Efficacy of a Chinese herbal formula on hepatitis B e antigenpositive chronic hepatitis B patients

BACKGROUND No guideline recommends antiviral therapy for hepatitis B e antigen(HBeAg)-positive chronic hepatitis B patients with persistently normal alanine aminotransferase levels and a high hepatitis B virus(HBV)DNA viral load.AIM To evaluate the feasibility and safety of a Chinese herbal formula as a therapeutic option for chronic HBV infection.METHODS In total,395 patients(30–65 years old)with confirmed HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase were randomized to receive either Chinese herbal formula or placebo for 96 wk.Endpoints to evaluate therapeutic efficacy included:(1)HBV DNA levels decreased to less than 4 log10 IU/mL at weeks 48 and 96;and(2)HBeAg clearance and seroconversion rates at weeks 48 and 96.RESULTS HBV DNA levels≤4 log10 IU/mL were 10.05%at week 48 and 18.59%at week 96 in the treatment group.The HBeAg clearance and conversion rates were 8.54%and 8.04%at week 48 and 16.08%and 14.57%at week 96,respectively.However,HBV DNA levels≤4 log10 IU/mL were 2.55%and 2.55%at weeks 48 and 96,respectively,and the HBeAg clearance rates were 3.06%and 5.61%at weeks 48 and 96,respectively,in the control group.The quantitative hepatitis B surface antigen and HBeAg levels at baseline and changes during the treatment period as well as the alanine aminotransferase elevation at weeks 12 and 24 were strong predictors of HBeAg clearance.CONCLUSION High rates of HBV DNA reduction,HBeAg clearance and seroconversion could be achieved with Chinese herbal formula treatments,and the treatments were relatively safe for HBeAg-positive chronic hepatitis B-infected patients with persistently normal alanine aminotransferase.The ability of the compound to modulate host immune function probably contributed to this effect.

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUND Nucleos(t)ide analogs(NAs)cessation in chronic hepatitis B(CHB)patients remains a matter of debate in clinical practice.Current guidelines recommend that patients with hepatitis B e antigen(HBeAg)seroconversion discontinue NAs after relatively long-term consolidation therapy.However,many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg,even if hepatitis B surface antigen(HBsAg)loss occurs.It remains unclear whether NAs can be discontinued in this subset of patients.AIM To investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss(without hepatitis B e antibody)after cessation of NAs.METHODS We studied patients who discontinued NAs after achieving HBeAg loss.The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs.The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves;we confirmed the cut-off value of HBsAg according to a previous study.The log-rank test was used to compare cumulative relapse rates among groups.We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates.Propensity score matching analysis(PSM)was used to balance baseline characteristics between the groups.RESULTS We included 83 patients with HBeAg loss.The mean age of these patients was 32.1±9.5 years,and the majority was male(67.5%).Thirty-eight patients relapsed,and the cumulative relapse rate at months 3,6,12,24,36,60,120,and 180 were 22.9%,36.1%,41.0%,43.5%,45.0%,45.0%,45.0%,and 52.8%,respectively.Twentysix(68.4%)patients relapsed in the first 3 mo after NAs cessation,and 35 patients(92.1%)relapsed in the first year after NAs cessation.Consolidation period(≥24 mo vs<24 mo)(HR 0.506,P=0.043)and HBsAg at cessation(≥100 IU/mL vs<100 IU/mL)(HR 14.869,P=0.008)were significant predictors in multivariate Cox regression.In the PSM cohort,which included 144 patients,there were lower cumulative relapse rates in patients with HBeAg seroconversion(P=0.036).CONCLUSION HBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation,especially in patients with HBsAg at cessation<100 IU/mL.Careful monitoring,especially in the early stages after cessation,may ensure a favorable outcome.

Significant histological changes are not rare in indeterminate‐phase chronic hepatitis B patients with hepatitis B e antigen‐negative and normal alanine aminotransferase levels

Background&Objectives:The degree of liver injury in indeterminate chronic hepatitis B(CHB)infection patients with Hepatitis B e antigen(HBeAg)‐negative and persistently normal alanine aminotransferase(PNALT)levels is yet unclear.Therefore,we aimed to assess liver histological changes in such patients by liver biopsy and explore possible predictors.Methods:Overall,711 HBeAg‐negative CHB patients with PNALT levels who underwent liver biopsy from January 2017 to June 2022 were included in this retrospective study.The relationships between histological changes and predictors were assessed by smooth curve fitting and multivariate logistic regression analysis models.Data were also analyzed using American Association for the Study of Liver Disease(AASLD)modified alanine aminotransferase(ALT)criteria.Results:The proportion of significant histological changes in the indeterminate phase was higher than that in the inactive phase(53.97%vs.41.33%).The adjusted odds ratios(aORs)of significant necroinflammation and histological changes for the indeterminate phase were 2.05 and 1.43,respectively,when compared with the inactive phase by multivariate logistic regression analyses.Significant histological changes in the‐phase were positively associated with age,ALT,Aspartate aminotransferase(AST),Hepatitis B surface antigen(HBsAg),and Hepatitis B virus(HBV)DNA levels but negatively correlated with platelet(PLT)levels.HBV DNA≥5 log10 U/L and PLT<200�109/L were independent predictive factors for assessing histological changes in indeterminate‐phase patients.Similar analysis findings were obtained using the two sets of modified ALT criteria.Conclusions:Significant histological changes are not rare in indeterminatephase CHB patients and are higher than in the inactive phase,regardless of the ALT criteria.Histological investigation is strongly suggested for intermediate stage patients with HBV DNA>5 log10 U/L or PLT<200�109/L and antiviral therapy should be considered for such patients.

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.

Hepatitis B core-related antigen:Are we near a treatment endpoint?

Different serological and virological markers in chronic hepatitis B patients guide staging of viral infection,and initiation and response to therapy.Due to the persistence of intrahepatic covalently closed circular DNA(cccDNA)in the hepatocyte nucleus,hepatitis B is not curable.Even after undetectable hepatitis B virus DNA levels,the persistence of hepatitis B surface antigen and novel markers such as hepatitis B core-related antigen(HBcrAg)indicate the persistence of intrahepatic cccDNA.In this study,HBcrAg levels at baseline and after 24 and 48 wk of antiviral therapy predicted hepatitis B e antigen seroconversion.Due to the poor sensitivity of assays and detectable levels in HBsAg-negative patients,the long-term utility of HBcrAg needs future research.

Soluble programmed death-1 is predictive of hepatitis B surface antigen loss in chronic hepatitis B patients after antiviral treatment

BACKGROUND Hepatitis B surface antigen(HBsAg)loss,a functional cure in patients with chronic hepatitis B(CHB)undergoing antiviral therapy,might be an ideal endpoint of antiviral treatment in clinical practice.The factors that contribute to the functional cure remain unclear,and the predictors of functional cure are worth exploring.The concentration and kinetics of soluble programmed death-1(sPD-1)in patients with CHB may play an important role in elucidating the immune response associated with functional cure after nucleos(t)ide analogs therapy.AIM To investigate the factors associated with HBsAg loss and explore the influence of sPD-1 Levels.METHODS This study analyzed the data and samples from patients with CHB who underwent antiviral treatment in a non-interventional observational study conducted at Peking University First Hospital in Beijing(between 2007 and 2019).All patients were followed up:Serum samples were collected every 3 mo during the first year of antiviral treatment and every 6 mo thereafter.Patients with positive hepatitis B e antigen levels at baseline and with available sequential samples who achieved HBsAg loss during antiviral treatment served as the case group.This case group(n=11)was further matched to 44 positive hepatitis B e anti patients without HBsAg loss as controls.The Spearman’s rank correlation test and receiver operating characteristic curves analysis were performed.RESULTS The sPD-1 Levels were higher in patients with HBsAg loss than in those without HBsAg loss from baseline to month 96,and the differences were significant between the groups at baseline(P=0.0136),months 6(P=0.0003),12(P<0.0001),24(P=0.0007),48(P<0.0001),and 96(P=0.0142).After 6 mo of antiviral treatment,the sPD-1 levels were positively correlated with alanine transaminase(ALT)levels(r=0.5103,P=0.0017),and the sPD-1 levels showed apparent correlation with ALT(r=0.6883,P=0.0192)and HBV DNA(r=0.5601,P=0.0703)levels in patients with HBsAg loss.After 12 mo of antiviral treatment,the sPD-1 levels also showed apparent correlation with ALT(r=0.8134,P=0.0042)and HBV DNA(r=0.6832,P=0.0205)levels in patients with HBsAg loss.The sPD-1 levels were negatively correlated with HBsAg levels in all patients after 12 mo of antiviral treatment,especially at 24(r=-0.356,P=0.0497)and 48(r=-0.4783,P=0.0037)mo.After 6 mo of antiviral treatment,the AUC of sPD-1 for HBsAg loss was 0.898(P=0.000),whereas that of HBsAg was 0.617(P=0.419).The cut-off value of sPD-1 was set at 2.34 log pg/mL;the sensitivity and specificity were 100%and 66.7%,respectively.CONCLUSION The sPD-1 levels at 6 mo can predict HBsAg loss after 144 mo of antiviral treatment.

Correlation of hepatitis B surface antigen expression with clinicopathological and biochemical parameters in liver biopsies: A comprehensive study

BACKGROUND Chronic viral B hepatitis(CHB)is a potentially life-threatening liver disease that may progress to liver failure and cirrhosis.Currently,although combinations of different laboratory methods are used in the follow-up and treatment of CHB,the failure of these procedures in some cases has led to the necessity of developing new approaches.In CHB,the intrahepatic expression pattern of viral antigens,including hepatitis B surface antigen(HBsAg),is related to different phases of inflammation.However,many studies have focused on the intracytoplasmic properties of HBsAg staining,and HBsAg positivity in liver tissue has not been evaluated by objective quantitative methods.AIM To investigate the relationship of image analysis-based quantitative HBsAg expression and its staining patterns with clinicopathological factors and treatment in CHB.METHODS A total of 140 liver biopsies from treatment-naïve cases with CHB infection were included in this study.Following diagnosis,all patients were treated with entecavir(0.5 mg)and followed up at three-month intervals.The percentage of immunohistochemical HBsAg(p-HBsAg)expression in the liver was determined in whole tissue sections of biopsies from each case by image analysis.The immunohistochemical staining pattern was also evaluated separately according to 3 different previously defined classifications.RESULTS A positive correlation between p-HBsAg and serum levels of hepatitis B virus(HBV)DNA and HBsAg was observed(P<0.001).The p-HBsAg value was significantly higher in younger patients than in older patients.When the groups were categorized according to the hepatitis B e antigen(HBeAg)status in HBeAgpositive cases,p-HBsAg was correlated with HBV DNA,hepatitis activity index(HAI)and fibrosis scores(P<0.001).In this group,p-HBsAg and HBsAg expression patterns were also correlated with the viral response(VR)and the serological response(SR)(P<0.001).Multivariate analysis revealed that p-HBsAg was an independent predictor of either VR or SR(P<0.001).In HBeAg-negative patients,although HBsAg expression patterns were correlated with both HAI and fibrosis,no relationship was observed among p-HBsAg,clinicopathological factors and VR.CONCLUSION In pretreatment liver biopsies,the immunohistochemical determination of HBsAg expression by quantitative methods,beyond its distribution within the cell,may be a good predictor of the treatment response,especially in HBeAg-positive cases.

Efficacy of telbivudine in HBeAg-positive chronic hepatitis B patients with high baseline ALT levels

AIM:To evaluate the efficacy and safety of telbivudine(LDT) in hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB) patients who have high baseline alanine aminotransferase(ALT) levels between 10 and 20 times the upper limit of normal.METHODS:Forty HBeAg-positive CHB patients with high baseline ALT levels between 10 and 20 times the upper limit of normal were enrolled and received LDT monotherapy for 52 wk.Another forty patients with baseline ALT levels between 2 and 10 times the upper limit of normal were included as controls.We compared the virological,biochemical,serological and side effect profiles between the two groups at 52 wk.RESULTS:By week 52,the mean decrease in hepatitis B virus(HBV) DNA level compared with baseline was 7.03 log10 copies/mL in the high baseline ALT group and 6.17 log10 copies/mL in the control group,respectively(P < 0.05).The proportion of patients in whom serum HBV DNA levels were undetectable by polymerase chain reaction assay was 72.5% in the high baseline ALT group and 60% in the control group,respectively(P < 0.05).In addition,45.0% of patients in the high baseline ALT group and 27.5% of controls became HBeAg-negative,and 37.5% of those in the high baseline group and 22.5% of controls,respectively,had HBeAg seroconversion(P < 0.05) at week 52.Moreover,in the high baseline group,4 out of 40 patients(10%) became hepatitis B surface antigen(HBsAg)-negative and 3(7.5%) of them seroconverted(became HBsAg-positive).Only 1 patient in the control group became HBsAg-negative,but had no seroconversion.The ALT normalization rate,viral breakthrough,genotypic resistance to LDT,and elevations in creatine kinase levels were similar in the two groups over the 52 wk.CONCLUSION:High baseline ALT level is a strong predictor for optimal results during LDT treatment.

mi R-29a promotes hepatitis B virus replication and expression by targeting SMARCE1 in hepatoma carcinoma

AIM To investigate the functional role and underlying molecular mechanism of mi R-29 a in hepatitis B virus(HBV) expression and replication.METHODS The levels of mi R-29 a and SMARCE1 in HBV-infected Hep G2.2.15 cells were measured by quantitative real-time PCR and western blot analysis. HBV DNA replication was measured by quantitative PCR and Southern blot analysis. The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8(CCK-8) was used to detect the viability of Hep G2.2.15 cells. The relationship between mi R-29 a and SMARCE1 were identified by target prediction and luciferase reporter analysis.RESULTS mi R-29 a promoted HBV replication and expression, w h i le S MA R C E 1 r e p r e s s e d H B V r e p lic a t io n a n d expression. Cell viability detection indicated that mi R-29 a transfection had no adverse effect on the host cells. Moreover, SMARCE1 was identified and validated to be a functional target of mi R-29 a. Furthermore, restored expression of SMARCE1 could relieve the increased HBV replication and expression caused by mi R-29 a overexpression.CONCLUSION mi R-29 a promotes HBV replication and expression through regulating SMARCE1. As a potential regulator of HBV replication and expression, mi R-29 a could be a promising therapeutic target for patients with HBV infection.

Interplay between chronic hepatitis B and atherosclerosis:Innovative perspectives and theories

Elaboration of carotid atherosclerosis in the setting of hepatitis B virus(HBV)infection should emphasize the significance of extrahepatic manifestations of the infection pathogenesis.Diverse processes comprise the pathoevolution of HBV infection,rendering it a multi-systemic disease in its essence.Our work not only exemplified atherosclerosis as an often-underestimated contributor to the severity of HBV infection but has also highlighted the bidirectional relationship between the two.Therefore,it is suggested that HBV-induced inflammation is one of the root causes of atherosclerosis,which in turn has a consequent effect on the severity of the chronic infection disease state,creating a vicious cycle.Additionally,we coupled prior data with the current concepts of HBV infection to postulate intriguing perspectives and theories.

Liver Histopathological Features Influencing HBeAg Seroconversion in Patients with HBeAg-positive Chronic Hepatitis B Treated with Pegylated Interferon α

Objective To investigate the efficiency of pegylated interferon α therapy for patients with HBe Ag-positive chronic hepatitis B(CHB) and explore whether liver histopathological features and other factors might influence HBe Ag seroconversion.Methods Total of 80 HBe Ag-positive CHB patients who received liver puncture were treated with pegylated interferon α once a week for 48 weeks. The rate of HBe Ag seroconversion was determined after therapy, and the factors influencing HBe Ag seroconversion were analyzed.Results The rate of HBe Ag seroconversion was 30.00% at the end of treatment. The rate of HBe Ag seroconversion gradually increased with the elevation of liver inflammatory activity(χ2 = 9.170, P = 0.027). But liver fibrosis has little correlation with the rate of HBeA g seroconversion(χ2 = 5.917, P = 0.116). Except HBeA g, other baseline indexes including gender, age, serum ALT and serum HBV DNA 1evels had no statistical difference between the patients with HBe Ag seroconversion and the patients without HBe Ag seroconversion. By binary logistic regression analysis, liver inflammation and HBeA g were influencing factors for HBeA g seroconversion. Conclusions Pegylated interferon α therapy induces a higher rate of HBeA g seroconversion in HBeA g-positive chronic hepatitis B patients with severe liver inflammation, so the liver biopsies should be performed in time.

Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity

Of 350 million people worldwide are chronically infected with hepatitis B virus(HBV)and are at risk of developing cirrhosis and hepatocellular carcinoma(HCC)later in life.HBV is the most diverse DNA virus,and its genome is composed of four open reading frames:Presurface antigen/surface antigen gene(preS/S),precore/core gene(preC/C),polymerase gene(P),and theχgene(χ).HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate.The virus has 10 genotypes(A to J)with different geographical distributions.There are various HBV mutations in the HBV genome,including preC/C mutations,preS/S mutations,P gene mutations,andχgene mutations.The core promoter region plays a vital part in the replication,morphogenesis and pathogenesis of the virus.The precore region also plays a crucial role in viral replication.Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity.preC/C mutations are associated with liver disease progression.Precore mutations stop hepatitis B e antigen(HBeAg)production and basal core promoter mutations downregulate HBeAg production.Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC.The emergence of antiviral-resistant mutations is the main reason for treatment failure.This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity.Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.

HBV genotype characterization and distribution in patients with HBV-related liver diseases in Zhejiang Province, P. R. China: possible association of co-infection with disease prevalence and severity

BACKGROUND: There are 8 well-documented genotypes of hepatitis B virus (HBV) at this time point. Genotyping can be accomplished based on a partial sequence of hepatitis B virus (HBV) genome such as the pre-S or S gene. Several methods have been developed and used for HBV genotyping including direct sequencing, restriction fragment length polymorphism, line probe assay and enzyme-linked immunoassay. Recently, a novel, rapid and cost-effective genotyping method based on PCR amplification assay using type-specific primers that can identify all six major genotypes has been developed. This study was undertaken to characterise HBV genotypes and investigate the association between the prevalence of different genotypes and the severity of HBV-induced liver diseases. METHODS: Serum samples from carriers of HBV and patients with HBV-related liver diseases from Zhejiang Province were screened for viral serological markers using commercially available radioimmunoassay (RIA) and enzyme linked immunosorbent assay (ELISA) kits. Serum HBV DNA load was determined by real-time detection PCR. A type-specific primer based the nested-PCR method was employed in the HBV genotyping. The genotype results obtained were confirmed by direct sequencing of nested PCR amplicons of the pre-S region. Ten samples of each genotype (B and C) were sequenced. RESULTS: The survey on a cohort of 125 HBV carriers in and around Hangzhou City, Zhejiang Province showed the existence of HBV genotypes A (0.8%), B (48%), C (40.8%), D (0.8%), mixed B and C (9.6%) and an absence of E and F genotypes. Distribution of HBV genotypes in patients with liver diseases revealed a statistically insignificant higher prevalence of genotype B in mild chronic hepatitis (CH). Among the three genotypes B, C and mixed B/C infections 11 (73.3%), 3 (20%) and 1 (6.7%), (P< 0.05), respectively in subjects with moderate CH, genotype B was significantly predominant. The infection patterns for genotypes B, C and B/C mixed in (i) liver cirrhosis (LC) 4 (23.5%), 10 (58.8%) and3 (17.7%) and (ii) hepatocellular carcinoma (HCC) 2 (28.6%), 5(71.4%) and 0 (0.0%) respectively revealed a marked association of C genotype with liver disease; however, the association was statistically insignificant (P >0.05). Differences in positive rate of HBeAg for the three genotypes B, 16(30.8%), C, 27(51.9%), and mixed B/C, 9(17.3%) were significant (P < 0. 05 ) , with genotype C showing predominance. CONCLUSIONS : These findings show an interesting distribution of HBV A-D genotypes in Zhejiang Province. Furthermore, our results indicate a novel and markedly high prevalence of mixed B/C genotype infections in subjects with severe CH and LC, and a possible association of mixed B/C infections with the severity of liver diseases in this region of China's Mainland.

The Change of Quantitative of HBeAg Can Predict the Efficacy of Peg-IFN-α 2a in HBeAgpositive CHB Patients

Objective To investigate the quantitation of hepatitis B e antigen (HBeAg) at week 24 in predicting the efifcacy of pegylated-interferon alfa-2a (Peg-IFN-α2a) in HBeAg-positive chronic hepatitis B (CHB) patients at week 48 and to find a useful predictor for treatment efficacy and investigate individualized treatment of antiviral therapy. Methods Ninety-six HBeAg-positive CHB patients with detectable HBeAg who were treated with Peg-IFN-α2a were enrolled in this trial. They were categorized into 3 groups according to the changes of HBeAg in week 24:HBeAg decline>2 log10 group (group A), HBeAg decline between 1 1og10-2 log10 (group B), HBeAg decline<1 log10 group (group C), and group C was randomly distributed into C1 and C2. The patients in group A, group B, and group C1 continued the original therapy and the patients in group C2 were given lamivudine plus Peg-IFN-α2a for 24 weeks. At week 48, the treatment efifcacy and hepatitis B virus covalently closed circular DNA (HBV cccDNA) in liver biopsies were analyzed. Results At week 48, mean reduction of serum HBV DNA:group A:5.8 log10 copies/ml, group B:3.8 log10 copies/ml, group C1:2.8 log10 copies/ml, group C2:5.7 log10 copies/ml, the reduction of HBV DNA in group A was greater than groups B and C1 (P<0.01), that in group C1 was greater than group C2 (P<0.01), the difference between groups B and C1 had no statistical signiifcance (P=0.19). Mean reduction of HBeAg:group A:2.7 log10S/CO, group B:1.9 log10S/CO, group C1:0.9 log10S/CO, group C2:1.5 log10S/CO, the difference among groups A, B and C1 and between groups C1 and C2 were statistically signiifcant (P<0.01). At week 48, HBV DNA undetectable rate in group A, group B, group C1 and group C2 were 87.5%, 34.5%, 17.4%and 81.9%, respectively, the rate in group A was greater than groups B and C1 (P<0.01),that in group C1 was greater than group C2 (P<0.01). HBeAg seroconversion rate were 75.0%, 24.1%, 13.0%and 22.7%, respectively, that in group A was greater than groups B and C1 (P<0.01). Group A had lower cccDNA in liver tissue than group B and group C1 (P<0.01). The difference of HBV cccDNA between groups B and C1 and that between groups C1 and C2 had no statistical signiifcance. Conclusions HBeAg decline > 2 log10 at week 24 in Peg-IFN-α 2a-treated hepatitis B patients suggested a better efficacy at week 48; HBeAg decline < 2 log10 at week 24 suggests a worse efficacy at week 48, the combined therapy of Peg-IFN-α and lamivudine could improve the clinical responses. The change of quantitative of HBeAg at week 24 may be used as a predictor of treatment effects at week 48.

Dynamic Characteristics of Serum Hepatitis B Surface Antigen in Chinese Chronic Hepatitis B Patients Receiving 7 Years of Entecavir Therapy

Background：The ultimate goal of hepatitis B treatment is hepatitis B surface antigen （HBsAg） seroclearance.Several factors have been suggested to be associated with the rate of HBsAg reduction in antiviral-naive or lamivudine therapy cohorts.However,there are few studies evaluating the factors during long-term entecavir （ETV） therapy.In the present study,we aimed to evaluate the factors to predict the outcome of ETV therapy for 7 years.Methods：A total of 47 chronic hepatitis B （CHB） patients treated with ETV monotherapy were included in this study.Liver biochemistry,hepatitis B virus （HBV） serological markers,serum HBV DNA,and HBsAg titers were tested at baseline,3 months,6 months,and yearly from 1 to 7.The associations between factors and HBsAg reduction were assessed using multivariate tests with repeated measure analysis of variance.Results：At baseline,serum HBsAg levels showed a positive correlation with baseline HBV DNA levels （r =0.625,P 〈 0.001）.The mean HBsAg titers after ETV treatment were significantly lower than the baseline titers （P ranges from 0.025 to 0.000,000,6）.The HBsAg reduction rate during the 1st year was greater compared to after 1 year of treatment （P 〈 0.05）.Multivariate test showed that hepatitis B e antigen （HBeAg） seroclearance and/or HBsAg reduction ≥0.5 log10 IU/ml at 6 months had a high negative predictive value （96.77%） for HBsAg seroclearance （P =0.002,P =0.012,respectively）.Conclusions：The HBsAg reduction rate during the 1st year was greater than that after 1 year of treatment.Further,HBeAg status and HBsAg levels at month 6 are the optimal factors for the early prediction of HBsAg seroclearance after long-term ETV therapy in CHB patients.

Hepatitis B core-related antigen reflects viral replication and protein production in chronic hepatitis B patients

Background:Hepatitis B core-related antigen(HBcrAg)is a promising disease-monitoring marker for chronic hepatitis B(CHB).We investigated correlations between HBcrAg with antiviral efficacy and virological and histological variables.Methods:One hundred and forty-five CHB patients from the mainland of China between August 2013 and September 2016 who underwent liver biopsy received entecavir therapy and had paired liver biopsy at 78 weeks.We analyzed correlations between HBcrAg and virological and histological variables in hepatitis B e antigen(HBeAg)-positive and HBeAg-negative patients.We also explored the predictors of HBeAg loss after 78 weeks of antiviral therapy.Pearson correlation analysis and logistic forward stepwise regression were the main statistic methods.Results:HBeAg-positive patients(n=93)had higher baseline HBcrAg(median 7.4 vs.5.3 log10 U/mL P<0.001)and greater HBcrAg declines(median 1.6 vs.0.9 log10 U/mL P=0.007)than HBeAg-negative patients after 78 weeks of therapy.At baseline,HBcrAg correlated with hepatitis B virus(HBV)DNA in both HBeAg-positive(r=0.641,P<0.001)and-negative patients(r=0.616,P<0.001),with hepatitis B surface antigen(HBsAg)in HBeAg-positive patients(r=0.495,P<0.001),but not with anti-hepatitis B virus core antibody(anti-HBc).Weak correlations existed between HBcrAg,histology activity index(HAI;r=0.232,P=0.025),and Ishak fibrosis score(r=-0.292,P=0.005)in HBeAg-positive patients.At 78 weeks,significant correlations existed only between HBcrAg and anti-HBc in HBeAg-positive(r=-0.263,P=0.014)and HBeAg-negative patients(r=-0.291,P=0.045).Decreased HBcrAg significantly correlated with reduced HBV DNA(r=0.366,P=0.001;r=0.626,P<0.001)and HBsAg(r=0.526,P=0.001;r=0.289,P=0.044)in HBeAg-positive and-negative patients,respectively,and with reduced HAI in HBeAg-positive patients(r=0.329,P=0.001).Patients with HBeAg loss(n=29)showed a larger reduction in HBcrAg than those without(median 2.3 vs.1.3 log10 U/mL,P=0.001).In multivariate analysis,decreased HBcrAg was an independent predictor of HBeAg loss(P=0.005).Conclusions:HBcrAg reflects viral replication and protein production.Decreased HBcrAg could predict HBeAg loss after antiviral therapy.Trial registration:Clinical Trials.gov:NCT01962155;https://www.clinicaltrials.gov/ct2/show/NCT01962155?term=NCT01962155&draw=2&rank=1.

Stopping nucleos(t)ide analog treatment in chronic hepatitis B-Who and when?

Nucleos(t)ide analogs(NAs)are one of the first-line treatments for chronic hepatitis B(CHB)infection.NAs are highly efficient in suppressing viral replication but are associated with a low rate of hepatitis B surface antigen(HBsAg)seroclearance and a high risk of post-treatment virologic relapse.As a result,the optimal timing of NA cessation remains unclear,and long-term treatment is often needed.While international guidelines suggest that NA can be discontinued in hepatitis B e antigen(HBeAg)-positive patients who achieve HBeAg seroconversion with undetectable hepatitis B virus(HBV)DNA levels,the recommendations for discontinuing NA treatment in HBeAg-negative patients remain controversial.Furthermore,there is no consensus regarding in whom and when to restart treatment among patients with hepatitis relapse after stopping NA therapy.Recent studies suggest that virologic markers such as HBsAg and hepatitis B core-related antigen(HBcrAg)titers may be useful to guide when to stop NAs in CHB,since both markers appear to correlate with intrahepatic covalently closed circular HBV DNA levels.However,additional studies are required to refine their use.