恩替卡韦治疗拉米夫定失效的慢性乙型肝炎7例临床观察

我们采用恩替卡韦(1.0mg/d)治疗7例拉米夫定治疗失效的患者,取得一定疗效,现报道如下。资料与方法7例均为我院门诊患者,诊断符合2000年9月中华医学会传染病与寄生虫病学分会、肝病学分会联合修订的《病毒性肝炎的诊断标准》。年龄(32±7)岁,HBeAg均阳性,服用拉米夫定至少1年,服     

恩替卡韦与拉米夫定治疗慢性乙型肝炎随机、双盲、双模拟对照研究

目的以拉米夫定（LVD）为对照,评估恩替卡韦（ETV）治疗中国成人慢性乙型肝炎（CHB）的抗病毒疗效和安全性。方法多中心（26个中心）、随机、双盲、双模拟的对照研究。519例核苷类初治的CHB患者,随机分为ETV组（0．5mg／d）258例和LVD组（100mg／d）261例,用药时间至少52周。应用两种HBV定量法（bDNA和PCR）于12、24、36和48周检测血清病毒载量,每隔4周随访患者,记录不良事件和实验室异常的数据,以监测研究药物的安全性。结果ETV和LVD两组患者的基础人口学、临床和病毒学特征相似。经过48周的治疗,到达主要疗效终点者,ETV组为90％,LVD组仅69％（P〈0．0001）。HBV DNA的载量（PCR定量）,ETV组平均下降5．9lg拷贝／ml,LVD组平均下降4．3lg拷贝／ml,二者相差超过1．5lg拷贝／ml（P〈0．0001）。用PCR法,ETV组中有76％的患者测不到病毒（〈300拷贝／ml）,而LVD组中仅为43％。ALT的复常,ETV组也优于LVD组,分别为90％和78％（P=0．0003）。两组患者HBeAg的血清学转换率分别为15％和18％,差异无统计学意义（P=0．39）。两组患者不良事件的发生率基本相似,分别为60％和56％,严重不良事件的发生率分别为3％和5％。在治疗期间,没有死亡病例。结论ETV治疗核苷类初治CHB患者,抑制病毒和改善肝脏生化功能方面均优于LVD,安全性与LVD相当。     

恩替卡韦治疗拉米夫定失效的慢性乙型肝炎患者3年临床研究

目的评价恩替卡韦对重庆地区拉米夫定治疗失效的CHB患者3年的疗效和安全性。方法选取拉米夫定治疗失效的CHB患者32例,其中恩替卡韦组28例(剂量1.0 mg/d),安慰剂组4例。完成12周的双盲冶疗后,所有患者均接受开放的恩替卡韦1.0mg/d,持续治疗至168周。定期检测血清HBV DNA水平、HBeAg、抗-HBe和肝功能的变化情况。结果在接受恩替卡韦治疗后,患者血清HBV DNA水平对数值的均数在2周内由9.14log10拷贝/ml迅速下降至6.72log10拷贝/ml,其后持续平稳下降,4、8、12、24、48周分别下降至6.28 log10、5.46 log10、5.10 log10、4.49 log10、4.41 log10拷贝/ml,至96周时下降至3.91 log10拷贝/ml,其后下降速度减慢,至144周和168周时分别为4.05 log10、4.21 log10拷贝/ml。HBV DNA>10~5拷贝/ml的百分比治疗前为100%,随着服药时间的延长逐渐下降,在12周时下降至46.43%,其后仍逐渐下降,到96周时仅为17.86%。与其相反,HBV DNA<10~3拷贝/ml的百分比在治疗前为0,从第8周开始逐渐上升(7.14%),12周时为10.71%,尤其在96周明显上升至46.43%,到168周时为57.14%。168周末HBeAg阴转率为10.07%。服用恩替卡韦后ALT下降较迅速,12周后均数达正常水平,且3年内持续低于40 U/L。3年治疗期间,患者不良事件发生率为21%,有1例发生严重不良事件。结论恩替卡韦治疗拉米夫定失效的CHB患者,可明显抑制HBV DNA复制,HBV DNA水平降低迅速且持久;能促进ALT复常;使用安全,耐受性良好。     

恩替卡韦治疗拉米夫定失效慢性乙型肝炎一年的疗效

目的评价恩替卡韦（ETV）对拉米夫定（LVD）失效的慢性乙型肝炎（CHB）患者治疗1年的疗效和安全性。方法选择LVD治疗失效的CHB患者145例，按4：1比例随机分为ETV组（1．0mg／d）116例和安慰剂组29例，治疗12周后，所有患者进入36周的开放用药阶段（ETV1．0mg／d）。观察血清HBVDNA水平、乙型肝炎e抗原（HBeAg）、肝生化功能的变化和不良事件的发生率。结果经12周的治疗，ETV组患者血清HBVDNA平均下降4．30log10拷贝／ml（聚合酶链反应法），安慰剂组下降0．15log10拷贝／ml（P＜0．01）。第12周时，在基线丙氨酸转氨酶（ALT）异常的患者中，ETV组的ALT复常率明显高于安慰剂组（分别为68％与6％，P＜0．01）。两组间不良事件的总发生率相当（33％与28％）。经48周的治疗，服用ETV48周患者HBVDNA的下降幅度为5．08log10拷贝／ml；服用ETV36周患者HBVDNA的下降幅度为4．86log10拷贝／ml；在治疗前ALT异常的患者中，上述两组ALT的复常率分别是85％和90％。治疗结束时，在基线HBeAg阳性的患者中，有6．2％（8／129）出现血清学转换。在治疗期间，未发生与耐药相关的变异。每天服用ETV1．0mg，持续48周的安全性和耐受性良好。结论ETV（1．0mg／d）治疗LVD失效的CHB患者具有显著的抗病毒和临床疗效。     

恩替卡韦替代拉米夫定治疗慢性乙型肝炎的疗效观察

目的观察恩替卡韦(ETV)替代拉米夫定(LAM)治疗未出现病毒变异的拉米夫定经治慢性乙型肝炎患者的疗效。方法 43例经拉米夫定治疗96周而没有出现病毒学突破的慢性乙型肝炎患者,分为2组,A组23例继续服用拉米夫定,100mg/d;B组20例,改口服恩替卡韦,0.5mg/d,随访3年,每12周检测患者肝功能、HBVDNA定量。结果 A组在继续治疗的第48、96、144周出现病毒学突破的患者数分别为2、6、9例。B组在换药的第48、96、144周出现病毒学突破的患者数分别为0、0、1例。结论恩替卡韦替代拉米夫定治疗未出现耐药的拉米夫定经治慢性乙型肝炎患者,其疗效与恩替卡韦初治相仿。     

恩替卡韦治疗慢性乙型肝炎的临床研究

目的探讨恩替卡韦治疗慢性乙型肝炎的疗效和安全性。方法选取慢性乙型肝炎患者77例,随机分为试验组和对照组。试验组给予口服恩替卡韦治疗,对照组给予口服拉米夫定治疗,疗程48周。于治疗前、治疗后12周、24周、48周观察患者的肝功能、HBs Ag、HBe Ag、HBV DNA等指标的变化。结果治疗48周时,试验组和对照组ALT复常率分别为66.7%和63.2%,差异无统计学意义;试验组HBe Ag阴转率和血清学转换率分别为30.8%和25.6%,高于对照组的10.5%和7.9%(P均0.05);试验组HBV DNA阴转率为71.8%,高于对照组的44.7%(P0.05);试验组HBs Ag阴转率和血清学转换率分别为5.1%和2.6%,对照组为2.6%和0,2组差异均无统计学意义。所有患者未出现严重不良反应。结论恩替卡韦对于慢性乙型肝炎具有显著的抗病毒作用,效果优于拉米夫定,且无严重不良反应。     

恩替卡韦治疗慢性乙型肝炎的临床研究

目的评价恩替卡韦治疗慢性乙型肝炎(CHB)的疗效和安全性。方法72例CHB患者随机分配到治疗组和对照组,治疗组(30例)予恩替卡韦0.5mg/d;对照组(42例)予拉米夫定100mg/d疗程均48周,基础治疗相似。结果治疗组和对照组在治疗24周、48周时:血清HBV-DNA水平比基线值(log10copies/ml)平均下降分别为5.48、6.87和2.84、5.38;病毒应答率分别为53%、67%和21%、43%。均P<0.001,两组均有显著差异。ALT复常率分别为67%、77%和60%、67%,血清HBeAg阴转率、HBsAg消失率、不良事件发生率,均P>0.05,差异无统计学意义。无严重不良反应发生。结论恩替卡韦治疗慢性乙型肝炎,可在病毒学及生物化学方面取得显著疗效,且安全性良好,无耐药发生。     

恩替卡韦治疗拉米夫定失效的慢性乙型肝炎患者5年的临床疗效

目的 评价恩替卡韦(ETV)对重庆地区拉米夫定治疗失效的慢性乙型肝炎(CHB)患者5年的疗效和安全性.方法 选取拉米夫定治疗失效的CHB患者32例,随机分为ETV组(剂量1.0 mg/d)28例和安慰剂组4例,完成12周的双盲治疗后,患者均接受开放的ETV(剂量1.0 mg/d)治疗,持续治疗至240周.分别检测治疗2、4、8、12、24、48、96、144、168、240周时患者的血清HBV DNA水平、HBsAg与HBeAg状态和肝功能情况.双盲阶段HBV DNA水平变化情况经Mauchly"球对称"检验后采用重复测量数据方差分析;连续性变量的统计描述用均数±标准差(x±s)表示.结果 在接受ETV治疗后,12周时ETV组患者血清HBV DNA水平平均下降4.05 log10拷贝/ml,安慰剂组平均下降0.08 log10拷贝/ml(P<0.05).治疗240周时,ETV组患者HBV DNA水平均值下降至2.58 log10拷贝/ml.HBV DNA<3 log10拷贝/ml患者的百分比在治疗前为0,从第8周开始上升(6.25%),24周时为15.6%,尤其在96周明显上升(50%),到240周末为57.14%.240周末有2例出现HBsAg血清学转换,4例出现HBeAg血清学转换.服用ETV后ALT水平下降较迅速,12周后均数达正常水平,且5年持续低于40 U/L.5年治疗期间,患者不良事件发生率为21%,有1例出现严重不良事件. 结论 ETV(1.0 mg/d)治疗拉米夫定失效的CHB患者具有显著的抗病毒和临床疗效,且安全性及耐受性良好.     

恩替卡韦治疗慢性乙型肝炎肝衰竭临床研究

目的观察恩替卡韦治疗慢性乙型肝炎肝衰竭的疗效。方法对20例慢性乙型肝炎肝衰竭患者在综合治疗的基础上加用恩替卡韦治疗,16例患者为对照组,观察3个月的疗效。结果治疗组存活14例（70.0%）,对照组存活9例（56.3%,P〉0.05）,但治疗组患者血清HBV DNA全转阴。结论恩替卡韦治疗慢性乙型肝炎肝衰竭可强效抑制病毒复制,能否提高存活率还有待观察。     

恩替卡韦和拉米夫定治疗慢性乙型肝炎二年病毒学、血清学和生化结果的随机对比研究

目的比较恩替卡韦（ETV）和拉米夫定（LVD）初治慢性乙型肝炎（CHB）患者2年的疗效和安全性。方法519例核苷类似物初治CHB患者随机分别接受ETV（0．5mg／d）或LVD（100mg／d）治疗,第一阶段疗程52周。在48周时获得综合应答的患者于52周停止治疗并随访。在48周时获得部分应答的患者将继续双盲治疗至96周。评估患者HBVDNA水平、丙氨酸氨基转移酶（ALT）复常、血清学标志和安全性方面的情况,并且对基线时HBeAg（＋）患者评估HBeAg转阴和血清转换。结果共338例患者进入96周治疗,其中ETV组193例,I。VD组145例。疗程结束时,ETV组有74％患者HBVDNA测不出（〈300拷贝／m1）,96％患者ALT复常。I。VD组HBVDNA测不出和ALT复常率分别为41％和82％。ETV组和LVD组实现HBeAg血清学转换的比例分别为11％和19％。总计2年内所有经治患者HBVDNA的累计转阴率ETV组为79％,LVD组为46％（P〈0．0001）。两组的不良事件和安全性特征相当。结论初治患者中,ETV治疗96周的HBVDNA抑制率和AI。T复常率优于I。VD,而两者的安全性相当。【关键词】乙型肝炎病毒;慢性乙型肝炎;恩替卡韦;拉米夫定;临床试验     

A one-year trial of entecavir treatment in patients with HBeAg-positive chronic hepatitis B

To evaluate the efficacy and safety of entecavir （ETV） in hepatitis Be antigen （HBeAg）-positive chronic hepatitis B （CriB） patients who had not received a nucleoside analogue and who had failed in lamivudine （LVD） therapy. METHODS： Sixty-one patients were divided into three groups. Forty-two patients who had not received a nucleoside analogue were randomized into two groups： group A （n = 21） received LVD 100 mg/d and group B （n -- 21） received ETV 0.5 mg/d. The remaing 19 patients treated with LVD （n = 19）, who switched to ETV 1.0 mg/d served as group C. All patients were treated for 48 wk. HBV DNA levels were measured with polimerase- chain-reaction （PCR） analysis. Liver function tests, HBV serology and safety assessments were also conducted. RESULTS： Significantly more patients in group B （52.1% and 71.4%） had undetectable HBV DNA levels than in groups A （35.8% and 38%; P 〈 0.0001） and C （10.6% and 21.1%, P 〈 0.0001） at wk 24 and 48, respectively. At wk 48, ALT levels were normalized in more patients in group B （85.7%） than in groups A （76.2%） and C （74%）. CONCLUSION： ETV had a significantly higher response rate than LVD in patients with HBeAg-positive CriB who had not previously received a nucleoside analogue; ETV can effectively inhibit the replication of HBV DNA and normalize the levels of ALT in refractory CriB patients treated with LVD; and ETV is safe in clinical application.     

Evaluation of long-term entecavir treatment in stable chronic hepatitis B patients switched from lamivudine therapy

Purpose

Current Japanese guidelines recommend that patients should be switched from lamivudine to entecavir when they meet certain criteria. This analysis examines the efficacy and safety of long-term entecavir therapy in patients who were switched to entecavir after 24 weeks’ lamivudine therapy in Japanese studies ETV-047 and ETV-060.

Methods

The Phase II Japanese study ETV-047 assessed the efficacy of different entecavir doses when compared with lamivudine. A total of 33 Japanese patients who received lamivudine 100 mg daily in ETV-047 entered the open-label rollover study ETV-060 and subsequently received treatment with entecavir 0.5 mg daily. Hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, and resistance were evaluated among patients with available samples for up to 96 weeks. Safety was assessed throughout the treatment period.

Results

After 96 weeks of entecavir therapy in ETV-060, 90% of patients achieved HBV DNA <400 copies/mL as compared to 21% of patients who completed 24 weeks of lamivudine therapy in ETV-047. Increasing proportions of patients achieved ALT normalization and HBeAg seroconversion following long-term entecavir treatment. No patients experienced virologic breakthrough, and substitutions associated with entecavir resistance were not observed in patients with detectable HBV DNA. Entecavir was well tolerated during long-term treatment.

Conclusions

Switching lamivudine-treated patients with chronic hepatitis B to entecavir results in increased virologic suppression with no evidence of resistance through 2 years of entecavir therapy. These findings support recommendations in the current Japanese treatment guidelines that stable lamivudine patients should be switched to entecavir.     

拉米夫定联合阿德福韦酯与换用恩替卡韦单药治疗拉米夫定应答不佳患者的疗效对比

目的 观察分别利用拉米夫定和阿德福韦酯联合治疗与换用恩替卡韦单药治疗拉米夫定应答不佳慢性乙型肝炎患者的临床疗效.方法 80例拉米夫定应答不佳的慢性乙型肝炎患者采用随机数字表法分为联合组和单药组,联合组服用拉米夫定100 mg/d和阿德福韦酯10mg/d;单药组服用恩替卡韦0.5 mg/d,观察两组患者治疗48周时的疗效.结果 治疗48周后,联合组的HBV DNA应答率、HBeAg转换率、ALT复常率分别为90.0％、40.0％和95.0％,远高于单药组的70.0％、15.0％和80.0％,两组比较差异均有统计学意义(P＜0.05).治疗48周后,联合组未出现病毒学突破病例;单药组共有2例患者出现病毒学突破.结论 对于拉米夫定应答不佳的慢性乙型肝炎患者,加用阿德福韦酯联合治疗的疗效优于换用恩替卡韦单药治疗,且可降低病毒耐药的发生率.     

Tenofovir,entecavir, and lamivudine in patients with severe acute exacerbation and hepatic decompensation of chronic hepatitis B

ObjectiveTo compare the efficacy of and mortality after lamivudine (LAM), tenofovir (TDF), and entecavir (ETV) treatment in patients with severe acute chronic hepatitis B (CHB) exacerbation.MethodsWe analyzed 91 patients with severe acute CHB exacerbation treated with LAM (n = 28), TDF (n = 26), or ETV (n = 37) for 10 years. The primary endpoint was overall mortality or liver transplantation (LT) by 48 weeks. The determined predictors of mortality, virologic and biochemical responses, and drug resistance were also evaluated.ResultsThe overall mortality or LT rate was not significantly different among the LAM (14.3%), ETV (10.8%), and TDF (3.8%) groups (P = 0.435). In the multivariate analysis, the occurrence of ascites (hazard ratio [HR] 10.467, 95% confidence interval [CI] 1.596–68.645, P = 0.014) and model for end-stage liver disease (MELD) scores above 25 (HR 28.920, CI 4.719-177.251, P = 0.000) increased the risk of mortality or LT. All groups showed similar biochemical responses (P = 0.134), virologic responses (HBV DNA <116 copies/mL, P = 0.151), and HBeAg seroconversion (P = 0.560). Antiviral resistance emerged in five patients treated with LAM by 48 weeks (17.9%, P = 0.003).ConclusionLAM, ETV, and TDF selection is not related with mortality and LT in patients with severe acute CHB exacerbation and hepatic decompensation. To reduce mortality, patients with ascites and MELD scores above 25 should be considered for LT.     

Histological outcome for chronic hepatitis B patients treated with entecavir vs lamivudine-based therapy

AIM: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy.METHODS: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People’s Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ² test or Fisher’s exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test.RESULTS: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The patients receiving ETV showed a more significant improvement in necroinflammation than the LAM-treated patients (P = 0.0003). However, there was no significant difference in fibrotic improvement between the two arms. Furthermore, two patients in each arm achieved a fibrosis score of 0 post-treatment, which indicates a full reversion of fibrosis after antiviral therapy.CONCLUSION: CHB patients with advanced fibrosis or cirrhosis benefit from antiviral treatment. ETV is superior to LAM therapy in improving necroinflammatory but not fibrotic outcome.     

恩替卡韦与拉米夫定治疗HBV相关性肝衰竭患者疗效Meta分析

目的：系统评价恩替卡韦（ETV）和拉米夫定（LAM）治疗乙型肝炎病毒（HBV）相关性肝衰竭患者的疗效。方法应用计算机检索PUBMED、MEDLINE、EMBASE、CNKI、VIP、中国生物医学文献数据库（CBM）和万方数据库,查找所有比较恩替卡韦和拉米夫定治疗重型乙型肝炎、HBV相关性肝衰竭的随机对照试验（RCT）,检索时间均为建库至2014年4月1日。同时手工检索纳入文献的参考文献。按纳入和排除标准,由2人独立进行RCT的筛选、资料提取和质量评价,采用RevMan5.2软件进行Meta分析。结果纳入14个研究,共1383例患者（ETV组622例,LAM组761例）。结果显示,在治疗HBV相关性肝衰竭12 w和24 w,ETV能更有效地降低血清ALT及总胆红素水平,差异具有统计学意义（z=3.24或z=2.26,P〈0.02;z=1.92或z=2.23,P〈0.03）;在治疗12 w时,相比LAM治疗,ETV显著提高PTA水平,差异具有统计学意义（z=2.09,P=0.04）,但在24 w时,两组无明显差异（z=1.76, P=0.08）;在治疗12 w和24 w时,ETV组HBeAg血清学转阴率分别为18.2%和49.5%,与LAM组相比均无显著性差异（13.6%和52.1%）;在治疗12 w和24 w时,ETV组HBV DNA转阴率分别为37.5%和77.5%,显著高于LAM组的23.0%（P=0.04）和52.0%（P=0.002）;在治疗12 w和24 w时,ETV组患者的病死率分别为8.2%和12.8%,显著低于LAM组的18.6%（P=0.02）和19.6%（P=0.0001）。结论恩替卡韦比拉米夫定能更有效改善HBV相关性肝衰竭患者的肝功能,抑制病毒复制,并且降低患者的病死率。