Hepatitis B surface antigen monitoring and management of chronic hepatitis B

Serum hepatitis B surface antigen (HBsAg) levels reflect intrahepatic hepatitis B virus (HBV) covalently closed circular DNA and may be a valuable addition to HBV DNA in the management of patients with chronic hepatitis B (CHB). Among HBeAg-negative CHB patients with low HBV DNA levels, HBsAg quantification may help distinguish those with active CHB from true inactive carriers with a very favourable prognosis, thus limiting the need for long-term intensive monitoring of ALT and HBV DNA levels. In patients treated with peginterferon (PEG-IFN), achievement of a decline in HBsAg during therapy appears to be an important marker for treatment outcome, and several groups have proposed stopping rules based on HBsAg thresholds. A recently described stopping rule incorporating a combination of HBsAg and HBV DNA levels can accurately identify HBeAg-negative patients, especially those with HBV genotype D, not responding to PEG-IFN. Current applications of HBsAg levels in the monitoring of patients treated with nucleo(s)tide analogues are still being evaluated. First data from these studies show that HBsAg decline, and thus subsequent clearance, is confined to those with an active immune response to HBV, such as HBeAg-positive patients with elevated ALT, or those who achieve HBeAg clearance.     

HBsAg, HBeAg and HBV DNA level changes and precore/basal core promoter mutations in the natural history of chronic hepatitis B in Indonesian patients

Introduction

Chronic hepatitis B (CHB) is a state of complex interactions between the hepatitis B virus (HBV) and host. We studied the changes in hepatitis B surface antigen (HBsAg), hepatitis B ‘e’ antigen (HBeAg) and HBV DNA levels, considering the implications of HBV genotype, basal core promoter (BCP) A1762T/G1764A and precore G1896A mutations in CHB.

Methods

One hundred fifty-two treatment-naïve CHB patients were classified into immune-tolerant (IT), immune-clearance (IC), low/non-replicative (LR) and ‘e’-negative hepatitis B (ENH) phases, based on HBeAg status, HBV DNA and ALT levels. HBV DNA was detected and quantified by polymerase chain reaction, then analyzed by sequencing. HBsAg and HBeAg levels were measured serologically.

Results

HBsAg and HBV DNA levels varied between CHB phases, with HBsAg highest in IT and lowest in LR, and HBV DNA high in IT and IC, and lowest in LR. Both markers increased in ENH. Correlation between HBsAg and HBV DNA was significant in IT and IC, modest in ENH, but missing in LR. HBeAg and HBV DNA levels were dissociated in HBeAg-positive patients. Genotypes B and C were similarly distributed, with precore mutations higher in HBeAg-negative patients and BCP mutations comparable in all phases. Temporal association between HBeAg seroconversion and an increase of BCP/precore mutations was observed.

Conclusion

HBsAg and HBV DNA levels were high and correlated in early CHB phases and dissociated after HBeAg seroconversion, indicating different controls affecting HBV replication and HBsAg production. Selection of BCP/precore mutants may affect disease course and explain the HBeAg–HBV DNA dissociation, a precaution for clinical application of quantitative HBeAg.     

聚乙二醇化干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者乙型肝炎病毒表面抗原消失的相关因素

目的 探讨聚乙二醇化干扰素（PEG-IFN α-2a）治疗HBeAg阳性慢性乙型肝炎(CHB)患者过程中预测HBsAg消失的相关因素。方法 对72例HBeAg阳性CHB患者,应用PEG-IFN α-2a 180 μg,每周1次,共48周。每3个月检测ALT、AST及HBV DNA、HBeAg和H BsAg定量,对48周治疗结束时HBsAg消失与基线、12周、24周的HBV DNA、HBeAg和HBsAg定量的相关关系进行分析。计数资料行Fisher精确检验及受试者工作特征(ROC)曲线分析。结果65例HBeAg阳性CHB患者完成本研究,其中7例HBsAg消失。48周时HBsAg的消失与治疗12周时H BeAg水平有关（Fisher确切概率法,P=0.023）,与治疗24周时HBeAg水平高度相关 （Fisher确切概率法,P=0.004）,与12周或24周时HBsAg＜250 IU/mL相关(Fisher确切概率法,P=0.001,P=0.002)。与12周时HBV DNA阴转相关（Fisher确切概率法,P=0.039）,而与24周时HBV DNA是否阴转无关（Fisher确切概率法,P= 0.130）。经ROC曲线分析显示,12周、24周HBsAg及24周HBeAg曲线下面积(AUC)分别为0.8584(P=0.0021)、0.9606(P=0.001)及0.8350(P=0.040)。结论 联合应用24周HBeAg和HBsAg定量水平可能是预测48周疗程结束时是否发生HBsAg消失的有效指标。     

Assessment of chronic hepatitis B: the importance of hepatitis B virus DNA testing

Background: Chronic hepatitis B (CHB) has an estimated prevalence of 90 000 to 160 000 in Australia. Cirrhosis and hepatocellular carcinoma are important complications of CHB and appropriate evaluation of hepatitis B surface antigen (HBsAg)‐positive individuals is vital to identify treatment candidates. Methods: A review of the database of a tertiary hospital was performed and 348 HBsAg‐positive individuals with baseline demographic, virological, serological and biochemical variables were identified and evaluated cross‐sectionally. A small subgroup of hepatitis B e antigen (HBeAg)‐negative patients with normal alanine aminotransferase (ALT) at baseline were identified and followed longitudinally. Results: 175/348 (50%) of patients were in the HBeAg‐negative, chronic hepatitis phase of disease, 22% in the HBeAg‐positive immune clearance and 6% in the immune tolerant phases. HBeAg‐negative patients were older and more likely to be male than HBeAg‐positive patients. The correlation between hepatitis B virus (HBV) DNA and ALT levels was examined. ALT and HBV DNA levels showed no correlation in HBeAg‐positive CHB and only a weak correlation in HBeAg‐negative patients. Furthermore, 35% of HBeAg‐negative patients with detectable HBV DNA had a normal ALT. Conversely 38% of HBeAg‐negative patients with no detectable HBV DNA had an elevated ALT. A persistently normal ALT over 24 months was seen in five of nine HBeAg‐negative patients with normal initial ALT and detectable HBV DNA. Conclusion: Appropriate evaluation of HBeAg‐negative CHB must include HBV DNA because the ALT is not a reliable guide to underlying viral replication.     

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels

Summary. Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on‐treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty‐two patients with HBeAg‐positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on‐treatment factors, on‐treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log₁₀ IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940–1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On‐treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut‐off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log₁₀ PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on‐treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg‐positive CHB patients with entecavir treatment.     

Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B

In chronic replicative hepatitis B the significance of mutations in the basic core promoter (BCP), core upstream regulatory sequences (CURS) and negative regulatory element (NRE) for response to interferon (IFN) is unknown. A sequence analysis of the NRE, CURS, BCP, and precore region was performed from sera of 96 patients with chronic replicative hepatitis B (64 hepatitis B e antigen [HBeAg]-positive patients and 32 HBeAg-negative patients) treated with alfa-IFN (IFN-alpha). The overall sustained response (SR) rate to IFN was 30% with no significant difference between HBeAg-positive and HBeAg-negative patients. IFN responsiveness correlated to hepatitis B virus (HBV)-DNA levels, hepatitis B surface antigen (HBsAg) levels, the number of mutations in the complete BCP, especially nucleotide (nt) region 1753 to 1766 and mutations at nt 1762 and 1764. In HBeAg-positive hepatitis, SR to IFN was associated with a high number of mutations in the BCP (P <.04) and nucleotide region 1753 to 1766 (P <.015) as well as mutations at nucleotide 1764 (P <.007). In HBeAg-negative hepatitis, SR to IFN correlated with a low number of mutations in the BCP (P <.04) and nucleotide region 1753 to 1766 (P <.02) and a wild-type sequence at nt 1764 (P <.003). Prediction of IFN response was possible on the basis of nt 1764 in 77% of HBeAg-positive patients and 78% of HBeAg-negative patients. IFN response did not correlate with the occurrence of the 1896 mutation, mutations in the CURS or NRE, disease duration, ethnic origin of the patient, alanine transaminase (ALT) levels and HBV genotype. Our data suggest that HBV genome mutations located within the BCP are determinants of a response to IFN therapy.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response

In chronic hepatitis B, it is difficult to predict an early therapeutic response. We investigated the viral decline during therapy with pegylated interferon alpha-2b (PEG-IFN) with or without lamivudine in 266 HBeAg-positive chronic hepatitis B patients. In patients treated with PEG-IFN and lamivudine, a uniform biphasic viral decline pattern was found during therapy and there were no marked differences in viral load between those who lost HBeAg at the end of follow-up (response) or not. In contrast, those treated with PEG-IFN monotherapy exhibited different viral decline patterns. A delayed decline of at least two log from baseline HBV DNA after week 4 but before week 32 was associated with the highest response rate (63%). In comparison, response was 52% for patients with an early decline (week 0-4), 38% for a late decline (week 32-52), 27% for a posttreatment decline (week 52-78) and 11% for patients with no substantial decline. The HBsAg loss was 22% in the delayed decline pattern compared to 4% for those with early decline and none for other decline patterns. In conclusion, different patterns of decline in viral load during treatment with PEG-IFN monotherapy were associated with different rates of HBeAg and HBsAg loss at the end of follow-up. Since there was a considerable response, even in patients with a late or posttreatment decline pattern, prediction of response based on viral decline during the first months of therapy was difficult.     

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 antiHBe 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"inactive HBsAg carriers".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.     

乙型肝炎病毒基因型及e抗原状态对聚乙二醇干扰素抗病毒疗效的影响

目的探讨乙型肝炎病毒(HBV)不同基因型及乙型肝炎e抗原(HBeAg)对聚乙二醇干扰素治疗慢性乙型肝炎(CHB)应答率的影响。方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP) 方法,分析42例用聚乙二醇干扰素治疗的CHB患者基因型及HBeAg不同状态时对抗病毒治疗的影响。结果不同基因型对聚乙二醇干扰素的应笞率不同,B基因型的持续应答率为66.7%(12/18),C基因型持续应答率为27.3%(3/11)。HBeAg阴性患者的持续应答率为87.5%(7/8),HBeAg阳性患者为38.1%(8/21), P<0.05。结论HBV基因型及HBeAg的不同状态是预测聚乙二醇干扰素疗效的重要因素,且后者比前者的意义更大。     

乙型肝炎病毒前核心区及基本核心启动子变异的检测及其对患者疾病谱的影响

目的探讨乙型肝炎病毒(HBV)前核心区(前C区,nt1896)及基本核心启动子(BCP,nt1762/1764)变异在慢性HBV感染者疾病谱的分布及对患者疾病谱的影响。方法416例血清HBsAg阳性、HBVDNA定量大于1.0×104拷贝/毫升的患者,采用微流基因芯片检测HBV前C区及BCP变异。结果416例HBV感染者中302例为HBeAg(-)患者,其中248例(82.12%)有前C区或BCP变异,41.06%为前C区变异,31.12%BCP变异,2种同时变异为9.94%。HBeAg(-)的慢性乙型肝炎和肝硬化患者前C区变异分别为64.72%和83.33%(x2=0.89,P>0.05),均大于HBeAg(-)无症状携带者的28.47%(x2=54.20,P<0.01;x2=5.29,P<0.05);而HBeAg(-)无症状携带者BCP变异达77.19%,大于HBeAg(-)慢性乙型肝炎和肝硬化患者(x2=69.73,P<0.01;x2=10.58,P<0.01)。而在114例HBeAg(+)患者中28.95%有前C区或BCP变异。结论前C区或BCP变异在慢性HBV感染者疾病谱的分布不同,在HBeAg(-)/HBVDNA(+)与HBeAg(+)/HBVDNA(+)患者变异率差异显著。HBV前C区可能是该病变反复及加重的一个重要原因,但BCP变异临床意义不明确。     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎病毒学应答的预测因素分析

目的 探讨阿德福韦酯(ADV)治疗HBeAg阳性慢性乙型肝炎(CHB)患者病毒学应答的预测因素.方法 对203例HBeAg阳性CHB患者采用ADV 10 mg/d治疗48周,PCR-限制性片段长度多态性检测TNF-α-238及TNF-α-308位点基因多态性,ELISA测定基线血清TNF-α水平,荧光定量PCR或HBV S基因直接测序法检测HBV基因型、亚型,Logistic回归分析影响ADV应答的因素.结果 203例患者ADV治疗24周和48周时HBV DNA转阴率、ALT复常率、HBeAg转阴率及转换率、联合应答率分别为31.5%(64/203)、59.1%(120/203)、15.8%(32/203)、8.9%(18/203)、13.3%(27/203)和58.6%(119/203)、78.3%(159/203)、29.6%(60/203)、16.7%(34/203)、25.6%(52/203).HBV基因型B、TNF-α-308G/A基因型、较高水平基线ALT及较低载量基线HBV DNA易于24周时HBV DNA转阴[OR=0.405,95%CI(0.191～0.859),P=0.019;OR=0.292,95%CI(0.132～0.643),P=0.002;OR=0.933,95%CI(0.989～0.997),P＜0.01;OR=2.089,95%CI(1.412～3.092),P＜0.01];24周HBV DNA高转阴率、较高水平基线ALT有利于48周时HBV DNA转阴[OR=0.029,95%CI(0.007～0.126),P＜0.01;OR=0.995,95%CI(0.991～0.999),P=0.016].结论 HBeAg阳性CHB患者ADV治疗24周病毒学应答的预测因素是HBV基因型、TNF-α-308基因型、基线ALT水平及HBV DNA载量;48周的预测因素是24周HBV DNA转阴率、基线ALT水平.

Abstract：

Objective To investigate the predictive factors of virological response in HBeAg-positive chronic hepatitis B (CHB)patients treated with adefovir dipivoxil (ADV).Methods A total of 203 HBeAg-positive CHB patients treated with ADV (Mingzheng)10 mg once daily for 48 weeks were recruited.The gene polymorphisms at positions-238 and-308 in tumor necrosis factor (TNF)-α promoter region were determined by the restriction fragment length polymorphism assay of products amplified using polymerase chain reaction (PCR-RFLP).The serum levels of TNF-a at baseline were measured by enzyme linked immunosorbent assay (ELISA).Hepatitis B virus (HBV)genotypes were tested by real-time fluorescent quantitative PCR and HBV subgenotypes were tested by HBV S gene sequencing.Factors related to ADV response were determined by Logistic regression analysis.Results The HBV DNA negative rate,alanine aminotransferase (ALT)normalization rate,HBeAg loss rate and seroconversion rate,and combined response rate at week 24 and 48 of treatment in 203 patients were 31.5% (64/203),59.1% (120/203),15.8% (32/203),8.9% (18/203),13.3% (27/203)and 58.6% (119/203),78.3% (159/203),29.6% (60/203),16.7% (34/203),25.6% (52/203),respectively.HBV DNA negative rate at week 24 was higher in patients with HBV genotype B,that was higher in patients with TNF-α-308G/A genotype,and that was higher in patients with higher baseline ALT level or lower baseline HBV DNA level [OR = 0.405,95 % CI (0.191 - 0.859),P =0.019;OR=0.292,95%CI(0.132-0.643),P=0.002;OR=0.933,95%CI(0.989-0.997),P＜0.01 ;OR=2.089,95%CI (1.412-3.092),P＜0.01].Meanwhile,HBV DNA negative rate at week 48 were higher in patients with higher HBV DNA negative rate at week 24 or higher baseline ALT level [OR=0.029,95%CI(0.007-0.126),P＜0.01;OR= 0.995,95%CI(0.991-0.999),P=0.016].Conclusions HBV genotype,TNF-α-308 genotype,baseline levels of ALT and HBV DNA are predictors of virological response at week 24 in HBeAg-positive CHB patients treated with ADV.And the HBV DNA negative rate at week 24 and baseline ALT level are predictors of virological response at week 48.     

替比夫定治疗HBeAg阳性慢性乙型肝炎的疗效及相关预测因子的Logistic回归分析

目的观察替比夫定（LdT）治疗HBeAg阳性慢性乙型肝炎（CHB）患者3年的疗效,应用Logistic回归探讨HBeAg血清学转换的预测因子。方法收集58例采用LdT治疗的HBeAg阳性CHB患者,分析其性别、年龄、基线ALT水平、基线HBV DNA载量、基线HBeAg和HBsAg滴度与治疗3年时ALT复常率、HBV DNA阴转率、HBeAg阴转率和HBeAg血清转换率的相关性;采用Logistic回归分析HBeAg血清转换的相关因素。结果治疗3年时ALT复常率为84.48%,HBV DNA阴转率为70.69%,HBeAg阴转率为50.00%,HBeAg血清转换率为43.10%。与ALT≤2倍正常值上限（2×ULN）相比,基线ALT〉5×ULN的患者HBeAg转换率显著增高（P〈0.05）;与HBeAg≤100（S/CO）组相比,基线HBeAg〉200 S/CO的患者HBeAg的阴转率和血清转换率均显著下降（P〈0.05）;与HBV DNA≤6 log拷贝/ml组相比,HBV DNA〉7 log拷贝/ml的患者HBV DNA转阴率、HBeAg转阴率和HBeAg转换率下降显著（P〈0.05）;患者性别、年龄及基线HBsAg滴度对以上疗效指标无影响（P〉0.05）。多因素Logistic回归分析发现仅基线HBeAg滴度低的患者更易出现HBeAg血清学转换。结论 LdT能有效恢复肝功能,抑制HBV复制和提高HBeAg血清转换;基线HBeAg滴度可预测LdT治疗HBeAg阳性CHB患者的HBeAg血清转换率。     

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon‐based therapy in patients with hepatitis B e antigen‐negative chronic hepatitis B

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long‐term outcome of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG‐IFN)‐based therapy. Serial serum samples from 91 patients with HBeAg‐negative CHB previously treated with PEG‐IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post‐treatment follow‐up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre‐treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut‐off 2.0 log₁₀ copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut‐off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log₁₀ copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG‐IFN‐based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising “stopping rule” in patients infected with HBV genotypes B or C.     

Baseline HBsAg predicts response to pegylated interferon-α2b in HBeAg-positive chronic hepatitis B patients

AIM: To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg) on response to pegylated interferon (PEG-IFN)-α2b in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.METHODS: This retrospective analysis compared the treatment efficacy of PEG-IFN-α2b alone in 55 HBeAg-positive CHB patients with different baseline HBsAg levels. Serum HBV DNA load was measured at baseline, and at 12, 24 and 48 wk of therapy. Virological response was defined as HBV DNA < 1000 IU/mL. Serum HBsAg titers were quantitatively assayed at baseline, and at 12 and 24 wk.RESULTS: Eighteen patients had baseline HBsAg > 20 000 IU/mL, 26 patients had 1500-20000 IU/mL, and 11 patients had < 1500 IU/mL. Three (16.7%), 11 (42.3%) and seven (63.6%) patients in each group achieved a virological response at week 48, with a significant difference between groups with baseline HBsAg levels > 20000 or < 20000 IU/mL (P = 0.02). Thirteen patients had an HBsAg decline > 0.5 log₁₀ and 30 patients < 0.5 log₁₀ at week 12; and 6 (46.2%) and 10 (33.3%) in each group achieved virological response at week 48, with no significant difference between the two groups (P = 0.502). Eighteen patients had an HBsAg decline > 1.0 log₁₀ and 30 patients < 1.0 log₁₀ at week 24, and 8 (44.4%) and 11 (36.7%) achieved a virological response at week 48, with no significant difference between the two groups (P = 0.762). None of the 16 patients with HBsAg > 20000 IU/mL at week 24 achieved a virological response at week 48.CONCLUSION: Baseline HBsAg level in combination with HBV DNA may become an effective predictor for guiding optimal therapy with PEG-IFN-α2b against HBeAg-positive CHB.     

Diagnosis and management of pre-core mutant chronic hepatitis B

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.     

核苷(酸)类似物序贯干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者的临床观察

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者在核苷(酸)类似物抗病毒治疗基础上序贯聚乙二醇干扰素α-2a(PEG IFNα-2a)治疗48周血清HBsAg的变化.方法 6例HBeAg阳性CHB患者中,3例采用核苷(酸)类似物序贯PEG IFNα-2a治疗48周,3例维持原核苷(酸)类似物治疗方案,每12周采用实时PCR定量检测HBV DNA,采用时间分辨免疫荧光分析法检测HBsAg、抗-HBs、HBeAg、抗-HBe及抗-HBc.结果 核苷(酸)类似物序贯PEG lFNα-2a治疗48周后,3例序贯治疗患者血清HBsAg均消失,而维持原核苷(酸)类似物治疗患者血清HBsAg效价为100～320 IU/mL.结论 对核苷(酸)类似物治疗产生较好应答反应且伴有血清HBsAg效价明显下降的HBeAg阳性CHB患者,在核苷(酸)类似物抗病毒治疗基础上序贯PEG IFNα-2a治疗48周能有效促进血清HBsAg下降,并出现血清HBsAg消失的现象.     

1686例慢性乙型肝炎中HBeAg阴性与阳性患者临床和病毒学特点比较分析

目的通过大样本横断面回顾性调查,了解HBeAg(-)和HBeAg( )两类慢性乙型肝炎(CHB)患者临床相关因素的异同。方法对1686例CHB患者的住院病历进行回顾性调查,分析HBeAg(-)和HBeAg( )CHB患者ALT、HBV DNA定量、肝组织病理(炎症及纤维化)等指标的组内和组间差异。结果HBeAg(-)CHB628例,占37·3%;HBeAg( )CHB1058例,占62·7%。HBeAg( )组ALT、HBV DNA总体上均高于HBeAg(-)组。HBeAg( )组肝组织炎症及纤维化程度总体上均轻于HBeAg(-)组。结论目前我国CHB病例以HBeAg( )者占多数。无论HBeAg(-)或HBeAg( )CHB,肝炎活动在病毒复制活跃时均重于病毒复制水平较低时。HBeAg(-)CHB肝组织学损害重于HBeAg( )CHB。     

Hepatitis B virus: prevalence of precore/core promoter mutants in different clinical categories of Indian patients

Summary. To determine the association of precore (Pre-C)/basal core promoter (BCP) mutants with clinical outcome of hepatitis B in Western India, 192 hepatitis B virus (HBV) infected individuals were investigated. HBV-DNA PCR positivity among asymptomatic hepatitis B surface antigen (HBsAg) positive carriers (61/100) was lower ( P  < 0.0001) than chronic hepatitis B (CHB), acute ( P  = 0.0001), and fulminant hepatitis B patients ( P  = 0.047). Pre-C status was based on restriction fragment length polymorphism (RFLP, n  = 153) and sequencing ( n  = 118). Prevalence of Pre-C mutants was higher among carriers (23/61) than CHB (10/62, P  = 0.0071) or acute (3/22; P  = 0.037) patients. Children from carrier and CHB categories showed significantly higher circulation of Pre-C-wild than mutant HBV. Clinical manifestations were independent of BCP mutations (1762/64-T/A). Hepatitis B e antigen (HBeAg) negative CHB patients [62.5% (15/24)] were circulating wild HBV. Higher HBV-DNA levels were associated with chronic hepatitis and HBeAg positivity, whilst Pre-C mutant positives had lower levels. BCP mutations did not affect HBV-DNA levels. Multivariate regression analysis identified HBeAg (OR = 4.3) and Pre-C mutants (OR = 3.1) to be associated with chronic hepatitis and carriers respectively. In a separate sub-set analysis ( n  = 59), HBV-DNA level was identified as the only variable. In conclusion, chronic or fulminant hepatitis B was not associated with Pre-C or BCP mutants and switching over to Pre-C mutant was beneficial for the infected individual in maintaining disease free status for extended periods.