聚乙二醇干扰素α-2a联合阿德福韦酯对HBeAg阳性慢性乙型肝炎的治疗

目的:分析聚乙二醇干扰素-2a(peginterferon-2a,Peg-IFN-2a)治疗HBeAg阳性慢性乙型肝炎应答不佳者联合阿德福韦酯(adefovirdipivoxil,ADV)治疗48 wk的疗效、安全性,并评价48 wk疗效预测指标.方法:140例患者初始均接受Peg-IFN-2a每周1次皮下注射单药治疗,根据24 wk时HBVDNA水平进行分组.A组90例患者治疗24 wk时HBV DNA≥2.0×103IU/mL且HBV DNA下降≥2 log10 IU/mL,其中A1组45例患者加用ADV治疗至48 wk,A2组45例患者继续Peg-IFN-2a单药治疗至48 wk;B组50例患者治疗24 wk时HBV DNA<2.0×103IU/mL,继续Peg-IFN-2a治疗至48 wk.比较各组基线及治疗中HBV DNA、HBsAg、HBeAg及ALT水平.结果:治疗36、48 wk时HBV DNA转阴率B组>A1组>A2组(P<0.01).治疗36 wk时HBV DNA下降值B组>A1组>A2组(P<0.01).48 wk时HBV DNA下降值A1组>A2组(P<0.01),A1、B组之间差异无统计学意义.治疗24-48 wk期间,A1组HBeAg血清转换率升高幅度>A2组和B组(P<0.01).治疗48 wk时HBsAg下降A1组4例、A2组1例、B组2例.治疗36、48 wk时A1与A2、B组ALT复常率差异无统计学意义.A1组治疗48 wk时HBV DNA阴转与治疗36 wk HBVDNA下降值有关.治疗36 wk时HBV DNA较基线下降值对48 wk时HBV DNA阴转的阳性预测值为90.5%,较24 wk时下降值对48 wk时HBV DNA阴转的阳性预测值为95.7%.结论:Peg-IFN-2a治疗HBeAg阳性慢性乙型肝炎应答不佳者联合ADV治疗提高病毒应答、HBeAg血清转换率,其中治疗36 wk时HBV DNA下降值可预测48 wk疗效.     

聚乙二醇干扰素α-2a联合阿德福韦酯治疗HBeAg阴性慢性乙型肝炎的临床研究

目的 探讨聚乙二醇干扰素(Peg-IFN) α-2a联合阿德福韦酯(ADV)治疗HBeAg阴性慢性乙型肝炎(CHB) 96周的疗效及安全性. 方法 25例初治HBeAg阴性CHB患者接受Peg-IFN α-2a(135μg/周或180μg/周)联合ADV (10 mg/d)治疗.96周治疗结束时,如获得HBsAg血清学转换则停药随访,否则停用Peg-IFN α-2a,继续ADV维持治疗.所有患者随访至120周.基线和治疗过程中每12周检测HBV DNA和HBsAg水平.计数资料采用x2检验或Fisher's exact test检验. 结果 Peg-IFNα-2a联合ADV治疗48周时,100％ (25/25)的患者HBV DNA低于检测值(＜ 500拷贝/ml),且在治疗过程中始终保持不可检测水平;治疗48周时HBsAg血清学转换率为12％ (3/25),96周上升至28％ (7/25).随访至120周,HBsAg血清学转换率为32％ (8/25).延长治疗至96周未见新的不良反应发生,其安全性同48周.结论 Peg-IFNα-2a联合ADV并延长疗程可显著提高HBeAg阴性CHB患者的抗病毒疗效,尤其可以提高HBsAg血清学转换率,是值得探索的优化治疗策略之一.     

聚乙二醇干扰素α-2a联合阿德福韦治疗HBeAg阳性慢性乙型肝炎疗效系统评价

目的探讨聚乙二醇干扰素α-2a(Peg-IFNα-2a)联合阿德福韦(ADV)治疗HBe Ag阳性慢性乙型肝炎(CHB)患者的临床疗效。方法通过检索2004年1月~2014年1月期间Pubmed、万方数据库(CECDB)、中文科技期刊数据库(VIP)、中国学术期刊全文数据库(CNKI)等有关Peg-IFNα-2a联合阿德福韦治疗HBe Ag的CHB患者的随机对照试验(RCT),对纳入文献的质量进行严格评价和资料提取,应用Stata/SE version 12.0软件对纳入研究进行系统评价。结果最终纳入7篇RCT,共529例患者,其中实验组261例(接受Peg-IFNα-2a联合ADV治疗),对照组268例(接受Peg-IFNα-2a治疗)。系统评价结果显示,相比单药治疗,经联合治疗48 w时CHB患者HBV DNA阴转率显著提高[OR=1.20,95%CI=(1.01,1.43)];48 w时CHB患者HBe Ag血清转换率显著提高[OR=1.24,95%CI=(1.02,1.52)],但联合治疗对ALT复常率的影响,系统评价显示结果存在显著偏倚[bias_P=0.012、bias_95CI=(1.442998,6.467852)],不具有推广性。结论 Peg-IFNα-2a联合ADV治疗HBe Ag阳性CHB患者能显著提高患者HBV DNA阴转率及HBe Ag血清转换率。     

聚乙二醇干扰素α-2b联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎疗效分析

目的观察聚乙二醇干扰素α-2a联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者的疗效。方法选择HBeAg阳性慢性乙型肝炎患者86例,其中39例为聚乙二醇干扰素α-2b,47例为聚乙二醇干扰素α-2b联合阿德福韦酯治疗。结果在治疗24周时,联合治疗组谷丙转氨酶复常率和HBV DNA转阴率分别为66%和68%,显著高于单药治疗组的41%和10%（P〈0.05或P〈0.01）;在治疗48周时,联合治疗组HBV DNA转阴率为85%,显著高于单药治疗组的51%（P〈0.01）。结论聚乙二醇干扰素α-2b联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎能明显增加HBV DNA转阴率及谷丙转氨酶复常率。     

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。     

干扰素α-2b联合阿德福韦酯治疗慢性乙型肝炎疗效观察

目的探讨干扰素（IFN）α-2b联合阿德福韦酯（ADv）治疗慢性乙型肝炎（chronic hepatitis B,CHB）患者的疗效。方法47例CHB患者随机分为2组,IFNα-2b联合ADV组（联合用药组）22例,单用ADV组（单药组）25例。监测2组患者治疗12、24、48、96周的HBVDNA水平、HBV血清标志物及ALT变化。结果治疗48周时,联合用药组患者血清中HBVDNA转阴率和ALT复常率明显高于单药组,联合用药组在停用IFNα-2b48周后上述指标仍高于单药组。治疗48周时,联合用药组完全应答率为59％,高于单药组的28％（P〈0．05）。结论IFNα-2b联合ADV治疗CHB优于单用ADV,可提高HBeAg／抗HBe血清学转换率及完全应答率。     

聚乙二醇干扰素α加用阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的效果观察

目的评价聚乙二醇干扰素(PEG-IFN)α治疗HBe Ag阳性慢性乙型肝炎(CHB)患者12/24周联合阿德福韦酯(ADV)的疗效。方法回顾性收集2009年10月~(-2)014年1月在福建医科大学附属第一医院接受PEG-IFNα治疗12周,HBV DNA≥105拷贝/ml的HBe Ag阳性CHB患者。根据治疗方案分为12周联合ADV组(A组,n=36)、24周联合ADV组(B组,n=19)及PEGIFNα单药治疗组(C组,n=19),比较治疗48周联合应答率,并分析影响疗效的因素。多组间比较采用单因素方差分析,计数资料比较采用χ~2检验,疗效预测采用受试者工作特征曲线和Cox多因素回归分析。结果治疗48周时,A组的联合应答率为27.78%(10/36),高于B组5.26%(1/19)和C组5.26%(1/19)(P值均为0.045);12周的HBe Ag下降值、24周HBe Ag下降值和24周HBV DNA下降值预测联合应答的阴性预测值分别为90.0%、94.44%和94.55%。24周HBV DNA水平103拷贝/ml和24周HBe Ag下降值1.06 log10S/CO是联合应答的独立预测因素。结论 PEG-IFNα治疗12周HBV DNA仍≥105拷贝/ml的HBe Ag阳性CHB患者,联合ADV可以提高48周联合应答率。24周HBe Ag下降值和24周HBV DNA下降值预测联合应答的阴性价值高。     

聚乙二醇干扰素α-2a治疗HBeAg阳性慢性乙型肝炎患儿的疗效观察

目的研究聚乙二醇干扰素(PEG-IFN)α-2a治疗HBe Ag阳性的慢性乙型肝炎(CHB)患儿的疗效。方法随机入组的来自昆明市第三人民医院31例2~16岁儿童CHB患儿,按年龄分为小龄组(2~6岁,n=17)及大龄组(7~16岁,n=14)。所有患儿均接受PEG-IFNα-2a治疗(首剂104μg/m2,1次/周,逐渐增加剂量至135μg/周),疗程24~72周不等。研究过程中监测ALT、HBV DNA、HBV血清学标志物及HBs Ag定量水平等指标,比较两年龄组在不同时间点的生化学、病毒学、血清学应答,分析疗效与年龄、疗程及治疗过程中HBs Ag定量水平动态变化的关系及安全性。计量资料组间比较采用t检验,计数资料比较采用χ2检验。结果小龄组与大龄组各时间点的生化学、病毒学应答方面差异均无统计学意义(P值均>0.05)。治疗24周时小龄组的HBs Ag阴转率明显高于大龄组(41.2%vs 7.1%;χ2=4.644,P<0.05);治疗52及72周时小龄组的HBs Ag定量水平分别为129.22±78.99和51.80±31.54 IU/ml;大龄组患儿52及72周HBs Ag定量水平分别为4677.12±2557.85和1031.37±546.37 IU/ml,与基线相比小龄组患儿52及72周HBs Ag定量水平下降幅度显著高于大龄组,差异有统计学意义(t值分别为2.25、2.23,P值均<0.05)。治疗52周,小龄组与大龄组HBV DNA阴转率、HBe Ag阴转率、HBe Ag血清学转换率、HBs Ag清除率与血清学转换率均有增加的趋势,但差异均无统计学意义(P值均>0.05)。延长治疗至72周的患儿HBV DNA阴转率100%,HBe Ag血清学转换率为80%,HBs Ag血清学转换率为60%。25例停药随访的患儿均无复发。研究中常见的不良反应为流感样症状、血象改变、食欲下降。治疗前后身高、体质量与同龄儿童差异无统计学意义。结论对于小儿CHB而言,PEG-IFNα-2a是可选治疗方案,PEG-IFNα-2a的疗效与患儿年龄和疗程有关。年龄越小,HBs Ag定量水平下降幅度越大,HBs Ag阴转率越高;延长疗程可提高疗效。治疗过程中HBs Ag定量水平变化具有预测疗效的价值。儿童应用安全性较好。     

阿德福韦酯联合聚乙二醇干扰素α-2a治疗HBeAg低效价慢性乙型肝炎的疗效观察

目的探讨阿德福韦酯联合聚乙二醇干扰素α-2a治疗HBeAg低效价慢性乙型肝炎的疗效。方法选择2013-02~2015-02该院收治的HBeAg低效价慢性乙型肝炎患者168例,按照随机对照表法分为观察组和对照组各84例,对照组单纯给予阿德福韦酯治疗,观察组在此基础上联合聚乙二醇干扰素α-2a治疗,均治疗48周。观察比较两组临床疗效和用药安全性。结果观察组HBeAg转阴率和HBeAg血清学转换率分别为78.6%和59.5%,显著高于对照组的56.0%和20.2%,P均0.05。治疗后两组肝组织HBV-DNA载量均低于治疗前(P0.05),但两组比较差异无统计学意义(P0.05)。观察组治疗后HBeAg效价和肝组织HBVcccDNA载量明显低于对照组(P0.05)。结论阿德福韦酯联合聚乙二醇干扰素α-2a治疗HBeAg低效价慢性乙型肝炎的临床疗效确切,可有效改善病毒学及血清学应答,但仍需进一步探讨。     

干扰素α与阿德福韦酯不同联合方法治疗HBeAg阳性慢性乙型肝炎的疗效

目的 观察IFNα联合阿德福韦酯(ADV)治疗HBeAg阳性慢性乙型肝炎(CHB)的临床疗效,探讨理想的联合治疗方案.方法 2005年1月至2009年6月纳入河北医科大学第三医院HBeAg阳性CHB患者156例.56例患者HBV DNA≥1×107拷贝/mL、或纤维化分期≥S3、或既往单药治疗失败(复发)者,予以初始IFNα联合ADV治疗;52例未达上述指标患者接受初始IFNα单药治疗.24周时依据患者HBV DNA、HBeAg、HBsAg变化调整治疗方案:16例取得早期应答的初始IFNα联合ADV治疗组患者调整为IFNα单药维持治疗,其余患者与初始IFNα单药治疗组未达到早期应答者共同接受IFNα联合ADV治疗.另选48例作为标准治疗组,接受全程IFNα单药治疗.48周时复评全部患者HBV DNA、HBeAg、HBsAg定量,并决定是否延长疗程.最终于72周评估患者疗效、安全性、耐药复发等,数据行卡方检验.结果 治疗24周,初始IFNα联合ADV治疗组早期应答率达28.6%,其中HBV DNA阴转率、ALT复常率(53.6%,62.5%)与初始IFNα单药治疗组(32.7%,x2=4.78;40.4%,x2=5.21)、标准治疗组(27.1%,x2=5.28;37.5%,x2=6.46)比较,差异均有统计学意义(均P<0.05),且HBeAg阴转率较标准治疗组更高(39.3%比18.8%,x2=7.48,P<0.05).48周时,初始IFNα联合ADV治疗组16例取得早期应答者停用ADV后,5例HBeAg复阳,3例病毒学反弹;HBV DNA阴转率为73.2%,HBeAg转换率为41.1%,HBsAg清除率为12.5%.其中96例接受不同联合方法治疗的患者HBV DNA阴转率、HBeAg转换率、HBsAg清除率分别为65.6%、33.3%和8.3%.72周时不同联合方法治疗组患者整体复发率与标准治疗组相当,HBsAg清除率上升2.7%.结论 IFNa联合ADV抗病毒治疗对提高应答率优势明显.结合患者基线特征、治疗反应,制订不同联合方案,不失为当前CHB抗病毒优化治疗理想策略之一.

Abstract：

Objective To investigate the efficacy of interferon α(IFNα)and adefovir dipivoxil (ADV)combination therapy in HBeAg positive chronic hepatitis B(CHB)patients and to explore the optimized strategy for individualized treatment.Methods A total of 156 HBeAg positive CHB patients were enrolled in the study from January 2005 to June 2009 in the Third Affiliated Hospital of Hebei Medical University.Fifty-six CHB patients with hepatitis B virus(HBV)DNA≥1 X 107copy/mLand/or liver fibrosis stage≥S3,or previous monotherapy failure(relapse)were treated with initial IFNα and ADV combination therapy.Fifty-two patients who didn't meet any of the above baseline characteristics received initial IFNα monotherapy.The remaining 48 patients treated with IFNα monotherapy for full treatment duration were considered as control.At week 24 of treatment,the treatment regimens were adjusted according to quantitative changes of HBV DNA,HBeAg and HBsAg:16 patients who achieved early response in group of initial IFNα and ADV combination therapy subsequently received IFNα monotherapy,the other patients in group of initial combination therapy together with patients who did not achieved early response in group of initial IFNα monotherapy subsequently received IFNα and ADV combination treatment.The HBV DNA levels,HBeAg and HBsAg titers were detected at the end of 48 weeks of treatment to determine the treatment duration.The treatment efficacy,safety,drug resistance and relapse rates were finally evaluated at week 72.All data were analyzed using chi square test.Results At week 24,the early response rate in group of initial combination therapy was 28.6%,and the HBV DNA negative rate and alanine aminotransferase(ALT)normalization rate were significantly higher than those in groups of initial IFNα monotherapy and control(53.6%vs 32.7%vs 27.1%and 62.5%vs 40.4%vs 37.5%,respectively,P<0.05);in addition,HBeAg loss rate was higher than control group(39.3%vs 18.8%,x2=7.48;P<0.05).At week 48,five of 16 patients who achieved early response developed HBeAg reversion and three cases accompanied with virological breakthrough in group of initial combination therapy after switching to IFNα monotherapy,while the rates of HBV DNA negative,HBeAg seroconversion and HBsAg clearance were 73.2%,41.1%and 12.5%,respectively.The HBV DNA negative rate,HBeAg seroconversion rate and HBsAg clearance rate in 96 patients Who had received different combination treatment regimens were 65.6%,33.3%and 8.3%,respectively.At week 72,the relapse rate in individualized treatment group was comparable to those in control group,while HBsAg clearance rate increased 2.7%in individualized treatment group.Conclusions IFNα and ADV combination treatment could improve early biochemical and virological responses.Individualized treatment strategy based on baseline characteristics and treatment responses may be helpful for optimizing antiviral treatment in CHB patients.     

不同疗程干扰素联合核苷(酸)类似物治疗HBeAg阳性慢性乙型肝炎的疗效

近年认为选用不同抗病毒作用机制的药物联合治疗慢性乙型肝炎可能是较佳的策略.本研究探讨不同疗程聚乙二醇干扰素(Peg-IFN)α -2a与重组人干扰素(IFN)α-2b联合核苷(酸)类似物治疗HBeAg阳性慢性乙型肝炎的疗效,探索提高抗病毒疗效的治疗方案.     

干扰素α-2b联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎近期疗效观察

目的探讨干扰素a-2b联合阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的近期疗效及安全性。方法将HBeAg阳性慢性乙型肝炎患者随机分为单药治疗组（40例）和联合治疗组（42例）,分别应用干扰素a-2b单药治疗或联合阿德福韦酯抗病毒治疗,疗程48周。结果在治疗结束时,联合治疗组ALT复常率为85．7％,HBVDNA阴转率为71．4％,HBeAg转阴率为61．9％,HBeAg血清学转换率为45．2％,均显著高于单药治疗组（分别为60．0％、45．0％、37．5％、25．0％,P〈0．05）;联合治疗组不良反应发生率与单药治疗组比无统计学差异（P〉0．05）。结论干扰素联合阿德福韦酯可提高慢性乙型肝炎抗病毒疗效且安全性良好。     

阿德福韦酯和恩替卡韦的疗效比较

已有大量研究数据表明核苷(酸)类似物抗HBV的效果良好,并被推荐使用~([1]).但随着临床应用病例数的增多,如何使初治患者尽可能避免或减少因长期应用所致的耐药性已成为临床医师需要积极面对的问题.     

De novo combination therapy with lamivudine and adefovir dipivoxil in chronic hepatitis B patients

AIM: To investigate the appropriate time for combination therapy in HBeAg positive chronic hepatitis B (CHB) patients with decompensated cirrhosis.METHODS: Thirty HBeAg positive CHB patients with decompensated cirrhosis were enrolled in the study. All of the patients were given 48 wk combination therapy with lamivudine (LAM) and adefovir dipivoxil (ADV). Briefly, 10 patients were given the de novo combination therapy with LAM and ADV, whereas the other 20 patients received ADV in addition to LAM after hepatitis B virus (HBV) genetic mutation.RESULTS: Serum alanine aminotransferase and total bilirubin were both improved in the two groups at 4, 12, 24 and 48 wk after treatment. Serum albumin was also improved at 24 and 48 wk after combination therapy in both groups. The serum HBV DNA level was still detectable in every patient in the two groups at 4 and 12 wk after combination treatment. However, in the de novo combination group, serum HBV DNA levels in 4 (40%) and 9 (90%) patients was decreased to below 1×10³ copies/mL at 24 and 48 wk after the combination treatment, respectively. In parallel, serum HBV DNA levels in 2 (20%) and 8 (40%) patients in the add-on combination group became undetectable at 24 and 48 wk after combination treatment, respectively. Furthermore, 6 (60%) patients in the de novo combination group achieved HBeAg seroconversion after 48 wk treatment, whereas only 4 (20%) patients in the add-on combination group achieved seroconversion. Child-Pugh score of patients in the de novo combination group was better than that of patients in the add-on combination group after 48 wk treatment. Moreover, patients in the de novo combination group had a significantly decreased serum creatinine level and elevated red blood cell counts.CONCLUSION: De novo combination therapy with LAM and ADV was better than add-on combination therapy in terms of Child-Pugh score, virus inhibition and renal function.     

拉米夫定单药及其初始联合阿德福韦酯治疗失代偿期乙型肝炎肝硬化的疗效比较

目的 比较拉米夫定与阿德福韦酯初始联合或拉米夫定单药治疗失代偿期乙型肝炎肝硬化患者2年的疗效.方法 60例失代偿期乙型肝炎肝硬化接受初始拉米夫定(LAM)与阿德福韦酯(ADV)联合抗病毒治疗,为初始联合组;55例接受拉米夫定(LAM)单药抗病毒治疗,为LAM单药组每1～3个月检测患者肝功能、肾功能、甲胎蛋白、乙型肝炎病毒标志物、血清HBV DNA、凝血酶原时间(PT)、肝脏的超声或CT检查,分别在治疗12个月和24个月时比较疗效.组间均数比较用Mann-Whitney检验,相关性分析时采用Pearson双侧t检验.结果 初始联合组45例治疗12个月时血清HBV DNA阴转率为51.1%(23/45),而40例LAM单药组HBV DNA阴转率为47.5%(19/40);至24个月时,初始联合组HBV DNA阴转率达86.7%(39/45),LAM单药组为60.0%(24/40),两组间差异有统计学意义(P＜0.05).初始联合组治疗24个月时,HBeAg血清学转换率为43.5%(10/23),LAM单药组HBeAg血清学转换率为30.0%(6/20),两组间差异有统计学意义(P＜0.05).ALT复常率在初始联合组治疗12个月时为71.1%(32/45),LAM单药组为65.0%(26/40),至24个月时两组ALT复常率分别为88.9%(40/45)和75.0%(30/40),差异有统计学意义(P＜0.05).初始联合组在治疗12个月和24个月时,分别有4.4%(2/45)和6.7%(3/45)发生病毒学突破,但均未检测到病毒学变异,LAM单药组在12个月和24个月时分别有22.5%(9/40)和37.5%(15/40)发生病毒学突破,并分别有17.5%(7/40)和32.5%(13/40)的患者中检测到病毒学变异,均较联合治疗组高(P＜0.05).初始联合治疗更能改善肝功能,Child-Turcotte-Pugh评分和终末期肝病模型评分亦有更明显下降.随访24个月,LAM和ADV初始联合治疗组累计死亡或肝移植率为16.7%,LAM单药组累计死亡或肝移植发生率为20.0%.两组均未发现有血清肌酐超过正常值上限的病例.结论 LAM与ADV初始联合治疗失代偿期乙型肝炎肝硬化患者能更明显抑制HBV复制,改善肝功能各项指标,降低病死率,值得临床应用.

Abstract：

Objective To compare the efficacy of Lamivudine (LAM) monotherapy and combination therapy with Adefovir Dipivoxil (ADV) for patients with hepatitis B virus (HBV) -related decompensated cirrhosis for 2 years.Methods A total of 115 patients with HBV-related decompensated cirrhosis were erolled in this study,among 60 patients were treated with LAM combined with ADV and 55 were treated with LAM.The liver and kidney functions,HBV DNA,HBV-M,AFP,Ultrasond or CT scan of liver were tested every l-3months.the treatment efficacy was evaluated by month 12 and 24.Results By month 12,the HBVDNA negative rates of combination therapy group and LAM monotherapy group were 51.1% (45 cases) and 47.5% (40 cases) respectively,by month 24 the rates were 86.7% and 60.0% respectively.By month 24 the HBeAg negative rates of combination therapy group and LAM monotherapy group were 43.5% and 30.0%respectively,with significant difference existed between the two therapy groups (P ＜ 0.05).By month 24,the ALT normalization rates of the two groups were 88.9% and 72.5% respectively.Viral breakthrough happened in 2 cases (4.4%) by month 12 and 3 cases (6.7%) by month 24 in LAM and ADV combination group,but no viral resistance observed.Viral breakthrough happened in 9 cases (22.5%) by month 12 and 15 cases (37.5%)by month 24 in LAM monotherapy group with viral resistance observed in 7 cases (17.5%) by month 12 and 13 cases (32.5) by month 24.Significant difference existed between the two groups (P ＜ 0.05).Improvement of liver function was more obviously in the combination group.The accumulative total mortality or liver transplantation rate were 16.7% and 20.0% respectively in combination therapy group and LAM monotheapy group.No renal dysfunction observed in both groups.Conclusion LAM combined with ADV is better choice for patients with HBV-related decompensated cirrhosis as compared to LAM monotherapy.     

恩替卡韦或其联合阿德福韦酯补救治疗拉米夫定联合阿德福韦酯应答不佳的慢性乙型肝炎

目的 对拉米夫定(LAM)初治耐药后,LAM联合阿德福韦酯(ADV)应答不佳的慢性乙型肝炎患者,分别采用恩替卡韦(ETV)单药或ETV联合ADV进行补救治疗,比较两种补救方案的疗效.方法 对LAM初治耐药后应用LAM联合ADV应答不佳的40例患者,分别应用ETV 1.0 mg/d(14例)及ETV 0.5 mg/d联合ADV 10mg/d (26例)两种方案进行补救治疗,至少观察48周,定期监测HBV DNA、肝肾功能、HBV标志物等指标.根据资料不同分别采用t检验Wilcoxon检验或x2检验.结果 两组患者采用补救治疗前的基线情况差异无统计学意义.分别采用两种补救方案治疗后,两组患者HBV DNA水平均有下降,但ETV联合ADV组下降幅度较大.补救治疗24周时,ETV 1,0mg组有28.6％％(4例)达到HBV DNA转阴,ETV联合ADV组则有80.8％ (21例)达到HBV DNA转阴,x2=8.469,P=0.004,差异具有统计学意义;48周时,ETV1.0mg组仍仅有4例患者HBV DNA转阴,而ETV联合ADV组全部26例患者均达到HBV DNA转阴.补救治疗24周时,ETV 1.0mg组有42.9％(6例)患者ALT复常,ETV联合ADV组有92.3％ (24例)患者ALT复常,x 2=9.337,P=0.002,差异具有统计学意义;48周时,ETV 1.0mg组有57.1％(8例)患者ALT复常,而ETV联合ADV组所有患者均达到ALT复常.补救治疗48周时,ETV 1.0mg组有1例患者发生HBeAg血清学转换,ETV联合ADV组有4例患者发生HBeAg血清学转换.结论 对于LAM耐药后LAM联合ADV应答不佳的慢性乙型肝炎患者,采用ETV联合ADV的补救方案较ETV单药1.0mg的方案更为有效,可以实现更好的病毒学及生物化学应答.     

拉米夫定和阿德福韦酯初始联合与恩替卡韦单药治疗慢性乙型肝炎的疗效和安全性比较

目的 观察拉米夫定(LAM)和阿德福韦酯(ADV)初始联合与恩替卡韦(ETV)单药治疗慢性乙型肝炎的疗效,并比较两者的安全性.方法 选择我院2007年6月-2008年1月符合抗病毒治疗的未曾使用核苷(酸)类似物的初治慢性乙型肝炎患者120例,分为联合组60例和单药组60例,联合组应用LAM 100 mg,ADV 10 mg,每日1次;单药组应用ETV 0.5 mg,每日1次.分别在基线、12、24、48、96周时留取血清,采用全自动分析生物化学仪检测肝功能、肾功能、血生物化学指标;采用化学发光法定量检测HBsAg和HBeAg;采用实时荧光定量PCR检测HBV DNA水平;采用PCR产物直接测序法检测病毒耐药基因.组间比较采用配对t检验,率的比较采用χ2检验.结果 (1)联合组54例,单药组50例完成了48周随访,联合组51例,单药组48例完成了96周随访.两组治疗前性别、年龄、血清ALT、血肌酐、HBV DNA、HBsAg水平及HBeAg阳性率,差异无统计学意义,具有可比性.(2)两组在治疗12周和24周时,HBV DNA＜300拷贝/ml和HBV DNA＜1000拷贝/ml的比率,差异无统计学意义.治疗12周时,单药组和联合组HBV DNA下降＜1 log10拷贝/ml的分别为3.7%(2/54)和18.0%(9/50),两组比较,χ2=5.556,P＜0.05,差异有统计学意义.(3)治疗48周时,单药组和联合组的ALT复常率、HBVDNA＜1000拷贝/ml的比率、HBeAg血清转换率以及与基线比较HBV DNA下降绝对值,差异均无统计学意义.联合组与单药组HBV DNA＜300拷贝/ml的患者分别为90.7%(49/54)和76.0%(38/50),两组比较,χ2=4.125,P＜0.05,差异有统计学意义.(4)治疗96周时,HBV DNA＜300拷贝/ml、HBV DNA＜1000拷贝/ml患者比率和HBeAg血清转换率,联合组分别为96.1%(49/51)、98.0%(50/51)、41.7%(15/36),单药组分别为79.2%(38/48)、87.5%(42/48)、16.7%(6/36),两组比较,χ2值分别为6.639、4.180、5.445,P值均＜0.05,差异有统计学意义;但两组患者与基线比较HBV DNA和HBsAg下降绝对值以及ALT复常率差异无统计学意义.(5)治疗96周时,联合组未见病毒学突破和耐药发生,而单药组累计发生病毒学突破4例,其中3例(6.3%,3/48)检测到ETV相关耐药基因变异位点,2例患者在基线时存在LAM相关耐药基因变异位点(rtL180M+M204V).(6)治疗48、96周时,联合组与单药组患者血肌酐水平及治疗前后血肌酐升高水平差异无统计学意义.在治疗期间,两组均无血清肌酐水平超过正常上限或由于肌酐升高0.5 mg/dl而调整剂量的患者.结论 LAM和ADV初始联合治疗,在减少病毒学突破和耐药发生,以及提高HBeAg血清转换率方面优于ETV单药治疗.

Abstract：

Objective To compare the efficacy and safety of Lamivudine (LAM) plus Adefovir dipivoxil (ADV) combination therapy and Entecavir(ETV) monotherapy for chronic hepatitis B patients.Methods 120 patients with chronic hepatitis B managed in a single-centre clinical practice (median 96 weeks)were split into 2 cohorts,one was treated with de-novo combination Lamivudine (100 mg/day) plus Adefovir (10 mg/day) (LAM+ADV),thc other with Entecavir (0.5 mg/day) monotherapy.Serum levels of ALT,creatinine,HBsAg,HBeAg and HBV viral load,together with genotypic resistence were analyzed at 0,12,24,48,96 weeks,respectively.HBV DNA was determined by real-time PCR.HBsAg and HBeAg were assessed by chemiluminescence.Serum levels of ALT and creatinine were detected by automatic biochemical analyzer.HBV genotypic resistence was tested by direct sequencing.Results (1) At the time point of 96 weeks,a total of 99 patients(51 cases in combination therapy cohort and 48 case in monotherapy cohort) were compared.The baseline characteristics as for HBV viral load,median age,serum levels of ALT and creatinine were compatible between combination therapy cohort and monotherapy cohort.(2) The rates of HBV DNA ＜300 copies/ml and HBV DNA ＜ 1000 copies/ml had no significant difference between LAM + ADV and ETV cohorts by the 12 and 24 weeks (P ＞ 0.05).(3) At the time point of 48 weeks,the rates of HBV DNA＜1000copies/ml,HBeAg seroconversion,and ALT normalization were similar in both cohorts,though the rate of HBV DNA ＜ 300 copies/ml was obviously higher in combination therapy cohort than that of monotherapy cohort (90.7% vs 76%,P ＜ 0.05).(4) At the time point of 96 weeks,the rates of HBV DNA ＜ 300 copies/ml (96.1% vs 79.2%),HBV DNA ＜ 1000 copies/ml (98% vs 87.5%) and the HBeAg seroconversion (41.7% vs 16.7%) were markedly higher in combination therapy cohort than those of monotherapy cohort statistically (P ＜ 0.05 for all).The mean values of decreases for HBV viral loads and HBsAg levels were smilar in both cohorts at 48 and 96 weeks.(5) Elevated serum creatinine not be found in both cohorts at the end of treatment.(6) No virological breakthrough occurred in combination therapy cohort at the end of treatment.Four patients in monotherapy cohort were found with virological breakthrough at 96 weeks and three cases among were confirmed to be of variants associated with ETV resistance (rtLl80M + T184L + M204V).Conclusions Present study suggests that Lamivudine plus Adefovir dipivoxil de-novo combination therapy was more efficacious than Entecavir monotherapy for CHB patients and the tolerance is compatible.     

阿德福韦治疗乙型肝炎e抗原阳性慢性乙型肝炎3年的临床研究

目的评价阿德福韦酯（ADV）10 mg／d治疗HBeAg阳性的慢性乙型肝炎患者52、104、156周末的临床疗效和安全性。方法第一阶段：为随机、双盲、安慰剂对照研究,患者按3：1的比例随机接受ADV 10 mg（36例）或安慰剂（12例）治疗,每日1次,持续12周。第二阶段：患者均接受开放的ADV 10mg治疗,每日1次,持续28周。第三阶段：完成40周的治疗后,最初接受ADV治疗的患者重新按2：1的比例随机分入ADV组（24例）或安慰剂组（12例）接受相应的治疗,持续12周。即分为A、B、C 3组,A组：12例,前12周为安慰剂治疗,后40周为ADV治疗;B组：24例,52周均为ADV治疗;C组：12例,前40周为ADV治疗,后12周为安慰剂治疗。第四阶段：所有仍在研究中的患者继续接受开放的ADV 10 mg治疗共208周（4年）。结果（1）治疗12周后,HBV DNA水平降低,安慰剂组为-0．2 log10拷贝／ml,ADV组为-3．7 log10拷贝／ml,差异有统计学意义（t=8．0,P〈0．01）。（2）治疗12周后,ALT复常率,安慰剂组为0（0／11）,ADV组为10／36（27．8％）,差异有统计学意义（χ^2=3．9,P〈0．05）。（3）治疗40周后,3个治疗组ALT复常率相似。在B组,ALT复常率呈累积性增加。而在C组,ALT复常率显著降低。（4）治疗40周后,3个治疗组HBV DNA水平对数值降低中位数相似。40周后继续12周ADV治疗可以保持HBV DNA水平持续降低至52周。而在C组,HBV DNA水平降低被显著逆转。（5）治疗40周后,3个治疗组HBV DNA转阴率相似。在C组,52周时HBV DNA转阴率显著降低。（6）对于B组,HBeAg消失患者在52周时为12．5％（3／24）。两因素（血清HBeAg转阴,血清抗-HBe转阳）和三因素（血清HBeAg转阴,血清抗-HBe转阳且HBV DNA水平下降到≤10^5拷贝／ml）血清转换比率均为8．3％（2／24）。（7）治疗104周末及156周末,HBV DNA被持续抑制,104周HBV DNA水平对数值降低中位数为-4．2 log10拷贝／ml,156周为-4．3 log10拷贝／ml。HBV DNA阴转率均为31．0％,ALT复常率分别为46．3％、85．4％,HBeAg阴转率分别为23．8％、31．0％,HBeAg血清转换率均为23．8％。（8）研究期间各治疗组肌酐及血磷值平均水平与基线相比无变化,无数据表明肾脏安全性问题。结论ADV 10 mg／d治疗HBeAg阳性慢性乙型肝炎,可明显抑制HBV DNA的复制,使ALT复常,促进HBeAg的血清学转换,使用安全且耐受性良好。     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者的组织学改变

目的评价国产阿德福韦酯（ADV）治疗HBeAg阳性慢性乙型肝炎患者的组织学改变。方法采用随机、双盲、安慰剂平行对照的研究方法，将HBeAg阳性慢性乙型肝炎患者按照1：1的比例分为A、B二组，A组120例服用ADV 10mg每日1次，连续口服48周；B组120例服用安慰剂10mg每日1次，口服12周，12周后改为口服ADV36周。对其中21例患者完成了48周治疗，并行两次肝穿刺。按照Knodell肝组织学活动指数（HAI）评分法和Ishak评分系统，盲法评价两次肝穿切片的组织学和纤维化改变。结果21例患者治疗前后两次肝组织学观察表明：治疗前Knodell炎症评分和Ishak纤维化评分中位数分别为11分和3分，治疗48周后中位数分别下降为5分和2分，治疗前后比较差异有统计学意义（P〈0．05）。ADV治疗48周后组织学改善率为43％，纤维化改善率为52％。结论国产ADV（商品名：名正）治疗HBeAg阳性慢性乙型肝炎患者48周，可以明显改善肝组织炎症、坏死和纤维化病变。     

六味五灵片联合阿德福韦酯治疗慢性乙型肝炎疗效观察

目的观察六味五灵片联合阿德福韦酯治疗慢性乙型肝炎(CHB)的效果。方法将82例CHB患者随机分成六味五灵片联合阿德福韦酯组(治疗组)44例和阿德福韦酯组(对照组)38例,疗程均为24周,观察临床症状、体征、生物化学、病毒复制指标的变化。结果治疗24周后,治疗组患者综合疗效、肝功能复常率、HBeAg、HBVDNA低于检测下限的比率均优于对照组,差异有统计学意义(P<0.05)。结论六味五灵片联合阿德福韦酯治疗慢性乙型肝炎在改善患者症状、恢复肝功能和抗病毒等方面均有很好疗效。