Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients

The aims of this study were to assess hepatitis B surface antigen (HBsAg) seroconversion and to determine its impact on the natural course of the disease in patients with HBeAg-negative chronic hepatitis B (CHB) during lamivudine (LMV) treatment. A total of 183 consecutive patients with HBeAg-negative CHB who were treated with LMV were included in the study. Data were retrospectively collected from outpatient visit charts. The primary endpoint was HBsAg seroconversion to anti-HBs. The secondary endpoint was to determine the development of cirrhosis. Loss of HBsAg was confirmed in 10 patients and seroconversion to anti-HBs in nine patients during LMV treatment or after its discontinuation. HBsAg seroconversion was achieved on-treatment in four patients after a median treatment duration of 30 months and off-treatment in the remaining five patients in a median 61 months after LMV discontinuation. The cumulative probability of HBsAg seroconversion increased from 0.6% at 1 year and 1.9% at 5 years to 21.5% at 10 years of LMV during and after LMV treatment. HBsAg clearance was preceded by undetectable serum hepatitis B virus (HBV) DNA. The majority of the patients responding to treatment had undetectable HBV DNA levels at 24 weeks of treatment. The cumulative probability of LMV resistance increased from 2.2% at 1 year to 37.3% at 5 years. No baseline parameter predicting either HBsAg seroconversion or the emergence of LMV resistance was identified. None of the patients with HBsAg seroconversion experienced virological breakthrough or disease progression during the follow-up period. These results indicate that HBsAg seroclearance can occur in patients with HBeAg-negative CHB under LMV therapy and predicts better clinical outcome.     

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.     

Analysis of serum hepatitis B virus RNA levels among HBsAg and HBsAb copositive patients and its correlation with HBV DNA

There are approximately 2 billion HBV-infected individuals worldwide, and approximately 1.87% to 7% of these individuals are copositive for HBsAg and HBsAb.Our study detected hepatitis B virus pgRNA (HBV RNA) levels in HBsAg and HBsAb copositive patients and then analyzed the correlation with HBV DNA, HBsAg, ALT, and AST levels. A total of 149 HBsAg and HBsAb copositive patients were identified from 66,617 outpatients.HBV RNA, HBV DNA, HBsAg, ALT, and AST serum levels were significantly different in different natural phases of HBV infection (immune tolerance phase, immune clearance phase, low replication phase, and reactivation phase) with statistical significance (P < .01). HBV RNA levels were positively correlated with HBV DNA, HBsAg, ALT, and AST levels. HBV RNA and HBV DNA levels were significantly increased in the HBeAg-positive group (66 patients) compared with the HBeAg-negative group (83 patients) (P < .01). In the HBeAg-positive group, HBV RNA levels were positively correlated with HBV DNA and HBsAg levels. In the HBeAg-negative group, HBV RNA levels were positively correlated with HBV DNA. Serum HBV RNA levels were positively correlated with HBV DNA, HBsAg, ALT, and AST levels.HBV RNA could be used as a virological indicator for antiviral therapy in HBsAg and HBsAb copositive hepatitis B patients.     

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.     

阿德福韦酯治疗HBeAg阴性慢性乙型肝炎疗效与HBV基因型的关系

目的探讨阿德福韦酯（ADv）治疗HBeAg阴性慢性乙型肝炎（chronic hepatitis B,CHB）的疗效与HBv基因型的关系。方法选择71例HBVDNA〉1×10^4copies／ml、ALT〉2倍正常值上限、TBIL正常的HBeAg阴性cHB患者,其中B基因型40例,C基因型31例,所有患者均口服ADV 10mg,1／d,治疗52周,动态观察治疗过程中HBV DNA和ALT水平的变化。结果在治疗12、24、52周时,B基因型患者ALT变化、血清HBVDNA水平下降≥2log。完全抑制比例与C基因型患者相比差异无统计学意义（P〉0．05）。结论ADV能有效抑制HBeAg阴性CHB患者HBV复制,促进肝功能好转,其疗效与HBV基因型B或C型无关。     

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.     

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。     

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。     

Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B

Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN ± lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.     

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community‐based real‐world study

Community‐based real‐world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re‐emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti‐HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re‐emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg‐positive and HBeAg‐negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti‐HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on‐treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re‐emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community‐based real‐world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti‐HBs, nearly all patients achieved sustained undetectable virus.     

Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients

To investigate the factors associated with active disease among hepatitis B surface antigen (HBsAg) positive/hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection we studied chronic HBV infected patients who had undetectable HBeAg at the first visit. HBV DNA was determined by the cross-linking assay (NAXCOR) and polymerase chain reaction (PCR). Mutations in the core promoter and precore regions and viral genotypes were studied. Clinical outcome of these patients were followed and categorized as: (i) relapse (ALT > 200 IU/L or three times the previous levels); (ii) active hepatitis (elevated ALT < 200 IU/L with concomitant detectable HBV DNA); or (iii) remission. A total of eighty-five patients were followed up for 5.5 ± 1.0 years. At first visit, 31 (36.5%) patients had elevated ALT levels, 12 (14.1%) had measurable HBV DNA by the cross-linking assay and 26 (30.6%) by PCR. Sixteen (18.8%) patients had hepatitis relapse, 13 (15.3%) had active hepatitis, and 56 (65.9%) remained in remission. Core promoter and precore stop codon mutants were found in 27 and 12 patients, respectively. Eleven and 20 had genotype B and C HBV, respectively. Initial elevated ALT and detectable HBV DNA were associated with active liver disease. Patient demographics, viral mutants or genotypes failed to predict disease activity. Hence, serum ALT and HBV DNA levels offer the best prediction of natural course of HBeAg-negative chronic HBV infection.     

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。     

Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection

Summary.  We evaluated the longitudinal changes of viraemia and predictors of progression in a prospectively followed cohort of 150 untreated patients with HBeAg-negative chronic hepatitis B virus (HBV) infection. According to the first year of follow-up, 85 patients were classified into inactive carrier state and 65 into chronic hepatitis B (CHB). Serum HBV DNA levels were determined at baseline in all patients, at year-1 in carriers or last pretherapy visit in CHB patients and during alanine aminotransferase (ALT) elevations in carriers progressing to CHB. HBV DNA levels at any occasion were ≥80, ≥2000 or ≥20 000 IU/mL in 81%, 23% or 0% of carriers and 100%, 95% or 83% of CHB patients. The cumulative progression rate from carrier to CHB was 11%, 16%, 24% at 2-, 3-, 4 years and was independently associated with higher baseline ALT (always within traditional normal range) and baseline HBV DNA ≥2000 or ≥5000 IU/mL. In 12 carriers progressed to CHB, HBV DNA increased by >1 log₁₀ IU/mL. During 7.5 months of median follow-up, HBV DNA change ≥1 log₁₀ IU/mL was observed in 49% of CHB patients. In conclusion, serum HBV DNA levels are detectable in the majority of inactive HBV carriers exceeding 2000 IU/mL in only 23% and 20 000 IU/mL in none of them. Carriers have approximately 15% 3-year risk of progression to CHB, which is associated with higher baseline ALT and viraemia ≥2000–5000 IU/mL, and thus should be closely followed. Approximately 20% of HBeAg-negative CHB patients have HBV DNA <20 000 IU/mL with fluctuations >1 log₁₀ occurring in many of them.     

Hepatitis B virus DNA prediction rules for hepatitis B e antigen-negative chronic hepatitis B

After hepatitis B e antigen (HBeAg) seroconversion, hepatitis B may become inactive or progress to HBeAg-negative hepatitis with persistent or intermittent alanine aminotransferase (ALT) elevation. The aim of this study was to prospectively identify factors predictive of the clinical course in HBeAg-negative chronic hepatitis B (CHB). Patients were stratified by ALT and HBeAg status and followed every 3 months for up to 5 years. Kaplan-Meier and Cox regression analysis using the change from normal ALT to elevated ALT as endpoints were performed to determine factors associated with ALT elevation/normalization. Seventy-four HBeAg-negative and 32 HBeAg-positive patients were prospectively evaluated. For HBeAg-negative patients, hepatitis B virus (HBV) DNA was predictive of future ALT. Only 1 patient with normal ALT and an HBV DNA value lower than 10,000 copies/mL developed an elevated ALT within the subsequent year, whereas 67% with an HBV DNA value greater than 100,000 copies/mL had a rise in ALT above normal within 1 year. Patients with a previous history of ALT elevation and longer follow-up at all levels of HBV DNA were more likely to experience ALT elevations. For HBeAg-negative patients with elevated ALT and all HBeAg-positive patients, HBV DNA did not predict future ALT. Other viral and host factors were not predictive of future ALT. CONCLUSION: HBeAg-negative CHB has a fluctuating course. HBV DNA values lower than 10,000 copies/mL predict persistently normal ALT for at least 1 year. Patients with HBV DNA values between 10,000 and 100,000 copies/mL can safely be followed at 6 monthly intervals, whereas HBV DNA values greater than 100,000 copies/mL are highly predictive of future ALT elevation and should prompt regular follow-up.     

慢性乙型肝炎合并非酒精性脂肪性肝病患者抗病毒治疗的疗效探讨

目的对慢性乙型肝炎（CHB）合并非酒精性脂肪性肝病（NAFLD）患者抗病毒治疗疗效进行回顾性分析,探讨肝细胞脂肪变是否影响CHB患者抗病毒的疗效。方法收集2004年1月至2011年12月在本院进行抗病毒治疗的110例CHB患者,CHB合并NAFLD患者99例,采用荧光定量PCR法检测血清HBV DNA水平,用化学发光法检测血清乙型肝炎两对半定量,采用全自动生物化学分析仪检测肝功能。计数资料采用χ2检验,计量资料采用t检验。结果 （1）干扰素抗病毒治疗时,24周单纯CHB患者较合并脂肪肝患者生化学应答率更高（χ2=4.069,P=0.044）;48周HBV DNA阴转率明显优于后者（χ2=17.327,P=0.000）。对于HBeAg阳性患者,单纯CHB患者在24周的生化学应答率、24和48周时的HBV DNA阴转率、HBeAg阴转率均显著优于合并脂肪肝患者,两者比较差异具有统计学意义（P〈0.05）,48周时两组的生化学应答差异无统计学意义（P〉0.05）。（2）核苷和核苷酸类药物抗病毒治疗时,48周单纯CHB患者的生化学应答率较高（χ2=7.620,P=0.006）,24和48周的HBV DNA阴转率差异无统计学意义。对于HBeAg阳性患者,24周时合并脂肪肝组患者的HBeAg转阴率高于单纯CHB患者,48周时ALT/AST复常率低于单纯CHB患者,差异均具有统计学意义（P〈0.05）,24周ALT/AST复常率、HBV DNA转阴率、48周HBV DNA转阴率、HBeAg转阴率差异均无统计学意义（P〉0.05）。结论肝细胞脂肪变对CHB患者的抗病毒治疗效果存在一定的影响。     

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.     

Current Trend in Antiviral Therapy for Chronic Hepatitis B

Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.     

慢性乙型肝炎患者血清HBV DNA水平与HBsAg和HBeAg水平的相关性分析

目的探讨慢性乙型肝炎患者血清HBV DNA水平与HBsAg和HBeAg滴度的关系。方法在951例慢性乙型肝炎患者,采用FQ-PCR法和Abbott化学发光微粒子免疫分析技术分别测定血清HBV DNA水平及HBsAg和HBeAg滴度,分析HBV DNA水平与HBsAg和HBeAg滴度的相关性。结果在951例患者中,HBVDNA阳性率为53.83%(512/951);患者血清HBV DNA水平与HBsAg和HBeAg滴度呈正相关(rs=0.45和re=0.49,P<0.05);在HBV DNA水平≥7lg拷贝/毫升患者,血清HBsAg和HBeAg滴度高于HBV DNA为3～7lg拷贝/毫升患者,HBV DNA为3～7lg拷贝/毫升患者血清HBsAg和HBeAg滴度大于HBV DNA<3lg拷贝/毫升患者,差异均有统计学意义(P<0.05);将HBsAg分为<1000 IU/ml、1000～10000 IU/ml和≥10000 IU/ml3组,结果不同HBsAg滴度患者血清HBV DNA水平差异有统计学意义(P<0.05)。结论在血清HBV DNA≥7lg拷贝/毫升和HBsAg滴度≥10000 IU/mL患者,HBV DNA水平与HBsAg滴度呈正相关,在HBV DNA>3 lg拷贝/毫升患者,血清HBV DNA水平与HBeAg滴度呈正相关。