Intracellular levels of hepatitis B virus DNA and pregenomic RNA in peripheral blood mononuclear cells of chronically infected patients

Summary.  It remains uncertain whether hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA) can be detected in the serum or peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B (CHB) infection. We examined HBV cccDNA and pgRNA in the serum and PBMC, and investigated the effect of lamivudine therapy on the viral loads in the PBMC of CHB patients. Paired serum and PBMC samples from 50 treatment-naïve CHB patients [25 hepatitis B e antigen (HBeAg) positive and 25 HBeAg negative] were quantified for total HBV DNA, cccDNA and pgRNA by real time polymerase chain reaction. HBV cccDNA and pgRNA were below the lower detection limit in all serum samples, and in 84% of PBMC. HBV DNA ( r  = 0.889, P  <   0.001) and pgRNA ( r  = 0.696, P  <   0.001) in PBMC correlated with the HBV DNA in serum. In the longitudinal study, 30 patients treated with lamivudine therapy for a median duration of 34 weeks (range 12–48 weeks) were examined. The median HBV DNA reduction in PBMC before and after treatment was 1.318 (range −0.471 to 3.846) log units, which was significantly lower than serum HBV DNA reduction [3.371 (range −0.883 to 9.454) log units, P  <   0.05]. HBV cccDNA and pgRNA were undetectable in the serum of CHB patients. HBV viral loads in PBMC correlated with serum HBV DNA. Lamivudine therapy had less effect on the HBV viral loads in PBMC compared with the serum viral loads.     

Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues

Quantification of hepatitis B surface antigen(HBsAg)has been suggested to be helpful in the management of chronic hepatitis B(CHB)patients.Nucleos(t)ide analogs(NAs)are the therapy of choice for CHB and are used in the majority of CHB patients.NAs are able to induce hepatitis B virus(HBV)viral suppression,normalization of alanine aminotransferase(ALT)levels,and improvement in liver histology.Automated quantitative assays for serum HBsAg have recently become available,facilitating standardized quantification of serum HBsAg.This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs.Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV,and can therefore be used to predict therapeutic response.NA treatment typically induces a less rapid decline in HBsAg than interferon treatment;it has been estimated that full HBsAg clearance can require decades of NA treatment.However,a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg.Currently,there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy.This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.     

血清HBsAg、HBcrAg和HBV DNA预测慢性乙型肝炎肝组织病理状态的性能评价

目的评价血清HBsAg、HBcrAg、HBV DNA预测慢性乙型肝炎肝组织病理状态的性能。方法将324例HBeAg阳性和255例HBeAg阴性慢性乙型肝炎患者随机分为3组匹配的训练集和验证集。血清HBsAg和HBcrAg分别采用Abbott Architect I2000和Fujirebio Lumipulse G1200全自动化学发光免疫系统检测,血清HBV DNA采用Bio-Rad Icycler荧光定量PCR仪检测。肝组织病理学诊断采用Scheuer评分系统,其中病理学分级包括G0~G4五级,分期包括S0~S4五期。结果无论HBeAg阳性或阴性患者,3个训练集与3个匹配的验证集性别比例和平均年龄、病理学分级和分期构成比之间的差异均无统计学意义(P0.05)。HBeAg阳性患者,血清HBsAg、HBcrAg、HBV DNA预测全集病理学分级≥G3和分期≥S4的ROC曲线下面积最大;参照预测3个训练集病理学分级≥G3和分期≥S4的最佳截断值,血清HBsAg、HBcrAg、HBV DNA预测3个匹配的验证集病理学分级≥G3和分期≥S4的灵敏度极差分别为37%和9%、30%和16%、17%和14%,特异度极差分别为12%和5%、13%和3%、15%和6%。HBeAg阴性患者,血清HBcrAg、HBV DNA预测全集病理学分级≥G2和分期≥S2的ROC曲线下面积最大;参照预测3个训练集病理学分级≥G2和分期≥S2的最佳截断值,血清HBcrAg、HBV DNA预测3个匹配的验证集病理学分级≥G2和分期≥S2的灵敏度极差分别为11%和20%、46%和19%,特异度极差分别为15%和2%、38%和16%。结论 HBeAg阳性患者,血清HBsAg、HBcrAg、HBV DNA可预测的最佳病理状态为病理学分级≥G3和分期≥S4,其预测理学分期≥S4的稳定性高于预测病理学分级≥G3;HBeAg阴性患者,血清HBcrAg和HBV DNA可预测的最佳病理状态为病理学分级≥G2和分期≥S2,血清HBcrAg预测病理学分级≥G2和分期≥S2的稳定性高于HBV DNA。     

乙型肝炎病毒核心相关抗原的监测及临床意义

监测乙型肝炎病毒核心相关抗原(HBcrAg),能有效预测核苷(酸)类药物抗病毒治疗后产生的病毒学反弹及耐药风险,具有重要的临床实用价值。     

恩替卡韦治疗慢性乙型肝炎患者血清HBV cccDNA和HBV pgRNA水平变化*

目的 探讨血清 HBV 共价闭合环状 DNA(HBV cccDNA)和HBV前基因组 RNA(HBV pgRNA)水平预测血清HBeAg阳性慢性乙型肝炎(CHB)患者接受恩替卡韦治疗后疗效的临床价值。方法 2018年1月～2020年1月我院收治的HBeAg阳性CHB患者89例,均口服恩替卡韦分散片治疗48 w。使用COOBAS TAQMAN和COBAS Amliprep系统和采用荧光定量PCR法检测血清HBV cccDNA和HBV pgRNA水平,采用化学发光法定量检测血清HBsAg和HBeAg水平。应用受试者工作特征曲线(ROC)分析血清各指标预测恩替卡韦治疗的CHB患者疗效的价值。结果 89例HBeAg阳性CHB患者经恩替卡韦治疗48 w后,获得病毒学应答85例(95.5%),生化学应答80例(89.9%),血清学应答9例(10.1%);获得完全应答75例(84.3%);完全应答组血清ALT、HBsAg、HBeAg、HBV DNA, HBV cccDNA和HBV pgRNA水平分别为(228.3±34.9)U/L、(2.5±0.4)lg IU/mL、(18.6±1.9)S/CO、(6.1±0.6)lg IU/mL、(2.2±0.2)cps/mL和(4.5±0.6)cps/mL,与非完全应答组【分别为(69.5±17.1)U/L、(3.7±0.7)lg IU/mL、(163.2±16.3)S/CO、(6.8±0.7)lg IU/mL、(3.9±0.4)cps/mL和(7.0±0.7)cps/mL】比,差异显著(P＜0.05);应用血清HBV cccDNA与HBV pgRNA水平联合预测CHB患者接受恩替卡韦治疗疗效的ROC曲线下面积为0.892,其敏感性为81.6%,特异性为89.5%。结论 在抗病毒治疗前,检测HBeAg阳性慢性乙型肝炎患者血清HBV cccDNA和HBV pgRNA水平预测疗效有一定的应用价值,值得进一步研究。     

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.     

Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA

The correlation between serum HBcrAg and HBV RNA is unclear, and correlations of intrahepatic cccDNA with HBcrAg, HBV RNA and HBsAg are rarely reported in the same cohort. This study aimed to assess the correlation of HBcrAg with HBV RNA and HBsAg, and investigate whether serum HBcrAg is superior to serum HBV RNA and HBsAg in reflecting intrahepatic HBV cccDNA in HBeAg‐positive and HBeAg‐negative CHB patients. In this study, 85 HBeAg‐positive and 25 HBeAg‐negative patients who have never received antiviral therapy were included. Among HBeAg‐positive patients, HBcrAg was correlated positively with HBsAg (r = 0.564, P < 0.001) and HBV RNA (r = 0.445, P < 0.001), and HBV RNA was also correlated positively with HBsAg (r = 0.323, P = 0.003). Among HBeAg‐negative patients, no significant correlation was observed between HBcrAg, HBsAg and HBV RNA. By multivariable linear regression, HBcrAg (β = ?0.563, P < 0.001), HBsAg (β = ?0.328, P < 0.001) and HBV RNA (β = 0.180, P = 0.003) were all associated with cccDNA levels among HBeAg‐positive patients, but only serum HBcrAg was associated with cccDNA level (β = 0.774, P = 0.000) among HBeAg‐negative patients. HBcrAg was better correlated with cccDNA as compared to HBsAg and HBV RNA, irrespective of HBeAg status. Among HBeAg‐positive patients, though HBcrAg level was influenced by hepatic inflammatory activity and HBV DNA levels, the good correlations of HBcrAg with cccDNA persisted after stratification by inflammatory activity and HBV DNA levels. In conclusion, correlations of serum HBcrAg, HBV RNA and HBsAg levels differ significantly between HBeAg‐positive and HBeAg‐negative patients, but serum HbcrAg correlates with cccDNA levels better than HBV RNA and HBsAg, irrespective of HBeAg status.     

Drug Discovery Study Aimed at a Functional Cure for HBV

Hepatitis B virus (HBV) causes acute and, most importantly, chronic hepatitis B worldwide. Antiviral treatments have been developed to reduce viral loads but few patients with chronic hepatitis B (CHB) achieve a functional cure. The development of new therapeutic agents is desirable. Recently, many novel agents have been developed, including drugs targeting HBV-DNA and HBV-RNA. This review provides an overview of the developmental status of these drugs, especially direct acting antiviral agents (DAAs). Serological biomarkers of HBV infection are essential for predicting the clinical course of CHB. It is also important to determine the amount and activity of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. Hepatitis B core-associated antigen (HBcrAg) is a new HBV marker that has an important role in reflecting cccDNA in CHB, because it is associated with hepatic cccDNA, as well as serum HBV DNA. The highly sensitive HBcrAg (iTACT-HBcrAg) assay could be a very sensitive HBV activation marker and an alternative to HBV DNA testing for monitoring reactivation. Many of the drugs currently in clinical trials have shown efficacy in reducing hepatitis B surface antigen (HBsAg) levels. Combination therapies with DAAs and boost immune response are also under development; finding the best combinations will be important for therapeutic development.     

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

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

监测核苷(酸)类抗HBV药物治疗CHB的停药指标

抗HBV感染的治疗难点之一是安全停药或治疗终点的确定,目前主要依靠血清HBV DNA、HBeAg/抗-HBe、HBsAg/抗-HBs和抗-HBc评估慢性乙型肝炎治疗效果,并以持久的HBsAg清除作为停药标准。但血清HBsAg阴转率很低且难以实现"临床治愈(或功能性治愈)",因此,近年来提出了许多新的指导慢性乙型肝炎患者停药的指标,如肝组织HBV ccc DNA、血清HBcrAg和血清HBV RNA。本文就以上指标的研究进展进行综述。     

Hepatitis B surface antigen and hepatitis B core-related antigen kinetics after adding pegylated-interferon to nucleos(t)ids analogues in hepatitis B e antigen-negative patients

BACKGROUNDHepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues (NAs) rarely achieve hepatitis B surface antigen (HBsAg) loss.AIMTo evaluate if the addition of pegylated interferon (Peg-IFN) could decrease HBsAg and hepatitis B core-related antigen (HBcrAg) levels and increase HBsAg loss rate in patients under NAs therapy.METHODSProspective, non-randomized, open-label trial evaluating the combination of Peg-IFN 180 µg/week plus NAs during forty-eight weeks vs NAs in monotherapy. Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital, under NAs therapy for at least 2 years and with undetectable viral load, were eligible. Patients with hepatitis C virus, hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded. HBsAg and HBcrAg levels (log10 U/mL) were measured at baseline and during ninety-six weeks. HBsAg loss rate was evaluated in both groups. Adverse events were recorded in both groups. The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline (log10 IU/mL/week) using a linear regression model.RESULTSSixty-five patients were enrolled, 61% receiving tenofovir and 33% entecavir. Thirty-six (55%) were included in Peg-IFN-NA group and 29 (44%) in NA group. After matching by age and treatment duration, baseline HBsAg levels were comparable between groups (3.1 vs 3.2) (P = 0.25). HBsAg levels at weeks 24, 48 and 96 declined in Peg-IFN-NA group (-0.26, -0.40 and -0.44) and remained stable in NA group (-0.10, -0.10 and -0.10) (P < 0.05). The slope of HBsAg decline in Peg-IFN-NA group (-0.02) was higher than in NA group (-0.00) (P = 0.015). HBcrAg levels did not change. Eight (22%) patients discontinued Peg-IFN due to adverse events. The HBsAg loss was achieved in 3 (8.3%) patients of the Peg-IFN-NA group and 0 (0%) of the NA group. CONCLUSIONThe addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy. Side effects of Peg-IFN can limit its use in clinical practice.     

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.     

血清乙型肝炎病毒前基因组RNA水平对核苷(酸)类似物初治的慢性乙型肝炎患者疗效预测价值*

目的 探讨应用血清乙型肝炎病毒前基因组RNA(HBV pgRNA)水平预测核苷(酸)类似物初治的慢性乙型肝炎(CHB)患者疗效的价值。方法 2015年8月～2019年12月我院诊治的初始治疗的CHB患者107例,接受恩替卡韦、替诺福韦或替比夫定治疗观察48 w。采用实时荧光定量PCR法检测血清HBV pgRNA,采用ELISA法检测血清HBsAg和HBeAg。应用Logistic回归分析影响疗效的因素,应用MedCalc1 5.1统计学软件绘制ROC,计算曲线下面积(AUC)评价血清HBV pgRNA水平预测核苷(酸)类似物治疗的疗效。结果 在治疗48周末,27例(25.2%)患者不应答,另80例(74.8%)患者获得完全应答或部分应答;(完全或部分)应答组血清HBV DNA载量为(6.1±1.0)lg copies/mL,显著低于不应答组【(7.2±1.2) lg copies/mL,P<0.05】,外周血CD4^＋/CD8^＋比值为(0.7±0.2),显著高于不应答组【(0.6±0.1),P<0.05】,血清HBeAg阳性率为41.3%,显著低于不应答组(70.4%,P<0.05),血清HBV pgRNA水平为(5.3±0.8)lg copies/mL,显著低于不应答组【(6.5±1.1)lg copies/mL,P<0.05】;Logistic回归分析显示,基线HBV DNA载量、HBeAg状态和血清HBV pgRNA水平均为影响核苷(酸)类似物治疗的CHB患者疗效的因素(OR=2.793、OR=3.827、OR=4.035,P均<0.05);经ROC分析显示,血清HBV pgRNA水平预测核苷(酸)类似物治疗CHB患者不应答的最佳截断点为5.89 lgcopies/mL,AUC值为0.865(95%CI:0.816～0.905),其预测的灵敏度为74.1%(20/27),特异度为88.8%(71/80)。结论 监测血清HBV pgRNA水平预测核苷(酸)类似物初治的CHB患者的疗效有一定的临床应用价值,如果检测结果稳定,不失为一种临床决策的参考依据。     

Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for viral persistence in the natural course of chronic HBV infection and during prolonged antiviral therapy and serves as the template for the production of HBV pregenomic RNA (pgRNA), the primary step in HBV replication. In this study, we have developed and applied sensitive and specific quantitative real-time polymerase chain reaction (PCR) assays for the measurement of intrahepatic concentration, pgRNA production, and replicative activity of cccDNA in liver biopsy samples from 34 non-treated patients with chronic hepatitis B (CHB); 12 hepatitis B e antigen (HBeAg)(+) and 22 HBeAg(-). Median copy number for cccDNA was 1.5 per cell and for pgRNA significantly higher, 6.5 copies per cell, with a good correlation between cccDNA and pgRNA levels in all samples. In HBeAg(-) patients, median values of cccDNA and pgRNA levels were 10-fold and 200-fold lower than in HBeAg(+), respectively, reflecting the differences in viral activity and clinical characteristics of the two groups. Furthermore, the replicative activity of intrahepatic cccDNA was significantly lower in HBeAg(-) patients harboring mutant HBV strains than in HBeAg(+) patients: median 3.5 versus 101 pgRNA copies per cccDNA molecule. In conclusion, the levels of both HBV cccDNA, a marker of HBV persistence, and pgRNA, an indicator of viral replication, in the liver of chronically infected patients correlate with viral activity and the phase of HBV infection. The combined measurement of cccDNA and pgRNA levels provides valuable information on the presence and replicative activity of intrahepatic HBV cccDNA.     

血清HBsAg滴度监测对恩替卡韦治疗的HBeAg阳性慢性乙型肝炎患者应答反应的预测价值

目的探讨HBeAg阳性慢性乙型肝炎（CHB）患者血清HBsAg滴度的动态变化对恩替卡韦（ETV）治疗反应的预测价值。方法选择2011年1月～2012年1月在我肝病中心住院及门诊接受ETV（0.5mg/d）治疗的HBeAg阳性CHB患者78例,随访1年。于抗病毒治疗的0、3、6、9和12 m分别收集患者血清,采用化学发光法定量检测各时间点的HBsAg和HBeAg滴度;采用实时荧光定量PCR法检测血清HBV DNA载量;采用Pearson相关分析分析HBsAg与HBV DNA水平相关性,采用受试者工作特征曲线（ROC）预测患者的病毒学应答和确定最佳临界值。结果在78例患者中,69例（88.5%）患者发生病毒学应答（VR）,9例未发生病毒学应答;VR组患者基线ALT水平[（141.8±27.2）IU/ml]与未发生VR患者[（136.2±29.7）IU/ml]比,无统计学意义（t=0.27,P=0.793）;HBV DNA[（6.7±1.0）lg IU/ml]明显低于未发生VR患者[（7.6±0.8）lg IU/ml,t=-2.27,P=0.033];HBsAg滴度与未发生VR患者比,无统计学意义[（3.8±0.6）lg IU/ml对（4.0±0.4）lg IU/ml,t=-1.75,P=0.094）];HBsAg与HBV DNA水平呈正相关（r=0.45,P=0.02）;HBsAg在治疗开始的前3个月下降较快,3个月后下降较缓慢,从基线到治疗3个月时,VR组患者较未发生VR患者HBsAg下降更快[（0.3±0.2）lg IU/ml对（0.2±0.1）lg IU/ml,t=2.245,P=0.035）];在治疗3个月时,lg HBsAg滴度的ROC曲线下面积最大（AUC=0.840,P=0.005）,临界值为3.85 lg IU/ml的Youden指数最大（0.602）,其诊断敏感度为84.2%,特异度为78.7%。结论 ETV治疗3个月时lg HBsAg≤3.85 lg IU/ml可作为预测ETV治疗1年发生病毒学应答的指标。     

Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review

This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice.     

Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review

This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice.     

Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection

Background

Prolonged lamivudine therapy has two major problems: breakthrough hepatitis during treatment and relapse of aminotransferase (ALT) after cessation of the therapy. The aim of this study was to examine factors that could predict ALT flare after stopping lamivudine therapy.

Methods

We analyzed 22 Japanese patients with chronic hepatitis B infection, in whom lamivudine therapy was stopped after HBV DNA level had been gone undetectable (<3.7 LGE/ml) during at least six consecutive months. The post-treatment followed up was carried for 28 months in median (range 9–41). HBV core-related antigen (HBcrAg) assay was assessed using newly developed assay.

Results

After cessation of lamivudine therapy, 11 patients (50%) had relapsed (reactivation of serum ALT >80 IU/l, relapsers) and remaining 11 (50%) did not relapse (non-relapsers). In the univariate comparison of relapsers versus non-relapsers, HBcrAg level at lamivudine cessation point (4.5 ± 1.0 versus 3.4 ± 0.9; p = 0.0145) has been shown as a significant predictive factor for non-relapse. All patients with HBcrAg <3.0 log U/ml at the cessation point had no ALT flares. Multivariate analysis on effects of 10 factors (age, sex, cirrhosis, pretreatment ALT level, HBV DNA level, HBcrAg level, mean months till undetectable HBV DNA, duration of undetectable HBV DNA and HBcrAg level at lamivudine cessation point), indicated that HBcrAg level at lamivudine cessation point <3.4 log U/ml was the only independent predictive factor for absence of the post-treatment relapse.

Conclusions

HBcrAg level at lamivudine cessation point might be useful as a prognostic predictor of response to lamivudine therapy cessation. The measurement of HBcrAg is a useful additional test for monitoring chronic HBV infection.