-lymphocyte sub-population profile and its correlation with hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB).METHODS: Distribution of T-lymphocyte subpopulations in peripheral blood was measured by flow cytometry in 206 CHB patients. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time polymerase chain reaction (PCR). The relationship between HBV replication and variation in peripheral T-cell subsets was analyzed.RESULTS: CHB patients had significantly decreased CD3+ and CD4+ cells and CD4+/CD8+ ratio, and increased CD8+ cells compared with uninfected controls (55.44 ± 12.39 vs 71.07 ± 4.76, 30.92 ± 7.48 vs 38.94 ± 3.39, 1.01 ± 0.49 vs 1.67 ± 0.33, and 34.39 ± 9.22 vs 24.02 ± 4.35; P < 0.001, respectively). Univariate analysis showed a similar pattern of these parameters was significantly associated with high viral load, presence of serum hepatitis B e antigen (HBeAg) expression, liver disease severity, history of maternal HBV infection, and young age at HBV infection, all with P < 0.01. There was a significant linear relationship between viral load and these parameters of T-lymphocyte subpopulations (linear trend test P < 0.001). There was a negative correlation between the levels of CD3+ and CD4+ cells and CD4+/CD8+ ratio and serum level of viral load in CHB patients (r = -0.68, -0.65 and -0.75, all P < 0.0001), and a positive correlation between CD8+ cells and viral load (r = 0.70, P < 0.0001). There was a significant decreasing trend in CD3+ and CD4+ cells and CD4+/CD8+ ratio with increasing severity of hepatocyte damage and decreasing age at HBV infection (linear trend test P < 0.01). In multiple regression (after adjustment for age at HBV infection, maternal HBV infection status and hepatocyte damage severity) log copies of HBV DNA maintained a highly significant predictive coefficient on T-lymphocyte subpopulations, and was the strongest predictor of variation in CD3+, CD4+, CD8+ cells and CD4+/CD8+ ratio. However, the effect of HBeAg was not significant.CONCLUSION: T-lymphocyte failure was signifi-cantly associated with viral replication level. The substantial linear dose-response relationship and strong independent predictive effect of viral load on T-lymphocyte subpopulations suggests the possibility of a causal relationship between them, and indicates the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients.

No association between IRF3 polymorphism and susceptibility to hepatitis B virus infection in Chinese patients

AIM:To investigate the association between three tag single nucleotide polymorphisms (tagSNPs) in inter-feron regulatory factors (IRF3) and the genetic suscep-tibility to chronic hepatitis B virus (HBV) infection.METHODS:We performed a case-control study of 985 Chinese cases of chronic HBV infection and 294 self-limiting HBV-infected individuals as controls.Three tagSNPs in IRF3 (rs10415576,rs2304204,rs2304206) were genotyped with the Multiplex SNaPshot technique.The genotype and allele frequencies were calculatedand analyzed.RESULTS:The three SNPs showed no significant geno-type/allele associations with chronic HBV infection.Overall allele P values were:rs10415576,P=0.0908,odds ratio (OR) [95% confidence interval (CI)]=1.1798 (0.9740-1.4291);rs2304204,P=0.5959,OR (95% CI)=1.0597 (0.8552-1.3133);rs2304206,P=0.8372,OR (95% CI)=1.0250 (0.8097-1.2976).Overall genotype P values were:rs10415576,P=0.2106;rs2304204,P=0.8458;rs2304206,P=0.8315.There were no statisti-cally significant differences between patients with chron-ic HBV infection and controls.Haplotypes generated by these three SNPs were also not significantly different between the two groups.CONCLUSION:The three tagSNPs of IRF3 are not asso-ciated with HBV infection in the Han Chinese population.

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Global prophylactic vaccination programmes have helped to curb new hepatitis B virus(HBV)infections.However,it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma.As such,HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed.Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA(cccDNA)which establishes itself as a minichromosome in the nucleus of hepatocytes.As the viral transcription intermediate,the cccDNA is responsible for producing new virions and perpetuating infection.HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications.Two HBV proteins,X(HBx)and core(HBc)promote viral replication by modulating the cccDNA epigenome and regulating host cell responses.This includes viral and host gene expression,chromatin remodeling,DNA methylation,the antiviral immune response,apoptosis,and ubiquitination.Elimination of the cccDNA minichromosome would result in a sterilizing cure;however,this may be difficult to achieve.Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure.This review explores the cccDNA epigenome,how host and viral factors influence transcription,and the recent epigenetic therapies and epigenome engineering approaches that have been described.

Treatment of Chronic Hepatitis B with Tenofovir Disoproxil Fumarate in Ivory Coast

Little data exist on patients treated with tenofovir in Sub-Saharan Africa. Objective: To describe the clinical and laboratory characteristics of patients with viral hepatitis B treated with tenofovir. Material and methods: A descriptive single-center retrospective study, on chronic viral hepatitis B mono-infected, followed in the hepatogastroenterology department of the University Hospital of Yopougon and treated with tenofovir from February 2012 to February 2015. The studied parameters were demographic, clinical, biochemical, serological, virological, abdominal ultrasound. Liver fibrosis was assessed either by liver biopsy or non-invasive tests. Results: 110 patients were treated with tenofovir disoproxil fumarate with a mean age of 40.4 years and a male predominance. Clinical examination revealed jaundice in 9% of cases, hepatomegaly in 7.3% of cases, splenomegaly in 9.1% of cases and ascites in 15.5% of cases. The AST averaged 77.3 IU/l, the ALT 76.8 IU/l, prothrombin rate at 76.6% , albumin level at 32.3 g/l, total bilirubin at 29.9 g/l, alpha fetoprotein rate at 15.3 ng/ml. HBe antigen was negative in 76.2% of cases. The average rate of DNA at baseline was 7.4 log10 IU/l. 27.5% was cirrhotic. The average time of starting treatment was 23.7 months. Conclusion: TDF is the first-line treatment for chronic hepatitis B in our country, because it is a well-tolerated, potent therapy with a high threshold for resistance development. Our study population had an average age of 40.4 years. Virological profile was dominated by HBe antigen negative patients and high viral load of HVB DNA. One third of patients were at the stage of cirrhosis. This treatment must be delivered free of charge in all the country hospitals, which is going to improve significantly the natural evolution of the disease and to decrease the incidence of the HCC.

Management of chronic hepatitis B in pregnancy

Pregnancy associated with chronic hepatitis B (CHB) is a common and important problem with unique challenges. Pregnant women infected with CHB are different from the general population, and their special problems need to be considered: such as the effect of hepatitis B virus (HBV) infection on the mother and fetus, the effect of pregnancy on replication of the HBV, whether mothers should take HBV antiviral therapy during pregnancy, the effect of these treatments on the mother and fetus, how to carry out immunization of neonates, whether it can induce hepatitis activity after delivery and other serious issues. At present, there are about 350 million individuals with HBV infection worldwide, of which 50% were infected during the perinatal or neonatal period, especially in HBV-endemic countries. Currently, the rate of HBV infection in thechild-bearing age group is still at a high level, and the infection rate is as high as 8.16%. Effective prevention of mother-to-child transmission is an important means of reducing the global burden of chronic HBV infection. Even after adopting the combined immunization measures, there are still 5%-10% of babies born with HBV infection in hepatitis B e antigen positive pregnant women. As HBV perinatal transmission is the main cause of chronic HBV infection, we must consider how to prevent this transmission to reduce the burden of HBV infection. In this population of chronic HBV infected women of childbearing age, specific detection, intervention and follow-up measures are particularly worthy of attention and discussion.

Peripheral T-lymphocyte subpopulations in different clinical stages of chronic HBV infection correlate with HBV load

AIM： To characterize the peripheral T-cell subpopulation profiles and their correlation with hepatitis B virus （HBV） replication in different dinical stages of chronic HBV infection. METHODS： A total of 422 patients with chronic HBV infection were enrolled in this study. The patients were divided into three stages： immune-tolerant stage, immune active stage, and immune-inactive carrier stage. Composition of peripheral T-cell subpopulations was determined by flow cytometry. HBV markers were detected by enzyme-linked immunosorbent assay. Serum HBV DNA load was assessed by quantitative real-time poiymerase chain reaction.RESULTS： CD8^＋ T-cells were significantly higher in patients at the immune-tolerant stage than in patients at the immune-active and -inactive carrier stages （36.87 ± 7.58 vs 34.37 ± 9.07, 36.87 ± 7.58 vs 28.09 ± 5.64, P 〈 0.001）. The peripheral blood in patients at the immune-tolerant and immune active stages contained more CD8^＋ T-cells than CD4^＋ T-cells （36.87 ± 7.58 vs 30.23 ± 6.35, 34.37 ± 9.07 vs 30.92 ± 7.40, P 〈 0.01）, whereas the peripheral blood in patients at the immune- inactive carrier stage and in normal controls contained less CD8^＋ T-cells than CD4^＋ T-cells （28.09 ± 5.64 vs 36.85 ±6.06, 24.02 ± 4.35 vs 38.94 ± 3.39, P 〈 0.01）. ANOVA linear trend test showed that CD8^＋ T-cells were significantly increased in patients with a high viral load （39.41 ± 7.36, 33.83 ± 7.50, 31.81 ± 5.95 and 26.89 ± 5.71, P 〈 0.001）, while CD4^＋ T-cells were significantly increased in patients with a low HBV DNA load （37.45 ± 6.24, 33.33 ± 5.61, 31.58 ± 6.99 and 27.56 ± 5.49, P 〈 0.001）. Nultiple regression analysis displayed that log copies of HBV DNA still maintained its highly significant coefficients for T-cell subpopulations, and was the strongest predictors for variations in CD3^＋, CD4^＋ and CD8^＋ cells and CD4^＋/CD8^＋ ratio after adjustment for age at HBV-infection, maternal HBV-infection status, presence of hepatitis B e antigen and HBV mutation.CONCLUSION： Differences in peripheral T-cell subpopulation profiles can be found in different clinical stages of chronic HBV infection. T-cell impairment is significantly associated with HBV load.

The “return” of hepatitis B

There has been a significant advance in the treatment of chronic Hepatitis B virus （HBV） infection and the following drugs were approved for therapy： Conventional interferon （IFN）, pegylated interferon alfa-2a （PEG IFN α2a）, lamivudine, adefovir and entecavir. Compared to nucleoside analogues IFN induces higher rates of sustained remission and HBsAg loss. Conventional TFN in lower doses （1, 5-3 MIU） tiw for 4-6 mo has similar efficacy in comparison to ＂standard IFN therapy＂. Longer IFN treatment is a significant factor for longterm remission in HBeAg-negative CHB, but the higher actual IFN dose is not such a factor. PEG IFN is superior to conventional IFN. There is no significant difference between PEG IFN α2a at doses 90 mcg/wk and 180 mcg/wk in HBeAg-positive patients. These results provide a rational for further clinical trials with lower doses PEG IFN α2a given in prolonged course as maintenance or intermittent treatment. Serious new problems arose after the introduction of nucleoside/nucleotide analogues in clinical practice. The most important ones are drugresistance and the high rates of relapse after treatment discontinuation. Therapy should only be recommended if the expected benefit exceeds significantly the abstain from treatment. The choice of therapy should take into account the patient＇s age, co-morbidity, severity of liver disease and the risk of drug-resistance. New antivirals significantly suppress HBV-replication, but have no effect on cccDNA in hepatocytes, and after the treatment discontinuation viral relapses occurs. At the present level of knowledge it is impossible ＂to eradicate the virus＂ The realistic treatment goal is to achieve durable response by clearance of HBeAg, sustained decrease of serum HBV DNA levels, normalization of ALT, improvement of liver histology and stopping of liver fibrogenesis. The competition between IFN based therapy and nucleoside or nucleotide analogues still remains. IFN can cure the liver disease while nucleotide analogues only suppress the viral replication during therapy and can reduce the liver fibrosis. Treatment should be prolonged for 24-mo or longer by using maintenance or intermittent treatment course with the lowest effective IFN and PEG IFN doses. Nucleoside/nucleotide analogues are a promising treatment option, but additional data for treatment duration and long-term post-treatment outcome are necessary.

Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naive Patients with Chronic Hepatitis B Virus Infection

Background： Estimating the grades of liver inflammation is critical in the determination ofantiviral therapy in patients chronically infected with hepatitis B virus （HBV）. The aim of this study was to investigate the correlation ofserum levels of hepatitis B surface antigen （HBsAg） and hepatitis B e antigen （HBeAg） with the liver inflammation grades in treatment-naTve patients with chronic HBV infection. Methods： We retrospectively enrolled 584 treatment-na＇l＇ve HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used lbr statistical analysis of all relevant data. Results： The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively （X2 =26.00, P 〈 0.001 ）. The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff. respectively; both antigens tended to decrease as the grade of inflammation increased （X2 = 99.68 and X2 =99.23, respectively; both P 〈 0.001 ）. The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 Iog S/CO, respectively, 1 to distinguish minimal grade and other grades of treatment-naTve HBeAg-positive patients with chronic HBV infection. Conclusions： Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values rnight help us to distinguish rninimal grades and other grades and detect those who do not need antiviral therapy in treatment-naive HBeAg-positive patients with chronic HBV infection.

Effectiveness of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase and Positive Hepatitis B Virus DNA

Background and Aims:With an increasing understanding of hepatitis B,the antiviral indications have been broadening gradually.To evaluate the effectiveness of tenofovir alafena-mide(TAF)in chronic hepatitis B(CHB)patients with normal alanine aminotransferase(ALT)and detectable hepatitis B virus(HBV)DNA,those who are ineligible for broader anti-viral criteria from the Chinese CHB prevention guide(2019).Methods:A total of 117 patients were recruited and their data were collected from paper or electronic medical records.HBV DNA and liver function were measured at baseline and throughout the 24-week follow-up.The effectiveness end-point was complete virological response.The safety endpoint was the first occurrence of any clinical adverse event during the treatment.Results:Among the 117 patients,45 had normal ALT as well as detectable HBV DNA and they were not recommended for antiviral therapy according to Chinese Guidelines(2019).After TAF antiviral therapy,the rates of patients who achieved HBV DNA<20 IU/mL at 4,12 and 24 weeks were 77.1%,96.7%and 96.8%respectively.Among them,the undetectable rates of HBV DNA in patients with low baseline viral load at 4,12 and 24 weeks were 92.3%,100%and 100%,while the rates of those with high baseline viral load were 68.2%,94.1%and 94.4%.Compared with 71.4%,94.4%and 94.7%in the high baseline group,the undetectable rates of HBV DNA at 4,12 and 24 weeks in the low baseline liver stiffness group were 85.7%,100%and 100%.There was no statistical significance among the above groups.Conclusions:CHB patients who had normal ALT and detectable HBV DNA and did not meet“CHB prevention guide(2019)”,could achieve complete virological response in 24 weeks after antiviral treatment by TAF.

A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection

Objective To evaluate the effect of lamivudine on the loss of serum he patitis B virus (HBV) DNA, HBeAg/antiHBe seroconversion and ALT levels in chron ic hepatitis B patients and its safety profile and tolerance compared with place bo.Methods Four hundred and twenty nine patients with chronic HBV infecti on as defined by positive HBsAg, HBeAg and HBV DNA were enrolled and randomized into lamivudine and placebo groups. Three hundred and twenty two patients recei ved lamivudine 100?mg daily and 107 patients received placebo treatment for 12 weeks. Then, all patients were offered a further 9 month open label lamivudine treatment. The efficacy and safety were evaluated with clinical, biochemical, hematological and virological parameters. Results During the 12 week treatment period, 92.2% of lamivudine t reate d patients became HBV DNA negative (below 1.6?pg/ml) compared with only 14.1% o f those receiving placebo (P<0.01). At the end of 12 week, the sust ained negative rate for HBV DNA in the lamivudine treated group was 78.5% compar ed with the placebo group (11.1%; P< 0.01). There was a trend to a high proportion of patients treated with lamivudine to lose HBeAg (8.1%) and d evelop antiHBe (10.2%) than treated with placebo (5.3% and 6.4% respectively), b ut this difference was not statistically significant. Patients with elevated AL T levels at baseline became normal in 60.3% of the lamivudine treated group comp ared with the placebo group where only 27.5% were normal (P<0.01). L amivudine was well tolerated in a dose of (100?mg daily) and the overall incide nce of adverse events was similar to that of the placebo. Conclusions Lamivudine (100 mg daily) is very effective in the inhibiti on of HBV replication, indicated by the rapid loss of serum HBV DNA, and often acco mpanied by a decrease of serum ALT levels. Lamivudine is well tolerated withou t severe adverse events during treatment.

Emerging Trends in Epidemiology of Hepatitis B Virus Infection

Although a vaccine against hepatitis B virus (HBV) has been available since 1982,the prevalence of adults with chronic HBV infection in sub-Saharan Africa and East Asia is still estimated at 5-10%.A high rate of chronic infections is also found in the Amazon and the southern parts of eastern and central Europe.In the Middle East and the Indian subcontinent,the prevalence is 2-5%.Less than 1% of the population of Western Europe and North America is chronically infected.Given the high prevalence of infections (such as hepatitis) among inmates,prison is considered a reservoir for facilitating such infections.Based on these premises,this current review examines and discusses emerging trends in the epidemiology of HBV infection,with particular attention to HBV infection in prison.The hepatitis B surface antigen (HBsAg) prevalence in prisoners in west and central Africa is very high (23.5%).The Centers for Disease Control and Prevention has highlighted the importance of HBV blood screening and subsequent anti-HBV vaccination in the prison population.The vaccination was recommended for all inmates,representing an opportunity to prevent HBV infection in a high-risk population.In these subjects,an accelerated hepatitis B immunisation schedule may result in rapid seroconversion for early short-term protection.Therefore,it is necessary to seek collaboration among public health officials,clinicians and correctional authorities to implement a vaccination programme.

Hepatitis B virus infection in undocumented immigrants and refugees in Southern Italy:demographic,virological,and clinical features

Background:The data on hepatitis b virus(HBV)infection in immigrants population are scanty.The porpoise of this study was to define the demographic,virological,and clinical characteristics of subjects infected with HBV chronic infection in a cohort of immigrants living in Naples,Italy.Methods:A screening for HBV infection was offered to 1,331 immigrants,of whom 1,212(91%)(831 undocumented immigrants and 381 refugees)accepted and were screened for hepatitis B surface antigen(HBsAg)and anti-hepatitis B core antibody(HBc).Those found to be HBsAg positive were further investigated at third-level infectious disease units.Results:Of the 1,212 immigrants screened,116(9.6%)were HBsAg positive,490(40.4%)were HBsAg negative/anti-HBc positive,and 606(50%)were seronegative for both.Moreover,21(1.7%)were anti-human immunodeficiency virus positive and 45(3.7%)were anti-hepatitis C virus positive.The logistic regression analysis showed that male sex(OR:1.79;95%CI:1.28-2.51),Sub-Saharan African origin(OR:6.18;95%CI:3.37-11.36),low level of schooling(OR:0.96;95%CI:0.94-0.99),and minor parenteral risks for acquiring HBV infection(acupuncture,tattoo,piercing,or tribal practices,OR:1.54;95%CI:1.1-2.16)were independently associated with ongoing or past HBV infection.Of the 116 HBsAg-positive immigrants,90(77.6%)completed their diagnostic itinerary at a third-level infectious disease unit:29(32.2%)were asymptomatic non-viremic HBsAg carriers,43(47.8%)were asymptomatic viremic carriers,14(15.6%)had chronic hepatitis,and four(4.4%)had liver cirrhosis,with superimposed hepatocellular carcinoma in two.Conclusions:The data illustrate the demographic,clinical and virological characteristics of HBV infection in immigrants in Italy and indicate the need for Italian healthcare authorities to enhance their support for providing screening,HBV vaccination,treatment,and educational programs for this populations.