Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.     

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.     

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.     

Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B

Aim: The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. Methods: A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. Results: Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core‐related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. Conclusions: It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core‐related antigens are also significant factors independently associated with relapse of hepatitis.     

Pronounced decline of serum HBsAg in chronic hepatitis B patients with long-term effective nucleos(t)ide analogs therapy

Aims: This study aims to investigate the kinetics of serum HBsAg levels in chronic hepatitis B patients with long-term nucleos(t)ide analogs (NAs) therapy.

Methods: This was a retrospective clinical study. Serum HBsAg in serial samples of 94 patients, who received at least 8 years of NAs therapy, were measured using Elecsys^® HBsAg II Quant Assay.

Results: In this cohort, serum HBsAg levels reduced from 3.80 log10?IU/mL at baseline to 2.72 log10?IU/mL at year 8 (p?p?p?=?.001). As compared to patients with slow (0–1 log10?IU/mL) or steady HBsAg(≤0 log10?IU/mL) decline at year 1, patients with a rapid HBsAg (≥1 log10?IU/mL) decline had a significantly lower HBsAg levels from year 2 to 8. However, Cox regression analysis showed that only absolute HBsAg levels at year 1 was an independent predictor of subsequent HBsAg <1000?IU/mL at year 8 of antiviral therapy(HR 0.242, p?=?.004).

Conclusion: Pronounced HBsAg declines could be achieved in patients after long-term effective therapy with NAs, and on-treatment low serum HBsAg level at year 1 might be a predictor of serum HBsAg <1000?IU/mL at year 8.     

Association of on‐treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e‐antigen positive chronic hepatitis B

Aim: This study evaluated the on‐treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off‐treatment sustained virological response (SVR). Methods: Fifty‐one consecutive patients with hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off‐treatment without reappearance of HBeAg. Results: Twenty‐two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off‐treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off‐treatment. A decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86–142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18–185.73 [P = 0.036]; respectively). Conclusion: On‐treatment serum HBsAg level predicted early off‐treatment SVR to NUC therapy in patients infected with genotype C.     

On-treatment quantitative hepatitis B e antigen predicted response to nucleos(t)ide analogues in chronic hepatitis B

AIM To investigate potential predictors for treatment response to nucleos(t)ide analogues(NAs) in hepatitis B e antigen(HBe Ag)-positive chronic hepatitis B(CHB) patients.METHODS Seventy-six HBeA g-positive CHB patients received 96-wkNAs optimized therapy(lamivudine and adefovir dipivoxil) were studied retrospectively. Serum hepatitis B surface antigen, HBeA g, hepatitis B core antibody, hepatitis B virus(HBV) DNA and alanine aminotransferase levels were quantitatively measured before and during the treatment at 12 and 24 wk. Stepwise logistic regression analyses were performed to identify predictors for treatment response, and areas under the receiver operating characteristic curves(AUROC) of the independent predictors were calculated.RESULTS Forty-three CHB patients(56.6%) achieved virological response(VR: HBV DNA ≤ 300 copies/mL) and 15 patients(19.7%) developed HBeA g seroconversion(SC) after the 96-wk NAs treatment. The HBe Ag level(OR = 0.45, P = 0.003) as well as its declined value(OR = 2.03, P = 0.024) at 24-wk independently predicted VR, with the AUROC of 0.788 and 0.736, respectively. The combination of HBe Ag titer 1.3 lg PEIU/mL and its decreased value 1.6 lg PEIU/mL at 24-wk predicted VR with a sensitivity, specificity, positive predictive value(PPV), negative predictive value(NPV) of 85%, 100%, 100% and 83%, respectively, and the AUROC increased to 0.923. The HBeA g level(OR = 0.37, P = 0.013) as well as its declined value(OR = 2.02, P = 0.012) at 24-wk also independently predicted HBeA g SC, with the AUROC of 0.828 and 0.814, respectively. The HBe Ag titer -0.5 lg PEIU/mL combined with its declined value 2.2 lg PEIU/mL at 24-wk predicted HBeA g SC with a sensitivity, specificity, PPV, NPV of 88%, 98%, 88% and 98%, respectively, and the AUROC reached 0.928.CONCLUSION The combination of HBeA g level and its declined value at 24-wk may be used as a reference parameter to optimize NAs therapy.     

48 weeks outcome after cessation of nucleos(t)ide analogue therapy in chronic hepatitis B patients

Introduction and objectiveThe aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection.MethodsIn 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500 IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation.ResultsThe sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50 IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50 IU/mL and 1000 IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000 IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses.ConclusionMonitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50 IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.     

慢性乙型肝炎肝组织内HBsAg、HBcAg的表达及临床研究进展

一直以来临床将血清乙型肝炎e抗原(HBeAg)、乙肝病毒DNA(HBV DNA)阳性作为乙肝病毒复制的标志,随着肝穿活检及抗病毒治疗的研究进展,肝活检组织中乙肝表面抗原(HBsAg)和乙肝核心抗原(HBcAg)的表达模式与血清乙型肝炎病毒(HBV)DNA定量、肝组织炎症活动度分级及纤维化分期之间关系的临床研究日益增多,本文就HBsAg和HBcAg在肝组织的表达模式及临床研究进展综述如下.     

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (−) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.     

Hepatitis B surface antigen levels during natural history of chronic hepatitis B: A Chinese perspective study

AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.METHODS: Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined.RESULTS: Median HBsAg titers were different in each phase of CHB (P < 0.001): IT (4.85 log₁₀ IU/mL), IC (4.36 log₁₀ IU/mL), ENH (2.95 log₁₀ IU/mL), LR (3.18 log₁₀ IU/mL) and LC (2.69 log₁₀ IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P < 0.001). No correlation between serum HBsAg level and ALT/AST was observed.CONCLUSION: The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.     

HBeAg血清学转换对核苷（酸）类似物治疗慢性乙型肝炎患者停药后复发的影响

目的探讨HBeAg血清学转换对核苷（酸）类似物治疗慢性乙型肝炎（CHB）患者停药后复发的影响。方法回顾性分析60例HBeAg阳性接受核苷（酸）类似物治疗的CHB患者,疗程至少1年的停药患者,于基线、治疗后每个月、HBV DNA转阴后每3个月检测ALT,HBV DNA,HBeAg和抗-HBe。停药后继续随访至少6个月,观察停药后复发情况。分析停药时是否发生HBeAg消失/转换对复发的影响;比较发生HBeAg/抗HBe血清转换后巩固治疗≤12个月、12～24个月、〉24个月三组患者的复发率。结果 60例患者中,60%（36例）的患者在停药后6个月内复发。8例患者未发生HBeAg消失（A组）,停药后4个月内100%复发;6例患者发生HBeAg消失,但无抗-HBe（B组）,停药后6个月内83.3%（5例）复发;46例发生HBeAg血清学转换（C组）,停药后6个月内50%（23例）复发,χ2=11.585,P=0.003,A组与C组相比,χ2=6.84,P=0.015,差异有统计学意义;B组与A组、C组相比,χ2=1.333,P=0.248,χ2=2.327,P=0.199,差异无统计学意义;HBeAg/抗-HBe血清转换后继续用药≤12个月（11例）、12～24个月（23例）、〉24个月（C组12例）,停药后6个月内复发率分别为100%（11例）、47.8%（11例）、8.3%（1例）,χ2=19.377,P=0.000,A组与B组、C组相比,χ2=8.609,P=0.003,χ2=19.326,P=0.000,B组与C组相比,χ2=5.303,P=0.027,均有统计学意义。结论 HBeAg血清学转换是HBeAg阳性CHB患者治疗终点的基本指标,HBeAg/抗-HBe血清转换后治疗≤12个月仍有较高的复发率,HBeAg/抗-HBe血清转换继续治疗〉24个月有望获得持久的病毒学应答,但对停药患者6个月内应密切随访观察。     

Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B

Purpose

The aim of this study was to elucidate the long-term outcome after hepatitis B surface antigen (HBsAg) seroclearance in a large number of Japanese patients.

Methods

We studied the biochemical, virologic, histologic, and prolonged prognoses of 231 Japanese patients with HBsAg seroclearance (median follow-up, 6.5 years). Serum alanine aminotransferase, serum hepatitis B virus (HBV) markers, liver histology, and clinical aspects were monitored. HBV-DNA levels were measured with the qualitative polymerase chain reaction assay. The mean age of patients with HBsAg seroclearance was 52 years.

Results

After HBsAg seroclearance, 203 patients (87.9%) had normal alanine aminotransferase levels 1 year after HBsAg seroclearance. HBV-DNA showed positive results in 4 patients (1.7%) 1 year after HBsAg seroclearance. Thirteen patients were examined for histologic changes of the liver after HBsAg seroclearance. All patients showed marked improvement of necroinflammation of the liver, but only 2 of the 13 patients showed no liver fibrosis. Liver cirrhosis and hepatocellular carcinoma did not develop in any of the 164 patients without evidence of liver cirrhosis at the time of HBsAg seroclearance. Hepatocellular carcinoma developed in 2 of the 67 patients with liver cirrhosis at the time of HBsAg seroclearance. During the observation period, 15 patients died. However, the cause of death of these 15 patients was not related to liver disease, such as hepatocellular carcinoma, decompensated liver cirrhosis, and rupture of esophageal varices.

Conclusion

Our results suggest that HBsAg seroclearance confers favorable long-term outcomes in patients without hepatocellular carcinoma or decompensated liver cirrhosis at the time of HBsAg seroclearance     

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level( 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable( 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.     

核苷(酸)类似物抗乙型肝炎病毒达到治疗终点标准停药后复发的相关因素分析

目的 探讨影响核苷(酸)类似物(NA)治疗慢性乙型肝炎(CHB)患者达到治疗终点标准(达标)停药后复发的相关因素.方法 CHB患者81例,接受NA抗病毒治疗.拉米夫定(LAM)治疗38例,阿德福韦酯(ADV)25例,恩替卡韦(ETV)12例,LAM+ADV 6例.HBeAg阳性40例,NA初治患者67例,耐药复治14例.达标停药或延长疗程后停药,分别于基线、病毒学应答前每个月、病毒学应答后每3个月、停药后半年内每个月、半年后每2个月检测HBV DNA、HBV血清学标志物和ALT.将性别、年龄、乙型肝炎家族史、基线HBV DNA、基线HBeAg、基线ALT、病毒学应答时间、总疗程(月)、延长疗程(月)、初治或耐药复治、停药时HBsAg水平、药物种类共12个可能影响复发的因素进行单因素、多因素Cox比例风险模型和分层分析,累计复发率采用Kaplan-Meier法计算.结果 81例患者达标停药后,36例患者在1年内复发,占44.4%.初治或耐药复治、乙型肝炎家族史、病毒学应答时间、停药时HBsAg水平分别是影响停药后复发的独立危险因素.耐药复治者复发率高于初治患者(78.6%比37.3%,χ2=7.983,P=0.005),有乙型肝炎家族史的患者复发率高于无乙型肝炎家族史者(64.5%比15.0%,χ2=12.096,P=0.002),病毒学应答发生在3个月内的患者复发率低于发生在3个月后的患者(34.0%比64.3%,χ2=6.823,P=0.009),停药时HBsAg≤150μg/L的患者复发率低于>150μg/L者(27.6%比53.8%,χ2=5.199,P=0.023).结论 耐药复治、有乙型肝炎家族史、病毒学应答时间晚、停药时高水平HBsAg是导致NA治疗停药后复发的主要因素.对此类患者治疗达标后应适当延长疗程,巩固疗效.

Abstract：

Objective To explore the influence factors on hepatitis B virus (HBV) relapse after nucleos(t)ide analogues (NA) withdrawal in the chronic hepatitis B (CHB) patients who met NA cessation criteria. Methods Eighty-one consecutive CHB patients were treated with NA, 38 with lamivudine (LAM), 25 with adefovir dipivoxil (ADV), 12 with entecavir (ETV), 6 with LAM +ADV. Among recruited patients, 40 were hepatitis B virus e antigen (HBeAg) positive, 41 were HBeAg negative, 67 of them were initial treatment, 14 were retreatment due to resistance to NA at baseline. The treatment was discontinued after meeting China therapeutic end-point criteria. HBV DNA, HBV serological markers, alanine aminotransferase (ALT) were measured respectively at baseline, every month before virological response, every 3 months after virological response, every month within first 6 months and every 2 months over 6 months after drugs withdrawal. Twelve probable influence factors on relapse which were sex, age, HBV family history, baseline HBV DNA,baseline HBeAg status, baseline ALT, virological response time, total duration of treatment, duration of additional treatment, the level of hepatitis B virus surface antigen (HBsAg) at cessation therapy,initial treatment or retreatment, drug category were analyzed with univariate, multivariate Cox regression modle and stratified analysis. The cumulative relapse was calculated by the Kaplan-Meier method. Results A total of 36 patients (44. 4%) relapsed within 1 year. Initial treatment or retreatment, HBV family history, virological response time, the level of HBsAg at cessation therapy were independent risk factors. The relapse rate of retreatment was higher than that of initial treatment (78.6% vs 37. 3% , χ2 = 7. 983, P = 0. 005) , those of patients with HBV family history higher than without family history (64. 5% vs 15.0%, χ2 =12. 096,P = 0.002), those of patients obtained virological response within 3 months lower than after 3 months(34. 0% vs 64. 3% , χ2 =6. 823,P=0. 009) , those of patients with HBsAg≤150 μg/L at cessation therapy lower than >150 μg/L(27. 6% vs 53. 8%, χ2=5. 199,P=0. 023). Conclusions Retreatment, HBV family history, later virological response and higher HBsAg level at cessation therapy are risk factors of relapse after NA withdrawal. Such patients should be treated with prolonged duration after meeting end-point criteria to strengthen the efficacy.     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients

This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)‐positive and ‐negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg‐positive and 104 HBeAg‐negative patients) who were previously treated with TDF and had post‐treatment follow‐up for at least 6 months (median: 55, IQR 36‐85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg‐positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg‐negative patients. Cox regression analysis revealed that the higher end‐of‐treatment HBsAg levels were an independent factor of virological relapse in HBeAg‐positive and HBeAg‐negative patients. The end‐of‐treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg‐positive and HBeAg‐negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off‐therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end‐of‐treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end‐of‐treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg‐positive and HBeAg‐negative CHB patients.     

Baseline predictors of virological response for chronic hepatitis B patients

AIM： To determine which baseline factors of chronic hepatitis B patients are predictive of virological response to Peginterferon α-2b therapy. METHODS： A total of 21 HBeAg-positive chronic hepatitis B （CriB） patients treated with Peginterferon α-2b were recruited. They were treated with Peginterferon α-2b （0.5-1.0 μg/kg per week） for 24 wk and followed up for 24 wk. Clinical and laboratory data of the patients were determined at pretreatment and at week 12, at 24 during treatment, and at week 48 during follow up. RESULTS： Ten patients achieved a virological response at the end of treatment. Their baseline serum alanine aminotransferase （ALT）, thyroid-stimulating hormone （TSH）, and total thyroxin （TT4） levels were significantly different from those who failed treatment. The positive predictive values （PPV） and negative predictive values （NPV） of ALT, TSH, and TT4 were 75% and 89 %, 75% and 89 %, and 75% and 75%, respectively. Moreover, combinations of the baseline ALT and TT4, ALT and TSH, TT4 and TSH levels had much higher PPV and NPV （86% and 88%, 89% and 100%, 83% and 100%, respectively）.CONCLUSION： Baseline serum ALT, TSH, and TT4 levels, especially in combination, have high predictive values of virological response to Peginterferon α-2b in HBeAg-positive CriB patients.