恩替卡韦联合阿德福韦酯对拉米夫定耐药乙肝肝硬化的疗效

目的 研究恩替卡韦（ENT）联合阿德福韦酯（ADV）治疗对拉米夫定耐药乙型肝炎肝硬化的临床疗效.方法 选取98例对拉米夫定耐药乙型肝炎肝硬化患者分为代偿期和失代偿期,两组患者均给予恩替卡韦（0.5 mg/d,qd）和阿德福韦酯（10 mg,qd）治疗.两组患者分别在治疗前、治疗24周和48周收集患者的血清样本检测HBV DNA阴转率、ALT复常率、评估Child-Pugh评分和与药物相关的不良反应.结果 治疗24周、48周时两组患者的HBV DNA阴转率、HBeAg阴转率、ALT复常率与治疗前相比均得到显著改善,治疗24周和48周时,两组HBeAg阴转率、HBV DNA阴转率、ALT复常率比较,差异有统计学意义（P＜0.05）.Child-Pugh评分与治疗前相比得到改善,但差异无统计学意义（P＞0.05）,治疗24周和48周时,两组Child-Pugh评分比较差异有统计学意义（P＜0.05）.未见不良反应和病毒学突破.结论 恩替卡韦联合阿德福韦酯治疗乙型肝炎肝硬化可以有效抑制乙肝病毒复制,延缓疾病进展,安全性良好.     

恩替卡韦联合阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎患者的疗效观察

目的观察恩替卡韦联合阿德福韦酯治疗拉米夫定耐药慢性乙型肝炎(CHB)患者的疗效和安全性。方法选取昆山市人民医院2011年5月至2013年5月门诊和住院的拉米夫定耐药患者45例,随机分成两组,治疗组23例应用恩替卡韦联合阿德福韦酯挽救治疗,对照组22例应用拉米夫定联合阿德福韦酯挽救治疗,观察两组治疗前及治疗后4、12、24、48周HBV DNA、ALT、AST、TBil、Alb、HBV血清学标志物含量变化以及治疗48周时非rtM204I位点变异发生率。计量资料组间比较用t检验,计数资料的组间比较用四格表χ2检验。结果治疗组挽救治疗后4、12周ALT、AST下降较对照组相比差异有统计学意义(t值为3.124、5.271、4.476、5.125,P值均0.01),挽救治疗24、48周后较对照组相比差异有统计学意义(t值为2.240、2.307、2.886、2.908,P值均0.05)。治疗4、12、24、48周后,治疗组HBV DNA转阴率分别为73.9%、86.8%、95.7%、100%,较对照组差异有统计学意义(χ2值为11.79、5.75、10.29、5.89,P值均0.05)。HBeAg阳性患者阴转率在治疗组及对照组间差异无统计学意义。治疗组48周后未出现新的非rtM204I位点变异,而对照组非rtM204I位点变异情况为4例,两组相比差异有统计学意义(χ2=4.59,P0.05)。结论恩替卡韦联合阿德福韦酯用于既往拉米夫定耐药的CHB患者的挽救治疗疗效明显,值得临床推广。     

慢性乙型肝炎初治后转换恩替卡韦干预的耐药及疗效观察

目的研究慢性乙型肝炎初治后转换恩替卡韦干预的耐药及疗效。方法纳入2012年10月至2015年12月于常州市第三人民医院收治的124例慢性乙型肝炎患者为对象,均已接受阿德福韦酯+拉米夫定初始联合抗病毒治疗>12个月。按照抽签随机对照法,将所有患者分为两组,各62例,其中观察组治疗方案替换为恩替卡韦干预,对照组仍按原方案持续治疗,均持续治疗3年。所有患者均随访3年,观察两组随访1、2、3年时病毒学应答及基因耐药情况,并分析两组随访1、2、3年时血肌酐、肾小球滤过率、尿视黄醇结合蛋白、尿β2-微球蛋白变化情况。结果观察组随访3年时HBV DNA转阴率显著高于随访1年(P<0.05),对照组随访3年时基因耐药发生率显著高于随访1年(P<0.05);观察组随访2、3年HBV DNA转阴率显著高于对照组(P<0.05),基因耐药发生率显著低于对照组(P<0.05)。随访1、2、3年,对照组血肌酐有不同程度的升高,肾小球女滤过率有不同程度的下降,其中随访2、3年时血肌酐显著高于随访1年(P<0.05),随访3年时肾小球女滤过率显著低于随访1、2年(P<0.05);而观察组血肌酐、肾小球滤过率基本保持基线水平。观察组随访1、2、3年血肌酐均显著低于对照组(P<0.05),肾小球滤过率均显著高于对照组(P<0.05)。观察组随访2、3年时血肌酐较基线上升>50μmol/L的比例显著低于对照组(P<0.05),随访1、2、3年时肾小球滤过率较基线下降30%的比例显著低于对照组(P<0.05)。观察组随访2、3年尿视黄醇结合蛋白异常率、尿β2-微球蛋白异常率显著低于对照组(P<0.05)。结论慢性乙型肝炎患者阿德福韦酯+拉米夫定初治后转换为恩替卡韦干预,能有效提高病毒学应答率,降低耐药及肾功能损害发生率。     

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.     

恩替卡韦对拉米夫定耐药的慢乙肝患者有效

据Medscape．com7月10日报道（原载Gastroenterology2006；130：2039—2049），对拉米夫定耐药的慢乙肝患在改用恩替卡韦后，其组织学、病毒学、血清学以及生化指标方面均有明显改善，并且与拉米夫定相比，其安全性也更好。     

拉米夫定联合阿德福韦酯治疗恩替卡韦抗HBV耐药1例

患者,阮XX,男性,19岁,因体检发现肝功能异常,于2004年11月17日来我院门诊就医。查体：皮肤、巩膜无黄染,肝脾不大;肝功能ALT110U／L、AST90U／L、HBsAg（＋）、HBeAg（＋）、抗-HBC（＋）、HBVDNA（＋）1．0×10^7拷贝／ml,     

恩替卡韦联合阿德福韦酯治疗耐拉米夫定慢性乙型肝炎患者48周的疗效分析

目的：观察恩替卡韦（ETV）联合阿德福韦酯（ADV）治疗耐拉米夫定（LAM）慢性乙型肝炎的疗效。方法选取 LAM 耐药患者66例,随机分成两组,治疗组36例应用 ETV 联合 ADV 挽救治疗,对照组30例应用 LAM 联合 ADV 挽救治疗,观察两组治疗前及治疗后12周、48周谷丙转氨酶（ALT）、谷草转氨酶（AST）、总胆红素（TBIL）、乙型肝炎病毒 DNA（HBV-DNA）、乙型肝炎 e 抗原（HBeAg）含量变化以及治疗48周时非 rtM204I 位点变异发生率。结果治疗组挽救治疗后12周 ALT 和 AST 分别降至（36．5±13．23）U／L 和（50．2±11．66）U／L,显著低于同期对照组 ALT[（60．3±12．28）U／L,P ＜0．01]及 AST [（69．7±13．56）U／L,P ＜0．01]含量;治疗后48周治疗组 ALT 和 AST 降至（27．9±10．58）U／L 和（26．7±10．95）U／L,低于同期对照组 ALT[（50．4±11．53）U／L,P ＜0．01]及 AST[（44．9±15．33）,P ＜0．05]含量。治疗12周及48周,治疗组 HBV-DNA 转阴率分别为85．5％及91．7％,显著高于同期对照组转阴率（53．3％和73．3％,P 均＜0．05）。治疗组48周后出现1例新的非 rtM204I 位点变异,而对照组非 rtM204I位点变异情况为6例,两组相比差异有统计学意义（χ2＝5．12,P ＝0．024）。结论ETV 联合 ADV 用于既往 LAM 耐药的慢性乙型肝炎患者的挽救治疗疗效明显,值得临床推广。     

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。     

恩替卡韦联合阿德福韦酯治疗拉米夫定耐药重度乙型肝炎2例及文献复习

拉米夫定治疗慢性乙型肝炎（CHB）的安全性和有效性已得到大多数患者认可,但长期应用易产生 YMDD 病毒变异耐药,其耐药突变发生率随着用药时间的延长而升高,1、2、3、4年的耐药突变率分别为14%、38%、49%、66%[1],发生耐药的部分患者在出现血清病毒载量的明显反弹后会导致病情恶化,甚至最终发生肝衰竭[2],此时加用阿德福韦酯可能为时已晚,对于这一人群的抗病毒药物的选择,相关的指南并没有明确指出,我科应用恩替卡韦联合阿德福韦酯治疗此类患者2例,疗效较好。     

拉米夫定联合阿德福韦酯与恩替卡韦单药治疗HBeAg阳性慢性乙型肝炎疗效观察

目的观察拉米夫定联合阿德福韦酯与恩替卡韦单药治疗HBeAg阳性慢性乙型肝炎96周的疗效,以探讨理想的初始抗病毒治疗方案。方法选择HBeAg阳性慢性乙型肝炎患者86例,随机分为单药治疗组44例和联合治疗组42例,分别给予恩替卡韦或拉米夫定联合阿德福韦酯治疗,观察96 w的疗效。结果在96 w治疗结束时,恩替卡韦治疗患者ALT复常率、血清HBV DNA阴转率和HBeAg阴转率分别为95.5%、84.1%和38.6%,而联合治疗患者则分别为88.1%、42.9%（P〈0.05）和31.0%;两组均无患者血清HBsAg转阴。两组均未发生严重的不良反应。结论应用恩替卡韦单药治疗对于HBeAg阳性慢性乙型肝炎初始抗病毒治疗在96 w时的病毒学应答率显著优于拉米夫定和阿德福韦酯联合治疗。     

Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance

This study aimed to evaluate the long-term efficacy of entecavir (ETV) in adefovir (ADV)-refractory chronic hepatitis B (CHB) patients with prior lamivudine (LMV) resistance. A total of 55 ADV-refractory CHB patients with prior LMV resistance, who received rescue therapy with ETV 1 mg daily for at least 12 months, were consecutively enrolled and analysed. Forty-four patients were men, and their median age was 47 (25-69). Ten patients had liver cirrhosis and 46 patients were positive for hepatitis B e antigen (HBeAg). Median hepatitis B virus DNA levels were 6.6 (4.3-8.0) log(10) copies/mL, and the median duration of ETV therapy was 24 (12-47) months. Cumulative virologic response rates at 6, 12, 24 and 36 months were 18%, 29%, 58% and 75%, respectively. HBeAg loss occurred in 10 (21.7%) of 46 HBeAg-positive patients. In multivariate analysis, only initial virologic response at 3 months remained as an independent predictor for virologic response (RR 3.143; 95% CI 1.387-7.120; P = 0.006). The patients with a virological response at 3 months had not only a significantly higher probability of achieving a virologic response (P < 0.001) but also lower probability of experiencing a virologic breakthrough (P = 0.043) than the patients without an early response. Viral breakthrough was observed in 29 patients during the follow-up period. Cumulative breakthrough rates at 6, 12, 24 and 36 months were 0%, 15%, 45% and 73%, respectively. ETV monotherapy may be considerably efficacious in cases with an initial virological response but its efficacy is attenuated by frequent emergence of ETV resistance in ADV-refractory CHB patients with prior LMV resistance.     

Long-term efficacy of entecavir therapy in chronic hepatitis B patients with antiviral resistance to lamivudine and adefovir

No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.     

恩替卡韦联合阿德福韦酯治疗高病毒载量慢性乙型肝炎的疗效观察

目的探讨恩替卡韦与阿德福韦酯联合治疗高病毒载量慢性乙型肝炎(CHB)的疗效及安全性。方法收集2008年12月至2011年12月收治的高病毒载量CHB初治患者80例,随机分为观察组和对照组各40例。对照组采用恩替卡韦(ETV)治疗,观察组采用ETV联合阿德福韦酯(ADV)治疗。观察2组患者治疗前和治疗3、6、12、24个月时的HBV DNA载量、HBsAg或HBeAg血清学转换、ALT复常及不良反应情况。计量资料2组间比较采用两独立样本t检验;计数资料2组间比较用χ2检验。结果观察组6、12、24个月时的HBV DNA载量(拷贝/ml)的对数值(3.4±0.4、2.6±0.3、1.2±0.4)比同期对照组降低程度更明显(3.7±0.3、2.9±0.4、1.6±0.7)(t值分别为3.339、5.657、2.806,P值均0.05)。观察组治疗12、24个月时HBV DNA阴转率(87.5%、95.0%)、HBeAg转阴率(80.0%、90.0%)明显高于对照组(70.0%、77.5%;55.0%、70.0%)(P值均0.05)。观察组治疗24个月时HBeAg血清学转换率及ALT复常率较对照组明显提高(77.5%vs 50.0%;82.5%vs 55.0%,P值均0.05)。治疗期间,2组不良反应发生率差异无统计学意义(P0.05),观察组病毒学突破发生率明显低于对照组(0 vs 10.0%,P0.05)。结论初始联合ETV、ADV治疗高病毒载量CHB具有较强的抗病毒作用,可减少应答不佳和耐药的发生,长期临床疗效比单一使用ETV好,且安全可靠。     

Factors associated with the virological response of lamivudine-resistant hepatitis B virus during combination therapy with adefovir dipivoxil plus lamivudine

Background The aim of this study was to investigate the factors associated with the response of lamivudine-resistant hepatitis B virus (HBV) during combination therapy with adefovir dipivoxil plus lamivudine. Methods Sixty-three patients with breakthrough hepatitis received a 10-mg once-daily dose of oral adefovir dipivoxil. Results The rates of undetectable serum HBV-DNA were 49.2% after 24 weeks, 61.9% after 48 weeks, and 67.2% after 72 weeks. The cumulative hepatitis B e antigen (HBeAg) loss rates in patients with alanine aminotransferase (ALT) levels of more than twice the upper limit of normal (ULN) were significantly higher than in patients with ALT less than twice the ULN (P = 0.0145). Multivariate analysis revealed that baseline ALT level (P = 0.003) and HBeAg status (P = 0.049) were associated with early virological response. Conclusions Baseline ALT level was associated with HBeAg loss and seroconversion, and baseline ALT level and HBeAg status were associated with the virological response of lamivudine-resistant HBV during combination therapy with adefovir dipivoxil plus lamivudine.     

恩替卡韦治疗慢性乙型肝炎的疗效观察

目的评价恩替卡韦治疗慢性乙型肝炎(CHB)患者96周的疗效。方法收集2011年7月-2014年7月在江苏省泰兴市人民医院门诊和住院的62例CHB患者,给予恩替卡韦0.5 mg/d抗病毒治疗96周。所有病例分为两组,HBe Ag阳性组患者43例,HBe Ag阴性组患者19例。其中HBV DNA106拷贝/ml患者38例,HBV DNA106拷贝/ml患者24例。比较两组治疗24、48及96周的疗效。计数资料组间比较采用χ2检验。结果在治疗24、48、96周时,HBe Ag阳性组患者HBV DNA阴转率分别为34.88%、65.12%、74.42%,明显低于HBe Ag阴性组的78.95%、89.47%、100%,差异均有统计学意义(P值分别为0.003、0.047、0.038)。两组患者的ALT复常率差异均无统计学意义(P值分别为0.102、0.779、0.638)。在38例HBV DNA载量106拷贝/ml和24例HBV DNA载量106拷贝/ml的两组中,治疗24、48、96周时,两组患者HBV DNA阴转率差异均有统计学意义(34.21%vs70.83%、57.89%vs 95.83%、76.32%vs 95.83%,P值分别为0.005、0.001、0.002);两组患者ALT复常率差异均无统计学意义(P值分别为0.940、0.150、0.280)。结论恩替卡韦治疗CHB有很好的抗病毒活性,在抑制病毒复制的同时能改善肝功能。     

New paradigms for the treatment of chronic hepatitis B

The main goals of chronic hepatitis B treatment should be the long-term suppression of viral replication to minimize disease progression and the risk for the development of hepatocellular carcinoma. Treatment end-points, depending on surrogate markers alone, in particular hepatitis B e-antigen seroconversion, may not be ideal for patients who acquire the disease early in life.
Currently-available drugs include interferons and oral nucleoside/nucleotide analogs. Although interferon therapy provides a finite treatment period, a significant proportion of patients may not respond, and long-term outcome is inconclusive. Long-term efficacy has been demonstrated for both lamivudine and adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide analogs with a high genetic barrier and potent antiviral activity, such as entecavir, should be used to reduce the chance of developing drug-resistant mutations. Drugs with a low genetic barrier, including lamivudine and telbivudine, should be used in conjunction with early testing for antiviral response. This can predict favorable outcomes in the long term. The early detection of drug-resistant mutations should prompt clinicians to either add or switch to another agent with a different drug-resistance profile. There are currently no treatment models in the use of combination or sequential therapy in treatment-naïve patients.
To date, long-term treatment appears to be the most effective option. Despite recent advances made with better understanding on the natural history of chronic hepatitis B infection and with newer antiviral drugs available, challenges remain with respect to treatment criteria, treatment end-points, and duration of treatment.     

Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment

Oral nucleoside/nucleotide analogues (NAs) are the mainstay of therapy for patients with chronic hepatitis B and are generally well tolerated. Despite this, the safety profile of NAs is of paramount importance since the majority of patients will require long‐term treatment. All NAs can potentially affect human DNA polymerase with decrease in mitochondrial DNA, leading to manifestations of mitochondrial toxicity. As a class effect, therefore, NAs can potentially cause extrahepatic conditions, such as myopathy, nephropathy, neuropathy, and lactic acidosis. Indeed, effects on muscles, including myopathy and creatine kinase elevations, have been described with clevudine and telbivudine use. Both adefovir and tenofovir are associated with dose‐dependent nephropathy, predominantly affecting the proximal renal tubules. Neuropathy appears to be rare, and most commonly reported in patients receiving combination therapy with telbivudine and interferon. Increased risk of lactic acidosis has also been described for those with impaired liver and renal function taking entecavir. Loss of bone mineral density and hypophosphatemia have been described with the use of NAs, although the overwhelming studies have been with human immunodeficiency virus‐infected patients. However, not all extrahepatic effects are detrimental. Recent evidence has suggested a potential renal beneficial effect with the use of telbivudine. The effect of NAs on pregnancy appears to be minimal for all NAs, with telbivudine and tenofovir having a more favorable category B rating. Ongoing pharmacovigilance is essential to identify new and monitor existing extrahepatic effects associated with NA use.     

Short-term entecavir therapy of chronic severe hepatitis B

BACKGROUND:Chronic severe hepatitis B patients often have limited survival.This investigation aimed to evaluate the short-term effects of nucleoside analog therapy on chronic severe hepatitis B. METHODS:We retrospectively,randomly collected the data of 129 chronic severe hepatitis B patients:55 were treated with entecavir,and the remaining 74 were not treated with nucleoside analogues. RESULTS:No significant difference in short-term survival rate was found between the group treated with entecavir and that t...     

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。     

An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults

Entecavir is a nucleoside analogue of 2?-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.