基线血清外泌体miR-155-5p联合乙型肝炎病毒DNA定量实验预测聚乙二醇干扰素治疗乙型肝炎e抗原阳性慢性乙型肝炎的疗效

探讨聚乙二醇干扰素(peginterferon, Peg-IFN)治疗乙型肝炎e抗原(hepatitis B e antigen, HBeAg)阳性慢性乙型肝炎(chronic hepatitis B, CHB)患者48周后,基线血清外泌体miR-155-5p表达水平联合乙型肝炎病毒DNA定量实验在预测HBeAg血清学转换中的价值。回顾性分析2016年6月至2019年6月在本中心初次接受抗病毒治疗的HBeAg阳性CHB患者88例。根据Peg-IFN治疗48周后是否发生HBeAg血清学转换,将患者分为治疗应答组和无应答组。采用多因素logistic回归探讨预测Peg-IFN治疗应答的因子,并应用受试者工作特征(receiver operating characteristic, ROC)曲线下面积评估预测效能。结果发现基线血清外泌体miR-155-5p(OR＝2.193,95% CI 1.315～3.655,P＝0.003)和HBV DNA(OR＝0.398,95% CI 0.163～0.976,P＝0.036)是Peg-IFN治疗效果的独立预测因子。基线血清外泌体miR-155-5p和HBV DNA的截断值分别取2.3和7.2 log₁₀IU/mL时,相应的ROC曲线下面积分别为0.788(95% CI 0.682～0.893)和0.704(95% CI 0.577～0.824)。基线血清外泌体miR-155-5p表达水平≥2.3且HBV DNA定量≤7.2 log₁₀IU/mL的患者,Peg-IFN治疗48周后其HBeAg血清学转换率最高,为66.67% (10/15);而基线血清外泌体miR-155-5p表达水平<2.3且HBV DNA定量>7.2 log₁₀IU/mL的患者,Peg-IFN 治疗48周后其HBeAg血清学转换率最低,仅为3.03%(1/33)。这些结果表明,基线血清外泌体miR-155-5p表达水平联合HBV DNA定量实验可以作为Peg-IFN 治疗HBeAg阳性CHB疗效的预测因子,对于优化CHB的抗病毒治疗有积极作用。     

基线HBsAg和ALT水平是替比夫定治疗HBeAg阳性慢性乙型肝炎患者e抗原血清学转换的重要预测因素

目的评价初治、单药使用替比夫定治疗HBeAg阳性的慢性乙型肝炎（CHB）患者48周的e抗原血清学转换的基线预测因素。方法97例HBeAg阳性CHB患者分别以基线HBsAg、ALT和HBVDNA水平高低分组,对比两组治疗48周时生化学、病毒学和血清学应答情况。结果基线HBsAg-101500IU／mL组e抗原阴转率和血清学转换率均为42．3％,基线HBsAg〉1500IU／mL组分别为20％和17．8％,两组比较差异均有统计学意义（P〈0．05）;基线ALT〉5ULN组e抗原阴转率和血清学转换率均为45．1％,基线ALT05ULN组分别17．4％和15．2％,两组比较差异均有统计学意义（P〈0．01）;基线HBVDNA〈8．0log-10copies／mL组和基线HBVDNA≥8．0log-10copies／mL组e抗原阴转率和血清学转换率相比,差异无统计学意义（P〉0．05）;基线水平HBsAg≤1500IU／mL且ALT〉5ULN的CHB患者共40例作为观察组,其余57例患者作为对照组,治疗48周时观察组e抗原阴转率和血清学转换率均为45％,对照组分别为22．8％和21．1％,两组比较差异均有统计学意义（P〈0．05）。结论基线HBsAg水平≤1500IU／mL和ALT水平〉5ULN的HBeAg阳性慢性乙型肝炎患者,在接受替比夫定治疗48周时,有较高的e抗原转阴率和血清学转换率;基线HBsAg和ALT水平是替比夫定治疗e抗原血清学转换的重要预测因素。     

慢性乙型肝炎潜在治疗靶点和新药研发进展

尽管预防性疫苗显著减少了乙型肝炎病毒(hepatitis B virus,HBV)新发感染,但目前全球仍有超过2.4亿慢性HBV感染者,其中每年因HBV感染相关的终末肝病和肝癌引起的死亡人数高达68万。目前用于慢性乙型肝炎(chronic hepatitis B,CHB)治疗的抗病毒药物包括干扰素和核苷/核苷酸类似物两大类,但均难以实现理想的临床治疗终点,即乙肝表面抗原(HBsAg)阴转或血清学转换。针对CHB患者尚未被满足的巨大医疗需求,国内外团队正在针对HBV生活周期的各个关键步骤以及潜在的宿主因子,尝试研发更为有效的CHB治疗药物,本文简要综述了当前处于临床开发阶段以及部分临床前阶段的CHB候选药物研发进展。     

预测核苷(酸)类似物停药后慢性乙型肝炎复发的生化标记筛查及其临床应用

为探寻核苷(酸)类似物停药后慢性乙型肝炎复发的相关因素及可能血清标记,收集经核苷(酸)类似物治疗的乙型肝炎病毒e抗原(hepatitis B virus e antigen,HBeAg)阳性或阴性慢性乙型肝炎患者,根据治疗应答对其能否停药进行临床评估,分析达到停药标准患者的临床资料,包括性别,年龄,疗程,HBeAg水平,基线丙氨酸氨基转移酶(alanine aminotransferase,ALT)、HBV DNA,停药时的肝硬度值、HBV表面抗原(HBV surface antigen,HBsAg)水平、白细胞介素21(interleukin 21,IL-21)水平、外周血CD4~+IL-21~+T细胞频数。结果显示,共47例患者符合停药标准,其中HBeAg阳性26例,HBeAg阴性21例;平均年龄(42.45±14.08)岁。抗病毒疗程平均为(4.60±1.61)年。抗病毒治疗初始ALT值为(174.38±200.84)U/L;基线HBV DNA为(5.87±1.06)log拷贝/mL;停药时HBsAg精确定量平均为(1 104.82±1 328.11)IU/mL,IL-21平均为(729.82±427.39)pg/mL,CD4~+IL-21~+T细胞频数平均为(0.79±0.49)%,肝硬度测定F1 27例、F2 16例、F3 4例、F4 0例。共27例患者复发,1年内累积复发率为57.45%。Logistic回归单因素分析提示,慢性乙型肝炎患者停用核苷(酸)类似物后复发与服药总疗程及停药时IL-21水平、CD4~+IL-21~+T细胞频数、HBsAg水平有关;Logistic回归多因素分析则提示,停药时HBsAg和IL-21水平与复发有关。因此,停药时HBsAg和IL-21水平可作为慢性乙型肝炎患者停用核苷(酸)类似物后复发的预测因素。     

聚乙二醇干扰素α-2b治疗61例e抗原阳性慢性乙型肝炎临床分析

目的探讨聚乙二醇化干扰素α-2b治疗e抗原(HBeAg)阳性慢性乙型肝炎的临床疗效和不良反应,同时探讨影响应答的相关因素。方法用聚乙二醇干扰素α-2b治疗61例HBeAg阳性慢性乙型肝炎,治疗期间定期监测血常规、生物化学指标、病毒学标志、甲状腺功能等。结果 48周,表面抗原(HBsAg)和HBeAg血清学转换率分别为5.26%、31.2%;血清HBV DNA阴转率为59.6%;ALT复常率为64.9%。随访半年,HBV DNA复发率为17.4%;HBeAg血清学转换者维持应答。治疗前ALT>5 ULN时,48周时HBeAg血清学转换率和HBV DNA阴转率明显高于ALT<5 ULN时,二者比较差异有统计学意义;而血清HBV DNA水平与其无明显相关性。结论聚乙二醇化干扰素α-2b具有免疫调节和抗病毒双重作用,48周时HBeAg血清学转换率和HBV DNA阴转率与治疗前血清ALT水平与相关,停药后具有持续应答效应。     

干扰素-α治疗HBeAg阴性慢性乙型肝炎患者的早期疗效及影响因素分析

目的探讨HBeAg阴性慢性乙型肝炎(CHB)患者干扰素-α(IFN-α)早期疗效的影响因素。方法收集40例HBeAg阴性CHB患者,检测IFN-α治疗前及治疗12周时的ALT、HBV DNA、HBsAg、HBsAb、HBeAg、HBeAb、HBcAb;分析年龄、性别、ALT基线水平、HBV DNA基线水平对IFN-α疗效的影响。结果性别组间、不同年龄段组间、不同ALT基线水平组间、不同HBV DNA基线水平组间比较IFN疗效差异无统计学意义(P>0.05)。结论性别、年龄、ALT基线水平、HBV DNA基线水平、年龄不可以作为预测IFN-α治疗HBeAg阴性慢性乙型肝炎患者的早期疗效指标。     

阿德福韦酯治疗乙型肝炎的疗效及安全性分析

目的探讨阿德福韦酯治疗慢性乙型病毒性肝炎患者的临床疗效及安全性。方法将我院2010年2月~2014年4月收治的90例慢性乙型肝炎患者给予阿德福韦酯治疗,并定期监测(丙氨酸氨基酸转移酶)ALT,HBV DNA,HBeAg和抗-HBe,观察其病毒学应答率、血清学转换率、病毒学突破率和复发率;分析抗病毒治疗基线ALT(u/L)与血清学转换率。结果 (1)6个月累计病毒学应答率91.11%(82/90),1年为100%;(2)HBeAg阳性者1、2、3年累计HBeAg血清学转换率分别为27.91%、34.69%、40.33%;(3)基线ALT≥5×正常值上限(u/L)的患者3年发生HBeAg血清学转换率高于基线ALT5×正常值上限(u/L)的患者(50.00%、42.22%,χ2=5.527,P=0.013)。结论基线ALT水平可作为3年HBeAg血清学转换率预测指标;抗病毒治疗达我国《指南》终点标准仅仅是基本的停药标准,部分病人达标后仍有复发风险;阿德福韦酯治疗慢性乙型肝炎疗效确切,安全性高,值得临床推广应用。     

慢性乙型肝炎病毒感染者HBeAg血清学自然转换及其影响因素分析

目的了解慢性乙型肝炎病毒(hepatitis B virus,HBV)感染者乙型肝炎e抗原(hepatitis Be antigen,HBe Ag)血清学自然转换及其影响因素。方法以寿光市2012年3个强化干预镇街道农村居民乙型病毒性肝炎(简称乙肝)专项调查确诊的HBe Ag阳性感染者的血清学检测结果为基线,与2015年随访的血清学检测结果对比分析。用ELISA检测乙肝血清标志物,用实时荧光定量PCR检测HBV DNA载量,采用速率法检测丙氨酸氨基转移酶(alanine aminotransferase,ALT)。结果 HBe Ag阳性者340例,随访3年,HBe Ag转阴142例,年转阴率13.92%;抗-HBe转换92例,年转换率9.02%。HBe Ag转阴/转换率与HBV DNA载量负相关(r=-0.227,P0.001;r=-0.193,P0.001);HBe Ag转阴/转换率与年龄有关,6~20岁组转阴/转换率低,随年龄增长HBe Ag转阴/转换率增高,各年龄组差异均有统计学意义(χ2=22.74,P0.01;χ2=30.34,P0.01);性别不是HBe Ag转换率的主要影响因素(P0.05)。血清学转换后,HBV DNA载量、ALT水平均较转换前有明显的下降,但仍有一定比例的感染者检出高拷贝的HBV DNA载量。结论 HBV感染过程中存在着HBe Ag血清学自然转换,年龄是HBV DNA载量的主要影响因素,HBe Ag与HBV DNA载量的变化并不完全一致。     

乙型肝炎病毒B,C基因型引起的慢性乙型肝炎患者特异性、非特异性细胞免疫比较

对138例CHB患者进行HBV基因分型,检测非特异性CTL,HBV特异性CTL,肝功能,HBVDNA,HBVM(HBsAg,抗-HBs,HBeAg,抗-HBe,抗-HBc).结果显示,C基因型感染者,非特异性CTL((19.91±6.01)%)高于B基因型感染者((16.12±3.12)%),t=3.05,P<0.01,HBVDNA水平((6.25±0.81)log10拷贝/mL)高于B基因型感染者((5.02±0.61)log10拷贝/mL),t=6.03,P<0.01,HBeAg阳性46例(74.19%),高于B基因型感染者(39例,占52%),χ2=7.09,P<0.01,丙氨酸氨基转移酶(ATL)、血清总胆红素(TBIL)水平(分别为(507.15±312.17)IU/L和(46.10±40.18)μmol/L)高于B基因型感染者(分别为(290.05±215.12)IU/L和(29.12±17.12)μmol/L),t=3.76,2.29,P<0.01,P<0.05.C基因型感染者的HBV特异性CTL((0.21±0.05)%),低于B基因型感染者((0.39±0.12)%),t=5.61,P<0....     

乙肝病毒载量与血清标志物及ALT相关性研究

探讨了乙型肝炎病毒核酸(HBV-DNA)水平与乙型肝炎免疫标志物(HBVM)和丙氨酸氨基转移酶(ALT)的关系。分别采用实时荧光定量聚合酶链反应(FQ-PCR),酶联免疫法和连续监测法检测了345例血清标本HBV-DNA含量,HBVM(HBsAg、HBsAb、HBeAg、HBeAb、抗HBcIgM)表达及ALT水平。HBsAg、HBeAg(和抗HBcIgM)阳性患者HBV DNA阳性率要明显高于HBsAg、HBeAb(和抗HBcIgM)阳性患者、仅HBsAg阳性患者及HBsAb、HBeAb阳性患者(P<0.01)。血清HBeAg阳性标本HBV-DNA阳性率为98.7%,明显高于HBeAg阴性标本的61.6%(P<0.01),并且血清HBeAg阳性标本HBV-DNA含量(log值,7.42±1.43)也明显高于HBeAg阴性标本(4.36±1.73)(P<0.01);在HBV-DNA含量小于107copy/mL的标本中,ALT与HBV-DNA含量呈正相关(P<0.01)。血清中HBV DNA含量与乙型肝炎免疫标志物以及肝细胞损伤三者之间存在密切的关系,在临床工作中应对血清HBVM、ALT和HBV-DNA含量联合检测,这样才能更准确地判断患者病情、预后及指导抗病毒药物的应用。     

乙型肝炎病毒e抗原的生物学功能及血清学转换的免疫学基础

目前在临床乙型肝炎的治疗中,乙型肝炎病毒e抗原(HBeAg)消失及其抗体的出现已成为重要的疗效指标.本文回顾了HBeAg的发现及其生物学和医学意义,对HBeAg与乙型肝炎病毒核心抗原(HBcAg)的免疫原性进行了比较,阐述了HBeAg血清学转换的免疫学基础,并对出现HBeAg血清学转换的意义作了分析.     

Pegylated-Interferon Alpha Therapy for Treatment-Experienced Chronic Hepatitis B Patients

Background

Studies are limited on pegylated interferon (Peg-IFN) therapy for chronic hepatitis B (CHB) patients who failed or relapsed on previous antiviral therapy.

Objectives

We aimed to investigate the effect of Peg-IFN therapy in treatment-experienced CHB patients.

Study Design

A total of 57 treatment-experienced CHB patients at two medical centers were enrolled. All of the patients were treated with Peg-IFN α-2a at 180 μg weekly for 24 or 48 weeks. The hepatitis B serological markers and viral loads were tested every 3 months until 1 year after stopping Peg-IFN therapy. The endpoints were HBV DNA <2000IU/mL, hepatitis B e antigen (HBeAg) seroconversion, and a hepatitis B surface antigen (HBsAg) loss at 12 months post-treatment.

Results

In HBeAg-positive patients, 25.0%, 29.2%, and 12.5% of the patients achieved HBeAg seroconversion, HBV DNA <2000 IU/mL and a combined response, respectively, at 12 months post-treatment. Prior IFN therapy, a high baseline ALT level, a low creatinine level, undetectable HBV DNA at 12 weeks and a decline in HBV DNA >2 log₁₀ IU/mL at 12 weeks of therapy were factors associated with treatment response. In HBeAg-negative patients, 9.1%, 15.2%, and 6.1% of the patients achieved undetectable HBV DNA, HBV DNA <2000 IU/mL, and an HBsAg loss, respectively, at 12 months post-treatment. No factor was significantly associated with the treatment response in the HBeAg-negative patients. The median HBsAg level declined from 3.4 to 2.6 log₁₀ IU/mL in all the patients, and the 5-year cumulative rate of the HBsAg loss was 9.8% in the HBeAg-negative patients. Overall, none of the patients prematurely discontinued the Peg-IFN therapy.

Conclusions

Peg-IFN re-treatment is effective for a proportion of HBeAg-positive treatment-experienced patients; it has limited efficacy for HBeAg-negative treatment-experienced patients. Peg-IFN might facilitate HBsAg loss in HBeAg-negative treatment-experienced patients.     

A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients

Background

The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed.

Methods and Principal Findings

Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 µg YIC, 60 µg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8%(17/78) and 9% (7/78) in the 60 µg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 µg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 µg YIC and 60 µg YIC groups respectively (p>0.05).

Conclusions

Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 µg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated.

Trial Registration

ChiCTR.org ChiCTR-TRC-00000022     

恩替卡韦治疗HBeAg阳性乙型肝炎临床观察

目的：探讨恩替卡韦治疗HBeAg阳性乙型肝炎的疗效与安全性。方法：140例慢性乙肝患者随机分为2组：观察组予恩替卡韦0．5mg／d,对照组予拉米夫定100mg／d,疗程均为48周。观察两组HBVDNA阴转率、ALT复常率、HbeAg血清转换率以及不良反应发生情况。结果：在治疗12周后,观察组与对照组HBVDNA阴转率分别为47．1％、22．9％（P〈0．01）,ALT复常率分别为51．4％、31．4％（P〈0．05）,在治疗48周后,观察组与对照组HBVDNA阴转率分别为88．6％、48．6％（P〈0．01）,ALT复常率分别为90．0％、72．9％（P〈0．01）。HbeAg血清转换率无统计学差异,两组患者未见严重不良反应。结论：恩替卡韦治疗HBeAg阳性乙肝患者,较拉米夫定起效快、作用强,且安全性好。     

不同临床类型乙型病毒感染者外周血T细胞亚群与血清HBVDNA载量及HBeAg滴度相关性分析

目的：探讨慢性乙型肝炎病毒（HBV）感染患者外周血T细胞亚群与血清HBVDNA载量及HbeAg滴度的关系。方法：选取103名HBV感染患者和20名健康者为研究对象。流式细胞术检测外周血T细胞亚群,聚合酶链式反应及酶免疫分析法分别检测血清HBVDNA载量及HbeAg滴度。结果：慢性乙型肝炎患者和慢性HBV携带者外周血CD3可、CD4T淋巴细胞亚群百分数低于健康对照组,结果有统计学意义（P〈0．05或0．01;而CD8＋T细胞亚群则呈现相反趋势,结果亦有统计学意义（P〈0．05或0．01）。HBeAg阴性组中,HBVDNA水平与CD8T细胞亚群百分数呈正相关（r=0．567,P〈0．01）,与CD47CD8＋T细胞亚群百分数比值呈负相关（r=-0．601,P〈0．01）,而与CD3＋T、CD4＋T细胞亚群百分数无相关性。HBeAg阳性组中,HBVDNA水平及HbeAg滴度与cD3＋1r、cD41、CD8叮细胞百分数及CD47CD8＋T细胞百分数均无相关性（P〉0．05）。结论：不同临床类型的慢性乙型肝炎病毒感染患者外周血T细胞亚群存在不同程度细胞免疫功能降低和细胞免疫调节异常。HbeAg阴性的HBV感染患者,其血清HBVDNA水平与外周血T淋巴细胞免疫存在相关性。     

Early Serum HBsAg Kinetics as Predictor of HBsAg Loss in Patients with HBeAg-Negative Chronic Hepatitis B after Treatment with Pegylated Interferonα-2a

Hepatitis B surface antigen (HBsAg) loss is an ideal treatment endpoint for patients with chronic hepatitis B (CHB). We investigated the predictive value of on-treatment HBsAg levels for HBsAg loss in hepatitis B e antigen (HBeAg)-negative CHB patients who received 120-week PEG-IFNα-2a treatment. Serum HBV DNA, HBsAg, and anti-HBs levels were assayed at baseline and every 3 months during the treatment. Of 81 patients, 12 achieved HBsAg loss, 20 achieved HBsAg < 100 IU/mL, and 49 maintained HBsAg≥100 IU/mL. HBsAg loss rate was only 3.7% at 48 weeks, while it reached to 11.1% and 14.8% after treatment of 96 weeks and 120 weeks. The cutoff HBsAg levels at 12 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 400 IU/mL and 750 IU/mL, with AUC 0.725 and 0.722, positive predictive value (PPV) 29.41% and 30.56%, and negative predictive value (NPV) 93.75% and 97.78%, respectively. The cutoff HBsAg levels at 24 weeks predicting HBsAg loss at 96 weeks and 120 weeks of treatment were 174 IU/mL and 236 IU/mL respectively, with AUC 0.925 and 0.922, PPV 40.0% and 46.15%, and both NPV 100%. The predictive ability of the cutoff HBsAg levels at 24 weeks was better than that at 12 weeks for HBsAg loss at either 96 or 120 weeks (χ²=3.880, P=0.049 and χ²=4.412, P=0.036). These results indicate that extended therapy is critical to HBsAg loss in HBeAg-negative CHB patients during PEG-IFN treatment, and the HBsAg level at 24 weeks can be used to predict HBsAg loss during tailoring PEG-IFN therapy.

     

乙型肝炎病人重叠感染丙型肝炎的评价

应用ＥＬＩＳＡ和ＰＣＲ法检测５０２例乙肝病人血清,４０１例ＨＢｓＡｇ阳性血清中,有１１４例（２８．４％）抗－ＨＣＶ和ＨＣＶＲＮＡ双项阳性,２５例（６．２％）ＨＣＶＲＮＡ单项阳性;２１例（５．２％）抗－ＨＣＶ单项阳性。将ＨＢｓＡｇ乙肝病人分成ＨＢＶＤＮＡ,ＨＢｅＡｇ阳性组和ＨＢＶＤＮＡ,ＨＢｅＡｇ阴性组。前者抗－ＨＣＶ阳性率为１１．６％～２０．５％,ＨＣＶＲＮＡ阳性率为１６．２％～２０．５％。后者抗－ＨＣＶ阳性率为２０．２％～５５．６％,ＨＣＶＲＮＡ阳性率为２３％～６０．３％。结果说明长期携带ＨＢＶ者和慢性乙肝病人均可重叠ＨＣＶ感染。ＨＢＶＤＮＡ阳性组抗－ＨＣＶ和ＨＣＶＲＮＡ阳性率明显高于ＨＢＶＤＮＡ阳性组