Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication

BACKGROUND Chronic hepatitis B virus(HBV)infection remains a major global public health problem.Chronic hepatitis B(CHB)patients can be divided into treatment indication and non-treatment indication individuals according to alanine transaminase(ALT),HBV DNA,serum hepatitis B e antigen status,disease status[liver cirrhosis,hepatocellular carcinoma(HCC),or liver failure],liver necroinflammation or fibrosis,patients’age,and family history of HCC or cirrhosis.For example,normal ALT patients in‘immune-tolerant’phase with HBV DNA higher than 10^(7)or 2×10^(7)IU/mL,and those in‘inactive-carrier’phase with HBV DNA lower than 2×10^(3)IU/mL do not require antiviral therapy.However,is it reasonable to set the defined values of HBV DNA as the fundamental basis to estimate the disease state and to determine whether to start treatment?In fact,we should pay more attention to those who do not match the treatment indications(grayzone patients both in the indeterminate phase and in the‘inactive-carrier’phase).AIM To analyze the correlation of HBV DNA level and liver histopathological severity,and to explore the significance of HBV DNA for CHB with normal ALT.METHODS From January 2017 to December 2021,a retrospective cross-sectional set of 1299 patients with chronic HBV infection(HBV DNA>30 IU/mL)who underwent liver biopsy from four hospitals,including 634 with ALT less than 40 U/L.None of the patients had received anti-HBV treatment.The degrees of liver necroinflammatory activity and liver fibrosis were evaluated according to the Metavir system.On the basis of the HBV DNA level,patients were divided into two groups:Low/moderate replication group,HBV DNA≤10^(7)IU/mL[7.00 Log IU/mL,the European Association for the Study of the Liver(EASL)guidelines]or≤2×10^(7)IU/mL[7.30 Log IU/mL,the Chinese Medical Association(CMA)guidelines];high replication group,HBV DNA>10^(7)IU/mL or>2×10^(7)IU/mL.Relevant factors(demographic characteristics,laboratory parameters and noninvasive models)for liver histopathological severity were analyzed by univariate analysis,logistics analysis and propensity score-matched analysis.RESULTS At entry,there were 21.45%,24.29%,and 30.28%of the patients had liver histopathological severities with≥A2,≥F2,and≥A2 or/and≥F2,respectively.HBV DNA level(negative correlation)and noninvasive model liver fibrosis 5 value(positive correlation)were independent risk factors for liver histopathological severities(liver necroinflammation,liver fibrosis,and treatment indication).The AUROCs of the prediction probabilities(PRE_)of the models mentioned above(<A2 vs≥A2,<F2 vs≥F2,<A2 and<F2 vs≥A2 or/and≥F2)were 0.814(95%CI:0.770-0.859),0.824(95%CI:0.785-0.863),and 0.799(95%CI:0.760-0.838),respectively.HBV DNA level(negative correlation)was still an independent risk factor when diagnostic models were excluded,the P values(<A2 vs≥A2,<F2 vs≥F2,<A2 and<F2 vs≥A2 or/and≥F2)were 0.011,0.000,and 0.000,respectively.For the propensity score-matched pairs,whether based on EASL guidelines or CMA guidelines,the group with significant liver histology damage(≥A2 or/and≥F2)showed much lower HBV DNA level than the group with non-significant liver histology damage(<A2 and<F2).Patients in the moderate replication group(with indeterminate phase)had the most serious liver disease pathologically and hematologically,followed by patients in the low replication group(with‘inactive-carrier’phase)and then the high replication group(with‘immune-tolerant’phase).CONCLUSION HBV DNA level is a negative risk factor for liver disease progression.The phase definition of CHB may be revised by whether the level of HBV DNA exceeds the detection low limit value.Patients who are in the indeterminate phase or‘inactive carriers’should receive antiviral therapy.

Correlation between HBeAg and Hepatitis B Virus DNA and RNA Levels in Diverse Liver Disease Cohorts

Objective:To investigate the disparities and associations between HBV DNA and HBV RNA in various liver disease groups with respect to HBeAg status.Methods:Between September 2020 and September 2023,90 patients diagnosed with chronic hepatitis B(CHB),74 patients diagnosed with liver cirrhosis(LC),and 102 patients diagnosed with hepatocellular carcinoma(HCC)from the Department of Gastroenterology or Infection at the First Affiliated Hospital of Xi’an Jiaotong University were selected.HBV DNA,HBV RNA,and HBeAg quantitative tests were conducted using serum samples from the same patients.Results:In the three groups of cases,the HBV RNA load was higher when HBeAg was positive than when HBeAg was negative,and this difference was statistically significant.Only in the HCC group was the HBV DNA load significantly higher when HBeAg was positive than when HBeAg was negative.Additionally,there was a positive correlation between HBV DNA and HBV RNA regardless of HBeAg status.Conclusion:During HBeAg conversion,HBV RNA demonstrates a more sensitive response than HBV DNA.As CHB progresses to LC or HCC,HBV RNA exhibits better diagnostic value than HBV DNA.

Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B

AIM： To study the relationship between hepatitis B virus （HBV） DNA levels and liver histology in patients with chronic hepatitis B （CHB） and to determine the prevalence and characteristics of hepatitis B e antigen （HBeAg） negative patients.METHODS： A total of 213 patients with CHB were studied, and serum HBV DNA levels were measured by the COBAS Amplicor HBV Monitor test. All patients were divided into two groups according to the HBeAg status.The correlation between serum HBV DNA levels and liver damage （liver histology and biochemistry） was explored.RESULTS： Of the 213 patients with serum HBV DNA levels higher than 10^5 copies/mL, 178 （83.6%） were HBeAg positive, 35 （16.4%） were HBeAg negative. The serum HBV DNA levels were not correlated to the age,history of CHB, histological grade and stage of liver disease in either HBeAg negative or HBeAg positive patients. There was no correlation between serum levels of HBV DNA and alanine aminotransferanse （ALT）,aspartate aminotrans-ferase （AST） in HBeAg positive patients. In HBeAg negative patients, there was no correlation between serum levels of HBV DNA and AST,while serum DNA levels correlated with ALT （r = 0.351, P = 0.042）. The grade （G） of liver disease correlated with ALT and AST （P 〈 0.05, r = 0.205, 0.327 respectively）in HBeAg positive patients. In HBeAg negative patients,correlations were shown between ALT, AST and the G （P 〈 0.01, and r = 0.862, 0.802 respectively）. HBeAg negative patients were older （35 ± 9 years vs 30 ±9 years, P 〈 0.05 ） and had a longer history of HBV infection （8 ± 4 years vs 6 ± 4 years, P 〈 0.05） and a lower HBV DNA level than HBeAg positive patients （8.4± 1.7 Log HBV DNA vs 9.8 ± 1.3 Log HBV DNA, P 〈0.001）. There were no significant differences in sex ratio,ALT and AST levels and liver histology between the two groups.CONCLUSION： Serum HBV DNA level is not correlated to histological grade or stage of liver disease in CHB patients with HBV DNA more than 10^5 copies/mL.Compared to HBeAg positive patients, HBeAg negative patients are older and have a lower HBV DNA level and a longer HBV infection history. There is no significant difference in sex ratio, ALT and AST levels and liver histology between the two groups.

Individualized management of pregnant women with high hepatitis B virus DNA levels

Hepatitis B is a major health concern in the Asia-Pacific region, and is endemic in China, Southeast Asia, and Africa. Chronic hepatitis B virus (HBV) infection may cause hepatic cirrhosis and liver cancer. It is estimated that there are more than 350 million chronic HBV carriers worldwide, of whom approximately one quarter will die of chronic hepatitis B-related liver diseases. HBV is transmitted horizontally through blood and blood products or by sexual transmission, and vertically from mother to infant. Perinatal infection is the predominant mode of transmission in countries with a high prevalence of hepatitis B surface antigen (HBsAg) carriage, and perinatal transmission leads to high rates of chronic infection. Therefore, it is important to prevent the mother-to-child transmission (MTCT) of HBV. Research has shown that pregnant women with high HBV DNA levels have an increased risk of MTCT. However, most of the obstetrics guidelines do not make a distinction between pregnant women with high HBV DNA levels and those who are HBsAg positive only. This review addresses the management of pregnant women with high levels of HBV viremia, in terms of antiviral therapy, use of hepatitis B immunoglobulin (HBIG), the combined application of hepatitis B vaccine and HBIG, choice of delivery mode and feeding practices. (C) 2014 Baishideng Publishing Group Inc. 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.

Performance verification and comparison of TianLong automatic hypersensitive hepatitis B virus DNA quantification system with Roche CAP/CTM system

AIM To investigate and compare the analytical and clinical performance of Tian Long automatic hypersensitive hepatitis B virus(HBV) DNA quantification system and Roche CAP/CTM system.METHODS Two hundred blood samples for HBV DNA testing, HBV-DNA negative samples and high-titer HBV-DNA mixture samples were collected and prepared. National standard materials for serum HBV and a worldwide HBV DNA panel were employed for performance verification. The analytical performance, such as limit of detection, limit of quantification, accuracy, precision, reproducibility, linearity, genotype coverage and cross-contamination, was determined using the Tian Long automatic hypersensitive HBV DNA quantification system(TL system). Correlation and Bland-Altman plot analyses were carried out to compare the clinical performance of the TL system assay and the CAP/CTM system. RESULTS The detection limit of the TL system was 10 IU/m L, and its limit of quantification was 30 IU/m L. The differences between the expected and tested concentrations of the national standards were less than ± 0.4 Log10 IU/m L, which showed high accuracy of the system. Results of the precision, reproducibility and linearity tests showed that the multiple test coefficient of variation(CV) of the same sample was less than 5% for 102-106 IU/m L; and for 30-108 IU/m L, the linear correlation coefficient r2 = 0.99. The TL system detected HBV DNA(A-H) genotypes and there was no cross-contamination during the "checkerboard" test. When compared with the CAP/CTM assay, the two assays showed 100% consistency in both negative and positive sample results(15 negative samples and 185 positive samples). No statistical differences between the two assays in the HBV DNA quantification values were observed(P > 0.05). Correlation analysis indicated a significant correlation between the two assays, r2 = 0.9774. The Bland-Altman plot analysis showed that 98.9% of the positive data were within the 95% acceptable range, and the maximum difference was-0.49.CONCLUSION The TL system has good analytical performance, and exhibits good agreement with the CAP/CTM system in clinical performance.

DUCK HEPATITIS B VIRUS DNA WITHIN HEPATIC MULTICENTRIC CANCER AND/OR METASTATIC CANCER

Duck hepatitis B vims (DHBV) DNA was detected in different tumorous nodules of ducks with hepatic multicentric cancer or intrahepatic metastasis by Southern blot technique. Among 7 ducks with hepatocellular carcinoma of multiple tumor nodules, the hybridization pattern of Integrated DHBV DNA In different tumorous nodules was identical in 3 cases and different in 2 cases. One case showed a similar hybridization pattern in two tumorous nodules and other one was negative tor DHBV DNA. Integrated DHBV DNA was also identified in a metastatic lung cancer of ducks with hepatocellular carcinoma. The hybridization pattern of metastasis of lungs was as the some as that in primary hepatocellular carcinoma. The same discrete hybridization bands In the different tumorous nodules indicate that these nodules might arise from one transformed cell. The different hybridization patterns In various tumorous nodules show that these tumorous nodules might arise from various transformed cells. The results suggest that the hybridization pattern of different nodules of hepatocellular carcinoma with viral DNA probe could make a cell clone origin marker of tumor nodule to differentiate hepatic multlcentric cancer from Intrahepatic metastatic cancer.

Detection of Hepatitis B Virus DNA by Duplex Scorpion Primer-based PCR Assay

The application of a new fluorogenic probe-based PCR assay (PCR duplex scorpion primer assay) to the detection of Hepatitis B virus (HBV) DNA in human sera was described. Duplex scorpion primer is a modified variant of duplex Amplifluor, and the incorporation of a PCR stopper between probe and primer sequences improve the detection specificity and sensitivity. Combined with PCR amplification, this probe can give unambiguous positive results for the reactions initiated with more than 20 HBV molecules. In addition, the particular unimolecular probing mechanism of this probe makes the use of short target-specific probe sequence possible, which will render this probe applicable in some specific systems.

Application of Single-labelled Probe-primer in PCR Amplification to the Detection of Hepatitis B Virus DNA

A new method based on the incorporation of a single-labelled probeprimer into polymerase chain reaction (PCR) for the detection of MR-amplified DNA in a closed system is reported. The probeprimer consists of a specific probe sequence on the 5'-end and a primer sequence on the 3'-end. A fluorophore is located at the 5'-end. The primer-quencher is an oligonucleotide, which is complementary to the probe sequence of probe-primer and labelled with,a quencher at the 3'-end. In the duplex formed by probe-primer and primer-quencher, the fluorophore and quencher am kept in close proximity to each other. Therefore the fluorescence is quenched. During PCR amplification, the specific probe sequence of probeprimer binds to its complement within the same strand of DNA, and is cleaved by Taq DNA polymerase, resulting in the restoration of fluorescence. This system has the same energy transfer mechanism as molecular beacons, and a good quenching efficiency can be ensured. Following optimization of PCR conditions, this method was used to detect hepatitis B virus (HBV) DNA in patient sera. This technology eliminates the risk of carry-over contamination, simplifies the amplification may and opens up new possibilities for the real-time detection of the amplified DNA.

Occult hepatitis B virus and hepatocellular carcinoma

Occult hepatitis B virus(HBV)infection(OBI)is a challenging pathobiological and clinical issue that has been widely debated for several decades.By definition,OBI is characterized by the persistence of HBV DNA in the liver tissue(and in some cases also in the serum)in the absence of circulating HBV surface antigen(HBsAg).Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma(HCC)development.OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection.Indeed,in OBI as in HBV-positive infection,HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome,and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein-provided with potential transforming properties.Furthermore,OBI may indirectly favor HCC development.It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life,and substantial clinical evidence indicates that OBI canaccelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.

Diagnostic strategy for occult hepatitis B virus infection

In 2008,the European Association for the study of the liver(EASL) defined occult hepatitis B virus infection (OBI) as the"presence of hepatitis B virus(HBV) DNA in the liver(with detectable or undetectable HBV DNA in the serum) of individuals testing hepatitis B surface antigen(HBsAg) negative by currently available assays".Several aspects of occult HBV infection are still poorly understood,including the definition itself and a standardized approach for laboratory-based detection,which is the purpose of this review.The clinical significance of OBI has not yet been established;however,in terms of public health,the clinical importance arises from the risk of HBV transmission.Consequently,it is important to detect high-risk groups for occult HBV infection to prevent transmission.The main issue is,perhaps,to identify the target population for screening OBI.Viremia is very low or undetectable in occult HBV infection,even when the most sensitive methods are used,and the detection of the viral DNA reservoir in hepatocytes would provide the best evaluation of occult HBV prevalence in a defined set of patients.However,this diagnostic approach is obviously unsuitable:blood detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection<10 IU/mL for HBV DNA and<0.1 ng/mL for HBsAg.

Prevalence of occult hepatitis B virus infection

Occult hepatitis B virus(HBV) infection(OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface antigen.The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world,the different assays utilized in the studies,and the different populations studied.Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals.The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.

Efficacies of β-L-D4A against Hepatitis B virus in 2.2.15 cells

AIM： To investigate the antiviral effect of beta-L- enantiomer of 2;3＇-didehydro-2＇,3″-dideoxyadenosine （13-L-D4A） on 2.2.15 cells transfected with the hepatitis B virus （HBV） genome.METHODS： Lamivudine （3TC） as a positive control. Then, HBV DNA in treated 2.2.15 cells and the Hepatitis B surface antigen （HBsAg） in the culture supernatants were detected to determine the inhibitory effect of β-L- D4A. At the same time, 3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyltetrazolium bromide （MTT） was used to detect the survival ratio of 2.2.15 cells.RESULTS： β-L-D4A has a dose-dependent inhibitory effect on HBV DNA replication; this effect was apparent when the concentration was above 1 mol/L. When β-L- D4A was at the highest concentration, 100 mol/L, the HBsAg inhibition ratio was above 50%. The Therapeutic index （TI） of β-L-D4A was above 2.1.CONCLUSION： β-L-D4A has a dose-dependent inhibitory effect on the replication of HBV DNA and the secretion of HBsAg at low toxicity,

Current treatment indications and strategies in chronic hepatitis B virus infection

The optimal approach to the management of several marginal cases with chronic hepatitis B virus (HBV) infection is controversial. Serum HBV DNA and ami-notransferase levels, and the degree of necroinflammation and fibrosis determine the therapeutic decisions. All patients with elevated aminotransferase (> twice the upper limit of normal) and serum HBV DNA above 20 000 IU/mL should be treated. Liver biopsy is important for therapeutic decisions in cases with mild aminotransferase elevations and serum HBV DNA below 20 000 IU/mL. Chronic HBV patients who do not receive treatment should be followed for life. There are seven agents licensed for chronic hepatitis B: standard and pegylated interferon-alpha, lamivudine, adefovir, entecavir, telbivudine and tenofovir. One-year courses with pegylated interferon-alpha induce sustained off-therapy remission in 30%-32% of patients with HBeAg-positive chronic hepatitis B and in a smaller proportion of patients with HBeAg-negative chronic hepatitis B. Oral antivirals achieve initial on-therapy responses in the majority of patients, but are intended as long-term therapies. Viral suppression has favourable effects on patients' outcome and modifies the natural course of the disease. Viral resistance, however, is the major drawback of long-term oral antiviral therapy. Lamivudine monotherapy is associated with the highest and ente-cavir monotherapy with the lowest resistance rate so far. There has been no resistance to tenofovir, but afteronly 18 mo of treatment to date. The optimal first-line anti-HBV therapy with the best long-term cost/benefit ratio remains unclear. If oral antiviral agents are used, compliance should always be ascertained and HBV DNA levels should be regularly tested.

Expression and semi-quantification of hepatitis B virus reverse transcriptase protein in a prokaryotic system

The reverse transcriptase （RT） protein of hepatitis B virus （HBV） has been successfully expressed by recombinant technology in Eschericahia coli （ E. coli ）. In this study we aimed to develop a semi-quantitative assay for the study of HBV RT protein using this system. Complete HBV polymerase gene from a wild type virus （rt306P） and the polymerase gene from a mutant, with rt306P substituted by serine （rtP306S） were separately fused to the maltose binding protein （MBP） gene and expressed in E. coli respectively. The expression levels of HBV polymerase genes from the wild type virus and its counterpart mutant at rt306 were compared. When these proteins were semi-quantified by Westem blotting using rabbit anti-TP serum, the rtP306S mutant showed decreased expression of MBP-HBV polymerase. By this method, we have shown that the expression level of HBV RT could be affected by substitutions in its amino acid sequences, and this method could be used to study the characteristics of HBV RT protein.

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.

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.

Serum hepatitis B core-related antigen as a surrogate marker of hepatitis B e antigen seroconversion in chronic hepatitis B

BACKGROUND Quantitative hepatitis B core-related antigen(qHBcrAg)has a better correlation with intrahepatic hepatitis B virus(HBV)covalently closed circular DNA(cccDNA)than HBV DNA or hepatitis B e antigen(HBeAg),but data are still lacking for its clinical application.AIM The aim was to investigate serum qHBcrAg levels in patients with chronic hepatitis B and assess the correlation of serum qHBcrAg with pregenomic RNA(pgRNA),cccDNA,and HBeAg seroconversion.METHODS This study was a secondary analysis of patients who underwent percutaneous liver biopsy between July 2014 and June 2019 in two multicenter randomized controlled clinical trials of peginterferon vs nucleos(t)ide analog(NUC)-based therapy(NCT03509688 and NCT03546530).Serum qHBcrAg,pgRNA,HBV DNA,hepatitis B core antigen,HBeAg,liver cccDNA,and HBV DNA were measured.The correlations of serum qHBcrAg with other biomarkers were analyzed.RESULTS A total of 139 patients were included.The mean qHBcrAg levels were 5.32±1.18 log10 U/mL at baseline and decreased during treatment(all P<0.0001).Serum qHBcrAg levels were positively correlated with pgRNA(r=0.597,P<0.0001)and cccDNA(r=0.527,P<0.0001)levels.The correlation of serum qHBcrAg level and intrahepatic HBV DNA levels at baseline was weak but significant(r=0.399,P<0.0001).HBcrAg predicted HBeAg seroconversion,with areas under the receiver operating characteristics curve of 0.788 at 24 wk and 0.825 at 48 wk.Log HBcrAg at wk 24 and 48 was independently associated with HBeAg seroconversion[odds ratio(OR)=2.402,95%confidence interval(CI):1.314-4.391,P=0.004;OR=3.587,95%CI:1.315-9.784,P=0.013].CONCLUSION Serum HBcrAg levels were correlated with HBV virological markers and could be used to predict HBeAg seroconversion.

Short-term overlap lamivudine treatment with adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

AIM： To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naive chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone. METHODS： Eighty patients who had received lamivudine treatment for various periods and had a lamivudineo resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for ≥ 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus （HBV） DNA at 0, 12 and 48 wk and serum alanine aminotransferase （ALT） levels after 0, 12, 24 and 48 wk of adefovir treatment in each group. RESULTS： We found serum ALT became normalized in 72 （87.5%） of the 80 patients, and HBV DNA decreased by ≥ 2 Ioglo copies/mL in 60 （75%） of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups. CONCLUSION： These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy.

Management of hepatitis B in developing countries

Hepatitis B is one of the leading causes of chronic hepatitis in developing countries, with 5% to 15% of the population carrying virus. The high prevalence is due to failure to adopt appropriate measure to confine the spread of infection. Most hepatitis B patients present with advanced diseases. Although perinatal transmission is believed to be an important mode, most infections in the developing world occur in childhood and early adulthood. Factors in developing countries associated with the progression of chronic hepatitis B (CHB) include co-infections with human immunodeficiency virus, delta hepatitis virus, hepatitis C virus, alcohol intake and aflatoxin. Treatment protocols extrapolated from developed countries may need modifications according to the resources available. There is some controversy as to when to start treatment, with what medication and for how long? There is now enough evidence to support that hepatitis B patients should be considered for treatment if they show persistently elevated abnormal aminotransferase levels in the last 6 mo, checked on at least three separate occasions, and a serum hepatitis B virus DNA level of > 2000 IU/mL. Therapeutic agents that were approved by Pure Food and Drug Administration are now available in many developing countries. These include standard interferon (INF)-α, pegylated INF-α, lamivudine, adefovir, entecavir and telbivudine. Drug resistance has emerged as a major challenge in the management of patients with CHB. The role of the universal vaccination program for effective control of hepatitis B cannot be emphasized enough.