干扰素治疗慢性乙型肝炎时e抗原血清学转换的相关因素

目的探讨HBeAg阳性慢性乙型肝炎在聚乙二醇干扰素α-2a（PEG-IFN α-2a）治疗过程中HBeAg血清学转换和病毒学应答的相关因素，HBeAg血清学转换与HBV DNA应答的相关性。方法患者采用PEG-IFNα-2a每次180μg，皮下注射，每周1次，共治疗48周，治疗结束后随访24周。用Abbott公司生产的第三代HBV血清学检测试剂和AXSYM自动酶标检测仪检测血清HBeAg、抗-HBe，实时荧光定量PCR检测HBVDNA载量，分析不同治疗阶段和随访结束的病毒学应答率（HBV DNA〈1．0×10^5拷贝／ml），HBeAg血清转换率及变化规律和影响病毒学应答和HBeAg血清转换的因素。结果治疗12周和随访结束时HBeAg血清转换组和非转换组的ALT水平比较，差异有统计学意义。病毒学应答无论在治疗期还是随访结束时，应答组与非应答组之间的ALT水平差异均有统计学意义。HBeAg血清学转换与非转换组之间的HBV DNA载量之间在治疗12周、治疗结束和随访结束时，差异无统计学意义。治疗期间病毒学应答与非应答组的HBV DNA载量之间的差异有统计学意义，但持续病毒学应答与HBV DNA载量无显著相关性。治疗12、24周和48周获得病毒学应答组的HBeAg血清转换率分别为43．8％、21．4％和18．9％。治疗12、24周和48周时病毒学应答组，在随访结束时的HBeAg的血清转换率分别为42．9％、33．3％和27．6％。多因素分析显示，治疗72周的HBeAg血清转换与治疗结束时的HBV DNA阴转显著相关（OR=2．15，95．0％CI=1．744-2．664，P〈0．01）。结论治疗12周和持续HBeAg血清学转换以及病毒学应答均与ALT基线水平相关，HBeAg血清学转换与基础HBV DNA载量无关，但与治疗过程中病毒学应答相关。     

替比夫定治疗HBeAg阳性慢性乙型肝炎48周疗效观察

目的观察比较替比夫定与拉米夫定治疗HBeAg阳性慢性乙型肝炎48周的疗效。方法73例患者按就诊顺序分别纳入治疗组（30例）和对照组（43例）。治疗组每天口服替比夫定600mg,对照组每天口服拉米夫定100mg,疗程均为48周。治疗前和治疗4、12、24、48周分别检测血清HBVDNA定量、血清HBV标志物、ALT水平。比较2组48周时HBVDNA水平、HBVDNA阴转率、HBeAg血清转换率、ALT复常率。结果2组HBVDNA水平随治疗时间延长均有所下降,治疗4周时下降最明显,治疗48周时治疗组平均下降水平大于对照组（P=0．001）。治疗组HBVDNA的阴转率为93．3％,高于对照组（69．3％）,P〈0．05,差异有统计学意义。48周时治疗组HBeAg血清转换率为33.3％,对照组为25．5％（P=0．472）,2组之间差异无统计学意义。2组间ALT复常率差异无统计学意义。结论替比夫定治疗HBeAg阳性慢性乙型肝炎48周的疗效优于拉米夫定。     

聚乙二醇干扰素α-2a与聚乙二醇干扰素α-2b治疗慢性乙型肝炎的效果及安全性比较

目的比较PEG-IFNα-2a与PEG-IFNα-2b治疗慢性乙型肝炎(CHB)的效果和安全性。方法选取2017年1月-2018年6月在徐州医科大学附属医院感染科接受PEG-IFNα-2a(180μg/周)(n=34)和PEG-IFNα-2b(180μg/周)(n=32)治疗的CHB患者,观察2组治疗4、12、24、48周时HBsAg、HBV DNA、HBeAg、ALT水平及应答率等指标,将第48周抗病毒疗效结果作为主要观察指标,同时比较应答组与非应答组上述指标有无统计学差异。服从正态分布的计量资料2组间比较采用独立样本t检验;非正态分布的计量资料2组间比较采用Mann-Whitney U检验;计数资料2组间比较采用χ2检验或Fisher确切概率法检验。结果 PEG-IFNα-2a、PEG-IFNα-2b治疗48周时CHB患者的血清HBV DNA应答率分别为67. 6%、59. 4%,HBeAg血清学转换率分别为27. 3%、34. 6%,2组比较差异均无统计学意义(P值均 0. 05)。PEG-IFNα-2a组中,HBV DNA应答组较非应答组基线ALT水平更低,差异有统计学意义(Z=2. 390,P=0. 016); HBeAg应答组基线HBeAg水平比非应答组更低,差异有统计学意义(Z=2. 286,P=0. 021)。PEG-IFNα-2b组中,HBV DNA应答组较非应答组具有更低的基线HBV DNA水平、基线HBeAg水平(Z值分别为2. 154、2. 057,P值分别为0. 030、0. 041); HBeAg应答组较非应答组具有更低的基线HBV DNA水平(Z=2. 052,P=0. 042)。2组不良反应发生率差异均无统计学意义(P值均 0. 05),PEG-IFNα-2b治疗组1例发生Purtscher样视网膜病变,1例发生血小板减少,而PEG-IFNα-2a组未见Purtscher样视网膜病变和血小板减少相关不良反应。结论 PEG-IFNα-2a、PEGIFNα-2b治疗CHB均有较强的抗病毒疗效和免疫调节作用,治疗效果及安全性相近。     

HBsAg 定量对 HBeAg 阴性患者 PEG-IFN治疗应答的预测

目的：评估 HBsAg 定量对 HBeAg 阴性患者聚乙二醇化干扰素α-2a（PEG-IFNα-2a）治疗应答的预测。方法HBeAg 阴性慢性乙型肝炎患者采用 PEG-IFNα-2a 每次180ug,皮下注射,每周1次,治疗48周。Architect HBsAg定量检测系统测定治疗前、后12、24、48周时血清 HBsAg 定量,并分析血清 HBsAg 动态定量与治疗应答相关性。结果完成48周疗程65例,其中有46例（70．8％）在48周疗程结束时获得病毒学应答;随访24周,有25例（38．5％）患者获得持续病毒学应答（SVR）;21例复发。获得 SVR 患者 HBsAg 基线水平低于非 SVR 患者（P ＜0．05）。治疗12、24周血清 HBsAg 水平及下降幅度差异有统计学意义（P ＜0．05）。治疗24周血清 HBsAg 定量水平＜1500 IU／mL,下降幅度≥1 lgIU／mL 的患者 SVR 率高（P ＜0．05）。结论采用 PEG-IFNα-2a 治疗的慢性乙型肝炎 HBeAg 阴性患者早期血清HBsAg 下降对于获得 SVR 具有高度的预测价值,进行血清 HBsAg 定量检测有助于优化 PEG-IFN 的治疗方案。     

阿德福韦酯序贯聚乙二醇干扰素α-2a治疗HBeAg低效价慢性乙型肝炎患者的疗效北大核心CSCD

目的探讨阿德福韦酯长期单药治疗后仍处于HBeAg低效价的慢性乙型肝炎患者,加用聚乙二醇干扰素α-2a治疗48周的疗效。方法本研究为随机、开放、前瞻性的临床试验。将阿德福韦酯单药治疗72～144周仍处于低HBeAg效价（5S／CO〈HBeAg〈50S／CO）,且血清HBsAg定量〈5000IU／mL的患者按随机数字表法分为单药组和加药组,单药组继续阿德福韦酯单药治疗48周,加药组加用聚乙二醇干扰素α-2a治疗48周,比较两组治疗前后血清HBeAg效价下降程度、阴转率、血清学转换率和肝组织HBVDNA、HBV共价闭合环状脱氧核糖核酸（cccDNA）载量的下降程度,对两种治疗方案进行疗效评估。患者治疗前后比较采用配对样本t检验,组间比较采用独立样本t检验,组间率的比较采用X^2检验。结果共纳入55例慢性乙型肝炎患者,单药组27例,加药组28例,两组患者年龄分布、性别比例、ALT、AST、TBil、血清HBeAg和HBsAg、肝组织HBVDNA和HBVcccDNA载量在基线水平比较差异均无统计学意义（均P〉0．05）。治疗48周后,单药组完成试验25例,加药组26例。加药组HBeAg阴转率、血清转换率均高于单药组（X^2值分别为5．38、4．69,均P〈0．05）。两组HBeAg效价均较基线值下降（t值分别为8．43和8．50,均P〈0．01）;加药组HBeAg效价低于单药组（t=5．60,P〈0．01）。加药组治疗48周HBVDNA和HBVcccDNA载量分别为（6．93±0．52）lgIU／mg和（5．63±0．54）lg IU／mg,与基线值比较差异均有统计学意义（t值分别=7．12和6．67,均P〈0．01）。单药组治疗48周HBVDNA载量为（7．09±0．43）lg IU／mg,与基线值比较差异有统计学意义（t=2．67,P=0．02）;治疗后48周,加药组与单药组HBVcccDNA载量比较差异有统计学意义（t=2．87,P=0．00）。结论经阿德福韦酯长期治疗后仍处于HBeAg低效价的慢性乙型肝炎患者,加用聚乙二醇干扰素α-2a,有利于提高血清HBeAg的阴转率和血清学转换率,并加速肝组织HBVDNA、HBVcccDNA的清除。     

拉米夫定和α-干扰素序贯联合治疗慢性乙型肝炎疗效观察

目的探讨拉米夫定与干扰素序贯联合治疗慢性乙型肝炎的疗效。方法30例慢性乙型肝炎患者接受拉米夫定100mg／13口服，直到血清HBVDNA转阴后，联合应用重组人IFN-α2b3MU肌肉注射24周，停拉米夫定，再单用IFN-α24周；对照组30例单用拉米夫定100mg口服，疗程1年。结果治疗结束时ALT复常率治疗组和对照组分别为90．0％和86．7％，两组差异无统计学意义（p〉0．05）。但随访6个月时ALT复常率治疗组和对照组分别为83．3％和56．7％，两组相比有显著性差异（P〈0．05）；治疗组治疗结束时及随访6个月时HBeAg阴转率分别为60．0％和56．7％，对照组阴转率分别为23．3％和20．0％（P〈0．01）；HBeAg转换率治疗组治疗结束时及随访6个月时分别为53．3％和53．3％，对照组分别为20．0％和20．0％（P〈0．01）；治疗结束时HBVDNA阴转率治疗组和对照组分别为86．7％和83．3％，两组差异无统计学意义（P〉0．05），但随访6个月时治疗组和对照组分别为70．0％和43．3％（P〈0．05）。结论拉米夫定与干扰素序贯联合治疗慢性乙型肝炎能明显提高抗病毒疗效，持续应答优于单用拉米夫定治疗者。     

慢性乙型肝炎治疗中影响HBeAg转阴和定量的有关因素分析

背景：慢性乙型肝炎抗病毒治疗的完全应答包括血清HBVDNA低于检测水平和HBeAg血清学转换,HBeAg是评估乙型肝炎治疗效果和停药的监测指标。目的：探讨替比夫定治疗HBeAg阳性慢性乙型肝炎患者时影响HBeAg转阴的因素。方法：采用替比夫定治疗156例HBeAg阳性慢性乙型肝炎患者48周,观察ALT、HBVDNA、HBeAg治疗前后变化,分析治疗前基线HBVDNA载量、ALT水平、HBVDNA降至检测下限的时间对HBeAg转阴和定量的影响。结果：替比夫定治疗48周后,HBVDNA转阴128例（82．1％）,ALT恢复正常153例（98．1％）,HBeAg转阴52例（33．3％）;HBVDNA载量、HBeAg定量、ALT水平均显著降低（P〈0．01）。治疗前HBVDNA〈10^7 copies／mL、ALT≥200U／L组的HBeAg转阴率分别显著高于HBVDNA≥10^7 copies／mL、ALT〈200U／L组（46．4％对23．0％,P〈0．01;55．2％对16．9％,P〈0．叭）,且HBeAg定量显著降低（P〈0．01）。HBVDNA降至检测下限的不同时间组HBeAg转阴率和定量相比差异均有统计学意义（P〈0．05）。结论：基线HBVDNA〈10^7 copies／mL、ALT水平较高、治疗后HBVDNA降至检测下限的时间对替比夫定治疗48周时HBeAg转阴和定量具有明显的影响。     

拉米夫定的疗程及早期应答与疗效的关系

目的探讨拉米夫定治疗慢性乙型肝炎的方法与疗效的关系。方法收集179例接受拉米夫定治疗的乙型肝炎e抗原（HBeAg）阳性的慢性乙型肝炎患者的资料，分析早期应答、病毒变异、疗程等与疗效的关系。结果随着治疗时间延长，丙氨酸氨基转移酶（ALT）、HBVDNA、HBeAg和HBeAg／抗-HBe各项指标逐渐改善；1年疗程的HBVDNA阴转率（57．0％）、HBeAg阴转率（39．7％）及HBeAg／抗-HBe转换率（16．8％）均明显高于治疗3个月时的水平（X2值分别为28．489、33．238、12．690，P〈0．01）。治疗12周时血清HBVDNA水平越低，到治疗52周及随访6个月末时HBVDNA转阴率及HBeAg／抗-HBe血清学转换率越高。疗程为1年、1．5年时，出现HBeAg／抗-HBe转换者HBVDNA反弹率均为40．0％，远低于无转换者（88．2％、85．0％，x^2值分别为12．424、10．237，P〈0．01）。结论拉米夫定治疗是安全有效的，疗程以1．5年为佳。早期应答者疗效较好，如不能在治疗的前3个月内达到DNA应答、1年内出现血清学转换，预示疗效欠佳。     

膦甲酸钠治疗重度慢性乙型肝炎的临床研究

目的探讨膦甲酸治疗重度慢性乙型病毒性肝炎的疗效和安全性。方法208例患者按1：1随机分为治疗组和对照组，治疗组109例，膦甲酸钠注射液3．0g／250ml静脉点滴，每日2次，疗程4周。对照组为99例，等渗盐水250ml静脉点滴，每日2次，疗程4周，随访24周。结果用药4周时，治疗组和对照组的HBV DNA阴转率分别为12．8％和7．1％，随访24周时分别为5．5％和3．0％，差异无统计学意义。治疗组治疗后HBV DNA≤10）拷贝／ml在用药4周．停药随访24周分别为64．2％（70／109）和40．4％（44／109），对照组分别为30．3％（30／99）和22．2％（22／99），x^2值分别为24．466和8．962，P值均〈0．01，差异有统计学意义。HBeAg转阴率用药4周、随访24周，治疗组分别为17．3％（14／81）、22．0％（11／50）；对照组分别为5．8％（5／87）和5．4％（4／74），P值分别为0．0266和0．0096，差异有统计学意义。HBeAg血清转换率用药4周、随访24周，治疗组分别为12．7％（10／79）和16．7％（8／48）；对照组分别为3．7％（3／82）和1．5％（1／69），P值分别为0．0445和0．0034。差异有统计学意义。治疗结束时，应答率分别为60．6％和21．2％，Z=5．6683，P〈0．05。结论膦甲酸钠注射液治疗重度慢性乙型病毒性肝炎有较好的疗效和安全性。     

e抗原定量对聚乙二醇干扰素治疗HBeAg阳性慢性乙型肝炎e抗原血清学转换的预测

目的 评估聚乙二醇化干扰素α-2a( PEG-IFNα-2a)治疗HBeAg阳性慢性乙型肝炎患者过程中,HBeAg定量预测HBeAg血清转换的价值.方法 HBeAg阳性慢性乙型肝炎(CHB)患者,采用PEG-IFNα-2a每次180 μg,皮下注射,每周1次,治疗48周.用HBV血清学检测试剂和i2000免疫发光检测系统检测HBeAg、抗-HBe,实时荧光定量PCR检测HBV-DNA载量.分析治疗12周、24周及48周的病毒学应答率(HBV-DNA<1.0×103拷贝/mL),HBeAg血清转换率及影响HBeAg血清转换的因素.受试者工作特征(ROC)曲线用于比较HBeAg和HBV-DNA水平作为HBeAg血清转换预测指标的相对敏感性和特异性.结果 65例完成48周疗程的HBeAg阳性CHB患者,19例(29.23%) 出现HBeAg阴转、17例(26.15%)出现HBeAg的血清转换.48周时HBeAg血清转换与基线HBeAg定量相关(P=0.003),与基线时的年龄、性别、ALT水平及HBV-DNA载量无关.依据基线、12周和24周的HBeAg定量获得的ROC曲线,以12周时 HBeAg 61 s/co为界值(AUC=0.705,P=0.042),其48周时HBeAg血清转换的阳性预测值(PPV)、阴性预测值(NPV)分别为0.361、0.862,敏感性与特异性分别为0.765 和 0.521;若以24周时 HBeAg 15 s/co为界值(AUC=0.828,P=0.001),其48周时HBeAg血清转换的阳性预测值(PPV)、阴性预测值(NPV)分别为0.452、0.912,敏感性与特异性分别为0.824 和0.646.与基线比较,12周和24周HBeAg下降的幅度(75%)与HBeAg血清转换相关;治疗过程中HBV-DNA变化与HBeAg血清转换无关.结论 HBeAg定量变化是聚乙二醇化干扰素α-2a治疗CHB过程中预测HBeAg血清转换的有价值的指标.     

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。     

Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine.

BACKGROUND: The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double-blinded, randomized, multi-center study we assessed histological changes in 110 hepatitis B e-antigen (HBeAg)-positive CHB patients treated for 52 weeks with Pegylated interferon alpha-2b (PEG-IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system. RESULTS: Necroinflammatory score improved (defined as a decrease of at least two points) in 25 patients (48%) of the PEG-IFN/lamivudine combination therapy group and in 31 patients (53%) of the PEG-IFN monotherapy group. The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combination therapy group vs. 13 patients (22%) of the PEG-IFN monotherapy group (P=0.23). Responders (n=42), defined as serum HBeAg negative at the end of therapy, showed a larger decline in necroinflammatory score than non-responders (mean decline 2.3 and 1.2 points, respectively, P=0.02). Among patients receiving PEG-IFN monotherapy necroinflammation improved more frequently in responders (78% of responders vs. 43% of non-responders, P=0.01) and in patients who showed normalization of ALT (76% of patients with normal ALT vs. 40% of patients with abnormal ALT, P=0.01). Fibrosis score in the PEG-IFN monotherapy group improved more often in responders (39%) than in non-responders (15%, P=0.04). In the PEG-IFN/lamivudine combination therapy group, we found no significant association between virological and biochemical endpoints and histological improvement. CONCLUSIONS: Treatment with PEG-IFN therapy improves liver necroinflammation in HBeAg-positive CHB patients, particularly in responders to therapy. PEG-IFN also improves fibrosis in responders. Addition of lamivudine to PEG-IFN did not further improve the histological outcome.     

聚乙二醇干扰素α-2a联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎疗效预测因素分析

目的 分析聚乙二醇干扰素（PEG-IFNα-2a）联合阿德福韦酯（ADV）治疗HBeAg阳性慢性乙型肝炎（CHB）患者48 w时的疗效及其预测因素。方法 将196例HBeAg阳性CHB患者分为PEG-IFNα-2a治疗64例,ADV治疗66例和PEG-IFNα-2a联合ADV治疗66例,疗程均为48 w。采用ELISA法检测INF-γ和IL-10;采用Achitect（Abbott）微粒子化学发光免疫分析法检测HBeAg定量。结果 在治疗48 w时,联合组HBV DNA阴转率、HBeAg阴转率、HBeAg转换率和ALT复常率分别为74.2%、24.2%、48.5%和80.3%,显著高于干扰素组（53.1%、10.9%、29.7%和54.7%,P<0.05）和阿德福韦组（62.1%、13.6%、9.1%和65.2%,P<0.05）;联合组INF-γ水平为（45.3±11.3） pg/ml,显著高于干扰素组[（37.1±10.3） pg/ml,P<0.05]和阿德福韦组[（36.3±11.5） pg/ml,P<0.05];联合组IL-10水平为（10.3±14.6） pg/ml,显著低于干扰素组[（17.1±11.3） pg/ml,P<0.05]和阿德福韦组[（18.3±10.5） pg/ml,P<0.05];联合组治疗48 w时HBeAg血清学转换与治疗24 w时HBeAg水平下降的百分比有关,即治疗24 w时HBeAg水平较基线下降大于89.1%的阳性预测值为88.7%,阴性预测值（NPV）为81.9%,灵敏度为83.1%,特异度为87.9%。结论 PEG-IFNα-2a联合ADV治疗HBeAg阳性慢性乙型肝炎能增强机体细胞免疫应答,疗效优于单药治疗,其中治疗24 w时HBeAg下降的百分比可预测48 w时的疗效。     

延长聚乙二醇干扰素α-2a疗程对乙型肝炎表面抗原消失/血清学转换的影响

目的 探讨延长聚乙二醇干扰素α-2a疗程对慢性乙型肝炎患者获得HBsAg消失/血清学转换的影响.方法将217例慢性乙型肝炎患者根据体质量分为＜60 kg和≥60 kg两组,分别皮下注射聚乙二醇干扰素α-2a 135μg或180 μg,治疗过程中根据患者外周血中性粒细胞数和血小板数调整药物剂量.每3个月采用酶免疫化学发光法定量检测HBsAg/抗-HBs、HBeAg/抗-HBe,HBV DNA采用实时荧光定量聚合酶链式反应检测,将治疗时间＞12周的患者纳入统计分析,在治疗过程中,对HBV DNA、HBsAg含量降低的患者,HBeAg含量下降的HBeAg阳性患者,治疗48周后HBsAg含量＜200 IU/ml患者进行延长治疗,经意向性分析治疗患者HBsAg血清学转换发生率.采用x2检验进行统计学分析.结果 217例慢性乙型肝炎患者,治疗时间为12.0～197.6周,平均(53.1±33.4)周,其中118例患者治疗时间≥48周,89例治疗时间＜48周.13.4%(29/217)的患者获得HBsAg消失/HBsAg血清学转换,其治疗时间为17.6～197.6周,平均(75.4±42.8)周,其中治疗时间＞48周24例(82.8%),小于48周5例(17.2%);HBV DNA平均转阴时间为(20.8±8.9)周.148例HBeAg阳性患者中,9.5%(14/148)的患者获得HBsAg消失/血清学转换,在获得HBsAg消失/血清学转换的患者中,治疗时间均＞48周(54～194周),平均(81.3±39.4)周.21.7%(15/69)的HBeAg阴性患者获得HBsAg消失/血清学转换,与HBeAg阳性患者的HBsAg消失/血清学转换率(9.5%)比较,x2=6.129,P=0.013,差异有统计学意义.获得HBsAg消失/血清学转换的患者中,HBeAg阴性患者平均治疗时间为(70.2±48.0)周,HBeAg阳性患者(81.3±39.4)周,差异无统计学意义(t=-0.522,P=0.602).结论 对聚乙二醇干扰素α-2a治疗HBV DNA和HBsAg应答良好的慢性乙型肝炎患者,延长疗程可提高HBsAg消失/血清学转换率,HBeAg阴性患者比HBeAg阳性患者更容易通过延长聚乙二醇干扰素α-2a治疗获得HBsAg的消失/血清学转换.

Abstract：

Objective HBsAg loss and seroconversion in patients with chronic hepatitis B leads to long-lasting good clinical outcomes. The aim of this paper was to investigate to improve the rate of HBsAg loss and seroconversion in chronic hepatitis B patients by prolonged treatment of PEG-IFN α -2a. Methods 217 cases of HBeAg-positive or negative patients were collected from inpatient and outpatient in Beijing Ditan Hospital from May 2005 to October 2009 and subcutaeous injection of 135μg or 180μg PEGASYS were given once a week acording to body weights. The drug doses were adjusted acording to the neutrophilic granulocyte and platelet counts during treament course. Quantitative HBV DNA test was conducted using a commercially available real-time fluorescence quantitative PCR kit. The serum HBsAg/anti-HBs and HBeAg/anti-HBe were quantitatively detected by Abbott i 2000 chemiluminescent kit before and during treatment every three months. Patients with HBsAg steadily decreased and reached serum HBsAg level below 200 IU/ml after 48 weeks of treatment would receive prolonged treatment. Patients with more than 12 weeks of treatment entered into analysis. Main efficacy of prolonged treatment was evaluated by the incidences of HBsAg loss and seroconversion. Results The treatment courses of the 217 patients ranged from 12.0 to 197.6weeks with an average of 53.1±33.4 weeks, 118 cases took more than 48 weeks and another 89 cases less than 48 weeks. 13.4% (29/217) of patients achieved HBsAg loss or HBsAg seroconversion with treatment courses from 17.6 to 197.6 weeks (average 75.4±42.8 weeks). Among these 29 patients 24 (82.8%) received more than 48 weeks of treatment, but the treatment courses of HBV DNA reached undetectable level were 20.8±8.9 weeks. In this study, 9.5% (14/148) of HBeAg-positive patients acchieved HBsAg loss or seroconversion, all of them treated more than 48 weeks, from 48 to 194 weeks, average 81.32 ± 39.36 weeks.21.7% (15/69) of HBeAg-negative patients achieved HBsAg loss or seroconversion, significantly higher than that of HBeAg-positive patients (9.5%) (x2=6.129, P=0.013). The average treatment course for HBeAgnegative patients with HBsAg loss was 70.2±48.0 weeks, shorter than that of HBeAg-positive patients with HBsAg loss (81.3±39.4 weeks), but no significant difference (t=-0.522, P = 0.602) found between. Conclusion Higher rate of HBsAg loss and seroconversion could be obtained by individual extended treatment courses in patients with rapid HBV DNA and HBsAg response to PEG-IFN α -2a treatment and the HBeAgnegative patients could got higher rate of HBsAg loss than HBeAg-positive patients.     

干扰素α-2b与聚乙二醇干扰素α-2a治疗慢性乙型肝炎患者疗效比较研究*

目的 观察干扰素α-2b与聚乙二醇干扰素α-2a（PEG-IFNα-2a）治疗慢性乙型肝炎（CHB）患者的临床疗效。方法 将116例CHB患者分成两组,每组58例。给予对照组普通干扰素α-2b治疗,给予观察组PEG-IFNα-2a,疗程均为48 w。检测血清层黏连蛋白（LN）、透明质酸（HA）、Ⅳ型胶原（Ⅳ-C）、Ⅲ型前胶原肽（PⅢP）及血清白介素4（IL-4）、白介素6（IL-6）、白介素10（IL-10）和干扰素γ（IFN-γ）变化。结果 在治疗结束时,观察组HBV DNA转阴率、HBeAg转阴率、HBeAg血清转换率和ALT复常率分别为75.9%、29.3%、22.4%和70.7%,显著高于对照组的51.7%、19.0%、10.3%和55.2%（P<0.05）;观察组血清LN为（148.5±46.0） μg/L,显著低于对照组【（162.6±26.7） μg/L,P<0.05】,血清HA为（158.7±67.9）μg/L,显著低于对照组【（201.4±55.1） μg/L,P<0.05】,血清Ⅳ-C为（108.3±33.4） μg/L,显著低于对照组【（119.2±62.4） μg/L,P<0.05】,血清PⅢP为（145.8±47.2） μg/L,显著低于对照组【（155.3±36.7）μg/L,P<0.05】;观察组血清IL-4水平为（1.5±0.6） pg/ml,显著低于对照组【（3.9±1.6） pg/ml,P<0.05】,而IL-6水平为（6.9±1.3） pg/ml,显著高于对照组【（3.6±0.9） pg/ml,P<0.05】,IL-10水平为（22.6±13.4） pg/ml,显著低于对照组【（17.3±11.4） pg/ml,P<0.05】,IFN-γ水平为（37.2±10.2） pg/ml,显著高于对照组【（28.3±10.5） pg/ml,P<0.05】;观察组血小板计数减少发生率为51.7%,显著高于对照组的12.1%（P<0.05）。结论 PEG-IFNα-2a治疗CHB患者临床疗效优于普通干扰素α-2b,能持久有效地抑制HBV复制,改善血清肝纤维化指标,但不良反应较大,应及时处理。     

Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C

As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 μg/week or 180 μg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 μg/week or 180 μg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 μg versus 180 μg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 μg/week was inferior to 180 μg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a. CONCLUSION: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180 μg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C.     

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.     

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

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

干扰素治疗慢性乙型肝炎的肝组织学及血清学前瞻性研究

目的 观察干扰素α-2b治疗18周后的慢性乙型肝炎患者肝组织学及血清HBV DNA等变化。方法 采用肝组织损伤程度Knodell计分法、免疫组织化学及血甭HBV DNA定量检测对22例患者治疗前后进行比较。结果 治疗结束时肝组织学中坏死及炎症程度与治疗前相比明显减轻（P＜0．01）;55％（12／22）患者肝组织学活动指数得以改善,其中门静脉炎症及纤维化程度无明显改善（P＞0．05）。免疫组织化学检测显示治疗后肝组织中HBeAg阴转率为53．8％（7／13）,活化的星状细胞数显著减少（P＝0．0004）。血清HBV DNA水平较治疗前明显下降（P＜0．01）。治疗结束HBeAg阴转率为42．9％（6／14）。HBeAg阳性与HBeAg阴性患者相比,其肝组织学损伤程度的改善及血清HBV DNA的下降无明显区别。结论 干扰素α-2b治疗慢性乙型肝炎可明显降低血清HBV DNA的水平,并改善其肝组织学的炎症及坏死程度。     

高效抗逆转录病毒药物联合聚乙二醇化干扰素α-2a治疗艾滋病合并丙型肝炎患者的效果评价

目的探讨高效抗逆转录病毒药物联合聚乙二醇化干扰素α-2a（PEG-IFNα-2a）治疗HIV合并HCV感染者的疗效和不良反应。方法22例HCV/HIV合并感染者,先予高效抗逆转录病毒药物治疗;待所有患者CD4^＋ T淋巴细胞上升至0.20×10^9/L以上,将患者分成CD4^＋T淋巴细胞≥0.35×10^9/L和〈0.35×10^9/L两组,给予PEG-IFNα-2a,180μg,每周肌肉注射1次,检测两组患者的HCV RNA和HIV RNA水平、肝功能和血常规,并做CD4^＋T淋巴细胞计数。结果CD4^＋T淋巴细胞≥0.35×10^9/L组13例,在治疗12、24、48周后,与治疗前比较,HCV RNA平均分别下降2.0650 log10拷贝/ml（t=3.8733,P〈0.01）、2.9146 log10拷贝/ml（t= 7.6741,P〈0.01）、2.4315 log10拷贝/ml（t=5.8202,P〈0.01）。CD4^＋T淋巴细胞〈0.35×10^9/L组9例,分别下降1.1522 log10拷贝/ml（t=2.8937,P〈0.05）、1.4189 log10拷贝/ml（t= 2.4422,P〈0.05）、1.1167 log10拷贝/ml（t=1.1261,P〉0.05）。两组患者HCV RNA早期应答率和治疗结束应答率比较,P值均〉0.05。CD4^＋T淋巴细胞〈0.35×10^9/L组,在治疗24周时白细胞较治疗前下降（t=2.4700,P〈0.05）。CD4^＋T淋巴细胞≥0.35×10^9/L组,治疗24周和48周血小板均较治疗前下降（t=2.3273,P〈0.05;t=3.6149,P〈0.01）。结论PEG-IFNα-2a治疗HIV/HCV患者,能有效降低HCV病毒载量,CD4^＋T淋巴细胞≥0.35×10^9/L组疗效更显著,但两组患者的HCV RNA早期应答率和治疗结束应答率差异无统计学意义。PEG-IFNα-2a可降低外周血白细胞和血小板。