Prediction model for hepatitis B e antigen seroconversion in chronic hepatitis B with peginterferon-alfa treated based on a responseguided therapy strategy

BACKGROUND Models for predicting hepatitis B e antigen(HBeAg)seroconversion in patients with HBeAg-positive chronic hepatitis B(CHB)after nucleos(t)ide analog treatment are rare.AIM To establish a simple scoring model based on a response-guided therapy(RGT)strategy for predicting HBeAg seroconversion and hepatitis B surface antigen(HBsAg)clearance.METHODS In this study,75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa(PEG-IFNα)treatment and a 24-wk follow-up.Logistic regression analysis was used to assess parameters at baseline,week 12,and week 24 to predict HBeAg seroconversion at 24 wk post-treatment.The two best predictors at each time point were used to establish a prediction model for PEG-IFNαtherapy efficacy.Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0.RESULTS The two most meaningful predictors were HBsAg≤1000 IU/mL and HBeAg≤3 S/CO at baseline,HBsAg≤600 IU/mL and HBeAg≤3 S/CO at week 12,and HBsAg≤300 IU/mL and HBeAg≤2 S/CO at week 24.With a total score of 0 vs 2 at baseline,week 12,and week 24,the response rates were 23.8%,15.2%,and 11.1%vs 81.8%,80.0%,and 82.4%,respectively,and the HBsAg clearance rates were 2.4%,3.0%,and 0.0%,vs 54.5%,40.0%,and 41.2%,respectively.CONCLUSION We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNαtherapy.

Antiviral effects of hepatitis B virus S gene-specific anti-gene locked nucleic acid in transgenic mice

AIM To assess the antiviral effects of hepatitis B virus(HBV) S gene-specific anti-gene locked nucleic acid(LNA) in transgenic mice.METHODS Thirty HBV transgenic mice were acclimatized to laboratory conditions and positive for serum HBV surface antigen(HBs Ag) and HBV DNA, were randomly divided into 5 groups(n = 7), including negative control(blank control, unrelated sequence control), positive control(lamivudine, anti-sense-LNA), and anti-gene-LNA experimental group. LNA was injected into transgenic mice by tail vein while lamivudine was administeredby gavage. Serum HBV DNA and HBs Ag levels were determined by fluorescence-based PCR and enzymelinked immune sorbent assay, respectively. HBV S gene expression amounts were assessed by reverse transcription polymerase chain reaction. Positive rates of HBsA g in liver cells were evaluated immunohistochemistry.RESULTS Average rate reductions of HBs Ag after treatment on the 3 rd, 5 th, and 7 th days were 32.34%, 45.96%, and 59.15%, respectively. The inhibitory effect of antigene-LNA on serum HBs Ag peaked on day 7, with statistically significant differences compared with pretreatment(0.96 ± 0.18 vs 2.35 ± 0.33, P < 0.05) and control values(P < 0.05 for all). Average reduction rates of HBV DNA on the 3 rd, 5 th, and 7 th days were 38.55%, 50.95%, and 62.26%, respectively. This inhibitory effect peaked on the 7 th day after treatment with anti-gene-LNA, with statistically significant differences compared with pre-treatment(4.17 ± 1.29 vs 11.05 ± 1.25, P < 0.05) and control values(P < 0.05 for all). The mR NA levels of the HBV S gene(P < 0.05 for all) and rates of HBsA g positive liver cells(P < 0.05 for all) were significantly reduced compared with the control groups. Liver and kidney function, and histology showed no abnormalities. CONCLUSION Anti-gene-LNA targeting the S gene of HBV displays strong inhibitory effects on HBV in transgenic mice, providing theoretical and experimental bases for gene therapy in HBV.

Current perspectives of viral hepatitis

Viral hepatitis represents a major danger to public health,and is a globally leading cause of death.The five liver-specific viruses:Hepatitis A virus,hepatitis B virus,hepatitis C virus,hepatitis D virus,and hepatitis E virus,each have their own unique epidemiology,structural biology,transmission,endemic patterns,risk of liver complications,and response to antiviral therapies.There remain few options for treatment,in spite of the increasing prevalence of viral-hepatitiscaused liver disease.Furthermore,chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality,even though effective treatments are available that could reduce or prevent most patients’complications.In 2016,the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030,along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis.Today,treatment is sufficiently able to prevent the disease from reaching advanced phases.However,future therapies must be extremely safe,and should ideally limit the period of treatment necessary.A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis.This review aims to summarize the current state of knowledge on each type of viral hepatitis,together with major innovations.

慢性乙型肝炎患者抗病毒治疗中血清HBV RNA水平变化与HBeAg阳性及肝硬化的关系

目的探讨慢性乙型肝炎(CHB)患者抗病毒治疗中血清乙型肝炎病毒(HBV)RNA水平变化与乙型肝炎病毒e抗原(HBeAg)及肝硬化的关系。方法选择核苷(酸)类似物抗病毒治疗中的CHB患者491例,其中HBeAg阳性206例、阴性285例,有肝硬化117例、无肝硬化374例。用全自动荧光定量PCR分析仪检测血清HBV DNA,用全自动核酸检测分析系统检测血清HBV RNA。二分类多因素非条件Logistic回归分析HBV RNA阳性对CHB患者抗病毒治疗中HBeAg阳性、肝硬化的影响,用Pearson相关法分析血清HBV RNA水平与HBV DNA水平的相关性。结果HBeAg阳性患者年龄小于HBeAg阴性患者(P<0.05),HBV RNA阳性率、HBV DNA阳性率及HBV RNA、HBV DNA水平高于HBeAg阴性患者(P均<0.05)。肝硬化患者年龄大于无肝硬化患者(P<0.05),HBV DNA阳性率、HBV DNA水平低于无肝硬化患者(P均<0.05)。肝硬化患者与无肝硬化患者性别、HBV RNA阳性率、HBV RNA水平比较差异无统计学意义(P均>0.05)。年龄小、HBV DNA阳性、HBV RNA阳性是CHB患者抗病毒治疗中HBeAg阳性的危险因素(P均<0.05)。男性、年龄大、HBV DNA阳性、HBV RNA阳性是CHB患者抗病毒治疗中肝硬化的危险因素(P均<0.05)。CHB患者血清HBV RNA水平与HBV DNA水平呈正相关(P均<0.05)。结论HBV RNA阳性是CHB患者抗病毒治疗中HBeAg阳性、肝硬化的危险因素,HBV RNA检测可作为HBV DNA评估病毒复制活性的有效补充。

Natural history of chronic hepatitis B:Phases in a complex relationship

Chronic hepatitis B(CHB)is a condition of globalprevalence and its sequelae include cirrhosis and hepatocellular carcinoma.The natural history of CHB isa complex interplay of virological,environmental andhost factors.The dynamic relationship between thevirus and host evolves over the duration of the infection and different phases of the disease have been observed and described.These have been conceptualizedin terms of the state of balance between the host immune system and the hepatitis B virus and have beengiven the labels immune tolerant,immune clearance,immune control and immune escape although othernomenclature is also used.Host factors,such as age atinfection,determine progression to chronicity.Virological factors including hepatitis B viral load,mutationsand genotype also have an impact on the adverseoutcomes of the infection,as do hepatotoxic cofactorssuch as alcohol.Our understanding of the natural history of CHB has evolved significantly over the past fewdecades and characterizing the phase of disease ofCHB remains an integral part of managing this virus in the clinic.

Preliminary results of Thymosin-a1 versus interferon-α treatment in patients with HBeAg negative and serum HBV DNA positive chronic hepatitis B

INTRODUCTIONIn China ,the incidence and mortality of gastric cancer rank the second among all cancers. Recent development of cancer [1-20].The aim of this study was investigat the insight of apoptosis and bcl-2, p53 and C-myc protein expression in the development of gastric cancer .

Models for predicting hepatitis B e antigen seroconversion in response to interferon-α in chronic hepatitis B patients

AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment.Patients were tested for serum alanine aminotransferase(ALT),hepatitis B virus-DNA,hepatitis B surface antigen(HBs Ag),antibody to hepatitis B surface antigen,HBe Ag,antibody to hepatitis B e antigen(anti-HBe),and antibody to hepatitis B core antigen(anti-HBc)at baseline and 12 wk,24 wk,and 52 wk after initiating treatment.We performed univariate analysis to identify response predictors among the variables.Multivariate models to predict treatment response were constructed at baseline,12 wk,and 24 wk.RESULTS:At baseline,the 3 factors correlating most with HBe Ag seroconversion were serum ALT level>4×the upper limit of normal(ULN),HBe Ag≤500 S/CO,and anti-HBc>11.4 S/CO.At 12 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤250 S/CO,decline in HBe Ag>1 log10 S/CO,and anti-HBc>11.8 S/CO.At 24 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤5 S/CO,anti-HBc>11.4 S/CO,and decline in HBe Ag>2 log10 S/CO.Each variable was assigned a score of1,a score of 0 was given if patients did not have any of the 3 variables.The 3 factors most strongly correlating with HBe Ag seroconversion at each time point were used to build models to predict the outcome after IFN-αtreatment.When the score was 3,the response rates at the 3 time points were 57.7%,83.3%,and 84.0%,respectively.When the score was 0,the response rates were 2.9%,0.0%,and 2.1%,respectively.CONCLUSION:Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-αtherapy.

Transformation of hepatitis B serologic markers in babies born to hepatitis B surface antigen positive mothers

AIM:To better understand the clinical significance of hepatitis B seroiogic markers in babies born to hepatitis B surface antigen (HBsAg) positive mothers, the incidence of maternal seroiogic markers of hepatitis B via placenta and its transformation in these babies were investigated. METHODS: Mothers with positive HBsAg were selected in the third trimester of pregnancy. Their babies received immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine after birth, and were consecutively followed up for hepatitis B seroiogic markers and HBV DNA at birth, mo 1, 4, 7, 12, and 24. RESULTS: Forty-two babies entered the study, including 16 born to hepatitis B e antigen (HBeAg)-positive HBsAg carrier mothers and 26 to HBeAg-negative HBsAg carrier mothers. Apart from four babies born to HBeAg-positive carrier mothers and demonstrated persistent positive HBeAg eventually became HBV carriers, all other babies developed anti-HBs before 12 mo of age. Among the other 12 babies born to HBeAg-positive carrier mothers, HBeAg was detected in 7 at birth, in 4 at mo 1, and in none of them thereafter. No antibody response to the transplacental HBeAg was detected. Among the babies born to HBeAg-negative carrier mothers, anti-HBe was detected 100% at birth and mo 1, in 88.5% at mo 4, in 46.2% at mo 7, in 4.2% at mo 12 and none in mo 24. Among all the immunoprophylaxis-protected babies born to either HBeAg-positive or HBeAg-negative carrier mothers, anti-HBc was detected in 100% at birth, mo 1 and mo 4, in 78.9% at mo 7, in 36.1% at mo 12 and in none at mo 24. CONCLUSION: HBeAg can pass through human placenta from mother to fetus and become undetectable before 4 mo of age, but no antibodies response to the transplacental HBeAg can be detected till mo 24 in the immunoprophylaxis-protected babies. The sole existence of anti-HBe before 1 year of age or anti-HBc before 2 years of age in babies born to HBsAg carrier mothers may simply represent the transplacental maternal antibodies, instead of indicators of HBV infection status.

Clinical utility of hepatitis B surface antigen kinetics in treatment-na?ve chronic hepatitis B patients during longterm entecavir therapy

AIM To investigate the utility of hepatitis B surface antigen(HBsAg) kinetics in chronic hepatitis B patients during long-term entecavir treatment.METHODS This retrospective study included treatment-na?ve chronic hepatitis B patients who received at least 2 years of consecutive entecavir treatment. Patients were followed up at three to six month intervals with liver biochemistry, hepatitis B virus DNA, and abdominal sonography. In hepatitis B e antigen(HBeAg)-positive patients, HBeAg levels were assessed every three to six month until results became negative. Serum HBsAg levels were determined at the baseline, oneyear and five-year time points. Liver cirrhosis was diagnosed through liver biopsy, imaging examinations, or clinical findings of portal hypertension. Hepatocellular carcinoma was diagnosed by histological examination or dynamic image studies.RESULTS A total of 211 patients were enrolled. The median treatment time was 5.24(2.00-9.62) years. Multivariate analysis showed that lower baseline HBsAg levels were associated with an earlier virological response, earlier hepatitis B e antigen(HBeAg) seroconversion, and earlier biochemical response in HBeAg-positive patients(cut-off value: 4 log IU/mL) and an earlier virological response in HBeAg-negative non-cirrhotic patients(cut-off value: 2.4 log IU/mL). Although HBsAg levels decreased slowly during long-term entecavir treatment, higher HBsAg decrease rates were found in the first year for HBeAg-positive non-cirrhotic patients, and patients with higher baseline HBsAg levels. More favorable clinical outcomes were not observed by a rapid HBsAg decline per se, but depended on lower baseline HBsAg levels.CONCLUSION Baseline HBsAg can be used to predict treatment responses. HBsAg levels and decrease rates should be considered together according to disease status while interpreting HBsAg changes.

Influence of chronic HBV infection on superimposed acute hepatitis E

AIM:To investigate the influence of chronic hepatitis B virus(HBV)infection[based on the status of hepatitis B e antigen(HBeAg),HBV DNA,and cirrhosis]on superimposed acute hepatitis E.METHODS:A total of 294 patients were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital,Sun Yat-sen University,from January 2003 to January 2012.The patients were classified into two groups:an HBV+hepatitis E virus(HEV)group(a group with chronic HBV infection that was superinfected with acute hepatitis E,n=118)and an HEV group(a group with acute hepatitis E,n=176).We retrospectively analyzed and compared the clinical features of the two groups.Statistical analyses were performed using theχ2test or Fisher’s exact test for categorical variables and the Student’s t test forcontinuous variables.A P value<0.05 was considered statistically significant.RESULTS:The peak values of prothrombin time,serum total bilirubin,and Model for End-Stage Liver Disease scores were significantly higher in the HBV+HEV group.More patients in the HBV+HEV group had complications(39.8%vs 16.5%,P=0.000)and developed liver failure(35.6%vs 8.5%,P=0.000).Additionally,the mortality of the HBV+HEV group was significantly higher(20.3%vs 7.4%,P=0.002).Further analysis of the HBV+HEV group showed that there were no significant differences in complication occurrence,liver failure incidence,or mortality between patients with different HBeAg and HBV DNA statuses.However,in patients with underlying cirrhosis,complication occurrence and liver failure incidence significantly increased.In total,12.7%of the patients in the HBV+HEV group received anti-HBV treatment,but this therapy failed to reduce mortality in patients who developed liver failure.CONCLUSION:The presence of underlying cirrhosis in chronic HBV infection results in more severe clinical outcomes with superimposed acute hepatitis E.AntiHBV treatment cannot improve the prognosis of liver failure caused by HBV-HEV superinfection.

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.

HBeAg negative variants and their role in the natural history of chronic hepatitis B virus infection

Molecular virology methods including polymerase chain reaction, cloning and sequencing have revolutionised our understanding of viral genome variation. In the case of hepatitis B virus (HBV), sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection. The appearance of the precore stop codon (with G-for-A substitution at position 1896) and basal core promoter (BCP) (with A-for-T and G-for-A, at positions 1762 and 1764, respectively) variants which reduce or abrogate hepatitis B e antigen (HBeAg) production, heralds the initiation of the seroconversion phase from HBeAg to anti-HBe positivity. The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response (immune clearance phase). Most patients after HBeAg seroconversion become &#x0201c;inactive HBsAg carriers&#x0201d;. However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B (CHB) with high viremia levels (reactivation phase). The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world. This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections. Frequent acute exacerbations accompanied by high viral replication, elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.

Hepatitis B virus pre S1 deletion is related to viral replication increase and disease progression

AIM:To investigate the clinical implications of hepatitis B virus(HBV) pre S1 deletion.METHODS:We developed a fluorescence resonance energy transfer-based real-time polymerase chain reaction(RT-PCR) that can detect four genotypes(wild type, 15-bp, 18-bp and 21-bp deletion).The PCR method was used in two cohorts of Korean chronic HBV subjects with genotype C infections.Cohort Ⅰ included 292 chronic HBV subjects randomly selected from Cheju National University Hospital(Jeju, South Korea) or Seoul National University Hospital(Seoul, South Korea), and cohort Ⅱ included 90 consecutive chronic HBV carriers recruited from Konkuk University Hospital(Seoul, South Korea); the cohort Ⅱ patients did not have hepatocellular carcinoma or liver cirrhosis.RESULTS:The method proposed in this study identified 341 of 382 samples(89.3%).Deletion variants were identified in 100(29.3%) of the 341 detected samples.In both cohorts, the subjects with deletions had a significantly higher Hepatitis B virus e antigen(HBe Ag)-positive seroprevalence [cohort Ⅰ, wild(51.0%) vs deletion(75.0%), P < 0.001; cohort Ⅱ, wild(69.2%) vs deletion(92.9%), P = 0.002] and higher HBV DNA levels [cohort Ⅰ, wild(797.7 pg/m L) vs deletion(1678.9 pg/m L), P = 0.013; cohort Ⅱ, wild(8.3 × 108 copies/m L) vs deletion(2.2 × 109 copies/m L), P = 0.049], compared to subjects with wild type HBV.CONCLUSION:HBV genotype C pre S1 deletion may affect disease progression in chronic HBV subjects through an extended duration of HBe Ag seropositive status and increased HBV replications.

Clinical features of HBs Ag seroclearance in hepatitis B virus carriers in South Korea: A retrospective longitudinal study

AIM To investigate the characteristic features of hepatitis B surface antigen(HBs Ag) seroclearance among Korean hepatitis B virus(HBV) carriers.METHODS Carriers with HBs Ag seroclearance were selected by analyzing longitudinal data collected from 2003 to 2015. The period of time from enrollment to the negative conversion of HBs Ag(HBs Ag-NC) was compared by stratifying various factors, including age, sex, hepatitis B e antigen(HBe Ag), HBV DNA, sequential changes in the signal-to-cutoff ratio of HBs Ag(HBs Ag-SCR), as measured by qualitative HBs Ag assay, and chronic liver disease on ultrasonography(US-CLD). Quantification of HBV DNA and HBs Ag(HBs Ag-QNT) in the serum was performed by commercial assay.RESULTS Among the 1919 carriers, 90(4.7%) exhibited HBs AgNC at 6.2 ± 3.6 years after registration, with no differences observed among the different age groups. Among these carriers, the percentages of those with asymptomatic liver cirrhosis(LC) and hepatocellular carcinoma(HCC) at registration were 31% and 7.8%, respectively. The frequency of HBs Ag-NC significantly differed according to the HBV DNA titer and US-CLD. HBe Ag influenced HBs Ag-NC in the 40-50 and 50-60 year age groups. HBs Ag-SCR < 1000 was correlated with an HBs Ag-QNT < 200 IU/m L. A gradual decrease in the HBs Ag-SCR to < 1000 predicted HBs Ag-NC. Six patients developed HCC after registration, including two before and four after HBs Ag-NC. The rate at which the patients developed new HCC after HBs Ag seroclearance was 4.8%. LC with excessive drinking and vertical infection were found to be risk factors for HCC in the HBs Ag-NC group.CONCLUSION HCC surveillance should be continued after HBs Ag seroclearance. An HBs Ag-SCR < 1000 and its decrease in sequential testing are worth noting as predictive markers of HBs Ag loss.

Relationship between HLA-DR gene polymorphisms and outcomes of hepatitis B viral infections:A meta-analysis

AIM:To assess the rigorous relationship between human leukocyte antigens(HLA)-DR alleles and outcomes of hepatitis B virus(HBV) infections by means of metaanalysis.METHODS:Medline/PubMed,EMBASE,CNKI and VIP were searched to identify relevant studies.Study quality was evaluated using the Newcastle-Ottawa Scale.Odds ratios(OR) and 95% confidence interval(95% CI) were pooled using Stata 11.0.Subgroup analyses were performed by ethnicity.Heterogeneity and publication bias analyses were performed to validate the credibility.RESULTS:A total of 2609 patients with chronic hepatitis B and 2606 controls spontaneously recovering from prior HBV infection were included.Meta-analysis showed that HLA-DR*04(OR = 0.72,95% CI:0.60-0.85) and DR*13(OR = 0.27,95% CI:0.19-0.37) alleles were significantly associated with HBV clearance while patients carrying HLA-DR*03(OR = 1.47,95% CI:1.16-1.87) or DR*07(OR = 1.59,95% CI:1.24-2.03) alleles had a significantly increased risk of chronic HBV persistence.For the HLA-DR*01 polymorphism,a significantly association with HBV clearance was found in Chinese Han group(OR = 0.48,95% CI:0.26-0.86),but not found in other ethnic groups(P = 0.191).For other polymorphisms,no association with the HBV infection outcome was found.CONCLUSION:HLA-DR*04 and DR*13 alleles may be the protective factors for HBV clearance and HLADR*03,and DR*07 alleles may be the risk factors for HBV persistence.

Association of serum gamma-glutamyl transferase with treatment outcome in chronic hepatitis B patients

AIM:To investigate the association of serum gammaglutamyl transferase(GGT) levels with chronic hepatitis B infection and hepatitis B e antigen(HBe Ag) seroconversion.METHODS:A retrospective study was performed on clinical data collected from patients who had been positive for hepatitis B surface antigen for > 6 mo and who were antiviral-treatment na?ve(n = 215) attending the Hepatitis Clinic at Nanjing Drum Tower Hospital between August 2010 and December 2013. Healthy individuals without liver disease(n = 83) were included as controls. Patients were categorized into four groups based on disease status as recommended by the European Association for the Study of the Liver:immune tolerance(IT; n = 47),HBe Ag-positive hepatitis(EPH; n = 93),HBe Ag-negative hepatitis(ENH;n = 20),and inactive carrier(IC; n = 55). Prediction of complete response(CR) based on serum GGT was also examined in EPH patients(n = 33) treated for 48 wk with nucleos(t)ide analogue(NA) therapy,including lamivudine plus adefovir combination therapy(n = 20) or entecavir monotherapy(n = 13). CR was defined as a serum hepatitis B virus DNA level < 500 copies/m L and HBe Ag seroconversion by 48 wk of treatment. RESULTS:Serum GGT levels were significantly increased in EPH and ENH patients relative to the IT,IC,and healthy control groups(P < 0.01 for all). However,no significant difference in serum GGT levels was found between the EPH and ENH groups. Baseline serum GGT levels were significantly higher in patients who achieved CR(7/33; 21.2%) compared to patients in the non-CR group(26/33; 78.8%; P = 0.011). In addition,the decline in serum GGT was greater in CR patients compared to non-CR patients after 24 wk and 48 wk of treatment(P = 0.012 and P = 0.008,respectively). The receiver operating characteristic curve yielded a sensitivity of 85.71% and a specificity of 61.54% at a threshold value of 0.89 times the upper limit of normal for baseline serum GGT in the prediction of CR following NA therapy. CONCLUSION:Serum GGT is significantly elevated in EPH and ENH patients and is a potential biomarker for the prediction of HBe Ag seroconversion following NA therapy.

Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma

AIM： To conduct a retrospective study in 400 chronic hepatitis B patients in order to identify hepatitis B viral factors associated with complications of liver disease or development of hepatocellular carcinoma. METHODS： The mean follow-up time was 83.6 ± 39.6 mo. Alpha-fetoprotein test and abdominal ultrasound were used for cancer surveillance. Hepatitis B basal core promoter mutants, precore mutants, genotypes, hepatitis B viral DNA （HBV DNA） level and hepatitis B e antigen （HBeAg） were measured. Univariate analysis and logistic regression were used to assess odds ratios for viral factors related to liver deaths and hepatocellular carcinoma development. RESULTS： During follow-up, 38 patients had liver deaths not related to hepatocellular carcinoma. On multivariate analysis, older age [odds ratio： 95.74 （12.13-891.31）, P 〈 0.0001], male sex [odds ratio： 7.61 （2.20-47.95）; P = 0.006], and higher Iogzo HBV DNA [odds ratio： 4.69 （1.16-20.43）; P 〈 0.0001] were independently predictive for these liver related deaths. Also, 31 patients developed hepatocellular carcinoma. Multivariate analysis showed that older age [odds ratio： 26.51 （2.36-381.47）; P = 0.007], presence of precore mutants [odds ratio： 4.23 （1.53-19.58）, P = 0.02] and presence of basal core promoter mutants [odds ratio： 2.93 （1.24-7.57）; P = 0.02] were independent predictors for progression to hepatocellular carcinoma. CONCLUSION： Our results show that high levels of baseline serum HBV DNA are associated with non- hepatocellular carcinoma-related deaths of liver failure, while genetic mutations in the basal core promoter and precore regions are predictive for development of hepatocellular carcinoma.

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.