Entecavir: a potent new antiviral drug for hepatitis B

Entecavir, a new deoxyguanine nucleoside analogue, is a selective inhibitor of the replication of the hepatitis B virus. In vitro this compound has proven to be far more effective than other nucleoside analogues. In animal models, an impressive reduction of serum viral DNA has been observed with covalently closed circular DNA and hepatitis B viral core antigen negativity in liver biopsy specimens. In clinical studies, entecavir revealed excellent suppression of hepatitis B virus replication without significant side effects or evidence of mitochondrial toxicity. Until now, no entecavir-resistant viral mutants have been described. Prolonged therapy as well as prophylactic therapy, for example, in liver transplant recipients, is feasible and not limited by breakthrough infections. Data on entecavir therapy for treatment of nucleoside-naive, wild-type hepatitis B virus is being generated in Phase III clinical trials worldwide for both hepatitis B envelope antigen-positive and -negative subpopulations, as well as in lamivudine-resistant patients. Based on mechanism and potency of interferon and entecavir, clinical trials with combination therapy are eagerly awaited.     

Telbivudine: a hepatitis B-specific antiviral

Telbivudine, a l-nucleoside enantiomer, is a potent specific inhibitor of hepatitis B virus (HBV) polymerase. It recently completed Phase III trials and has been licensed in most countries worldwide. It has shown superior efficacy compared with lamivudine in therapeutic response, reduction in HBV DNA, proportion of patients with undetectable HBV DNA, reduced primary treatment failure and reduced viral resistance over 2 years, in Hepatitis B e antigen-positive and -negative patients. Further studies show that switching to telbivudine in lamivudine-suboptimal responders improves the reduction in HBV DNA at week 24 and shows superiority compared with adefovir in reduction of HBV DNA at week 24. Multivariate analysis showed that week 24 HBV DNA best predicted outcomes at 2 years and a ‘hepatitis B roadmap’ concept has been proposed to manage patients based on this. Thus, telbivudine is a useful addition to the current landscape of hepatitis B therapeutic agents.     

抗乙型肝炎病毒药物研发现状

从1983年到2005年11月．被美国FDA批准用于慢性乙型肝炎治疗的有5种药物．但其在疗效和不良反应等方面均有一定的局限性。目前．一批用于治疗慢性乙型肝炎的新药正处于研发阶段，其中已进入临床试验后期的药物以核苷类似物为主。本文对已上市及进入临床试验的治疗乙型肝炎的药物进行了总结．并对已完成Ⅱ期临床试验的治疗慢性乙型肝炎的药物进行了评述。     

慢性乙型肝炎患者口服抗病毒药物治疗的病毒学突破与耐药情况分析

目的:探讨慢性乙型肝炎患者口服核苷类似物抗病毒药物治疗的病毒学突破与耐药情况。方法:调查统计389例慢性乙型肝炎患者口服核苷类似物抗病毒治疗的效果、病毒突破产生及病毒耐药基因产生等情况,并进行相应分析。结果:389例慢性乙型肝炎患者接受口服抗病毒药物治疗后,93例在治疗开始1年后发生病毒学突破,其中58例检测出基因型耐药,31例发生生化学突破。在93例首次发生病毒学突破的患者中,57例1～3个月复查证实其为病毒学突破患者,28例经复查不能确定其为病毒学突破患者。57例确诊病毒学突破患者中,45例检测出基因型耐药,并且调整了治疗方案,所有患者HBV-DNA水平均有下降,最终40例患者的HBV-DNA降至最低检出范围以下;另有12例未检测出基因型耐药的患者,其中5例继续原治疗方案不变,7例调整了治疗方案,最终HBV-DNA均能降至最低检出范围以下。结论:病毒学突破在口服核苷类似物抗病毒药物治疗时比较多见,但有些病毒突破患者并不产生基因型耐药。了解治疗依从性及复查确诊病毒学突破发生情况对评估患者治疗效果及调整用药有积极意义。     

恩替卡韦和拉米夫定治疗慢性乙型肝炎的Meta分析

目的系统评价恩替卡韦和拉米夫定治疗慢性乙型肝炎的疗效与安全性。方法检索Cochrane Library,PubMed,Ovid,Elsevier,中国期刊全文数据库（CNKI）,万方数字化期刊全文库,中文科技期刊全文数据库（维普）公开发表的相关随机对照试验（RCT）,并手工检索纳入研究的参考文献。对纳入的研究进行质量评价和数据提取,采用RevMan5．2软件进行Meta分析。当,〈50％时认为纳入研究结果同质性较好．采用固定效应模型计算合并统计量;当I^2≥50％时,则选择随机效应模型计算合并统计量。结果最终纳入27篇文献。Meta分析结果显示,对于HBVDNA转阴率、ALT复常率,HBeAg转阴率和HBeAg血清学转化率,恩替卡韦组均显著高于拉米夫定组;在不良反应发生率方面,2组无统计学差异。结论当前的研究显示,恩替卡韦对慢性乙型肝炎的疗效优于拉米夫定,2药的不良反应发生率相似。相关结果需要样本量更大,设计更严谨的大型多中心的临床随机对照试验。     

LB80380: a promising new drug for the treatment of chronic hepatitis B

Hepatitis B virus is a significant cause of liver cirrhosis and hepatocellular carcinoma in patients with chronic infection. Higher levels of viral load are associated with increased risk of developing liver-related complications. The current available oral therapies suppress viral replication through their action on the hepatitis B virus polymerase. As treatment with oral nucleoside/nucleotide analogues is associated with the development of drug-resistant mutations, there is continuing research for newer and more potent antiviral agents to reduce the chance of drug resistance. LB80380, a prodrug, is an oral nucleotide analogue that inhibits viral replication by incorporation into the viral DNA. Antiviral activity against wild-type virus and virus with drug-resistant mutations was demonstrated in Phase II trials, with significant reduction of viral load in patients treated with LB80380. LB80380 was also shown to be safe and well tolerated.     

恩替卡韦治疗耐阿德福韦酯慢性乙型肝炎的临床研究

目的：观察恩替卡韦治疗耐阿德福韦酯慢性乙型肝炎的疗效。方法随机选取2012年1月至2013年1月肝病门诊就诊的耐阿德福韦酯慢性乙型肝炎患者46例,停用阿德福韦酯,改用恩替卡韦分散片,用量0.5 mg/d,于治疗前及治疗后12周、24周、36周、48周检测肝功能、乙肝标志物等指标。结果治疗后第48周,患者HBV-DNA水平低于检测下限（〈5.00×102拷贝/mL）者,乙型肝炎病毒e抗原（ HBeAg ）阳性组25例,HBeAg阴性组19例,组间比较差异无统计学意义（ P＞0.05）;治疗后第12周、24周、36周、48周,患者ALT复常率HBeAg阳性组分别为46.15%,53.85%,88.46%,96.15%,HBeAg阴性组分别为35.00%,50.00%,85.00%,90.00%,组间比较差异无统计学意义（ P＞0.05）;治疗后第12周、24周、36周、48周,HBeAg阳性组HBeAg阴转率分别为26.92%,38.46%,46.15%,57.69%,HBeAg血清学转换率分别为34.62%,50.00%,61.54%,73.08%,其中12周与48周比较差异有统计学意义（ P〈0.05）。结论采用恩替卡韦治疗耐阿德福韦酯慢性乙型肝炎患者,疗效显著且不良反应少,值得推广。     

Entecavir for the treatment of patients with hepatitis B virus-related decompensated cirrhosis

Introduction: Chronic hepatitis B (CHB) infection is common and carries a significant risk for the development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The goal of treatment in patients with CHB-related decompensated cirrhosis is to improve hepatic dysfunction and reduce mortality through the inhibition of viral replication. Several studies have now shown nucleot(s)ide analogs to be safe and effective in decompensated cirrhosis due to CHB.

Areas covered: A review of the evidence for the use of entecavir in the treatment of decompensated hepatitis B cirrhosis is discussed.

Expert opinion: Entecavir is an effective treatment option for most patients with CHB. In treatment naïve patients, it is a potent antiviral agent with a very low resistance rate, making it an excellent option for the treatment of decompensated hepatitis B cirrhosis. The use of entecavir monotherapy in patients with a known rtM204V lamivudine-resistant mutation should be avoided due to increased risk of developing entecavir resistance and failing treatment.     

恩替卡韦与拉米夫定对慢性乙型肝炎抗病毒作用与安全性的对照研究

目的:比较恩替卡韦和拉米夫定治疗慢性乙型肝炎的抗病毒作用与安全性。方法:33例未经抗病毒治疗的慢性乙型肝炎患者随机分为2组:恩替卡韦组(16例)、拉米夫定组(17例)。恩替卡韦组与拉米夫定组的剂量分别为0.5mg/d和100mg/d。疗程为48～96周。观察两药对HBV DNA、ALT、e抗原/e抗体血清转换的影响及其所致不良反应。结果:在治疗24周和48周时,恩替卡韦组和拉米夫定组未检测到HBV DNA的病例分别为56.25%,29.41%;87.50%,29.41%。e抗原阴转率与e抗原/e抗体血清学转换率以及不良反应2组无明显差异。结论:恩替卡韦与拉米夫定比较能更有效的抑制HBV复制,不良反应与拉米夫定相似。因此,可以用于慢性乙型肝炎的长期治疗。     

恩替卡韦治疗慢性乙型肝炎的最新进展

慢性乙肝病毒感染一直是全球公共卫生的问题,开发抗乙肝病毒药物也一直是个热点.恩替卡韦是美国FDA批准的第3个用于治疗乙肝病毒感染的新的核苷类似物药物,现综述恩替卡韦的药理作用、药动学及治疗慢性乙型肝炎的Ⅰ-Ⅲ期临床研究进展,并给出临床应用建议.     

慢性乙型肝炎的抗病毒研究进展

慢性乙型肝炎是由乙型肝炎病毒(hepatitis B virus,HBV)引起的全球性传染病,HBV感染是我国肝硬化、原发性肝癌的重要原因。目前,干扰素类与核苷(酸)类似物抗病毒药物已广泛应用于临床,在一定程度上抑制了病毒的复制并控制了疾病的发展,但仍未从根本上清除病毒;各种治疗性疫苗在抗HBV方面也取得了一定疗效,但临床效果不佳。目前不少研究结果表明,生物免疫治疗可以成功清除体内的HBV,从而为乙肝的治疗带来新的希望。     

Recommendations and potential future options in the treatment of hepatitis B

The natural history of chronic hepatitis B should be clearly defined before appropriate recommendations for treatment can be advocated. In patients who acquire the disease in early life, the complications of chronic hepatitis B continue to occur as a result of prolonged insidious damage to the liver, even in the low viraemic phase. Treatment that ends with hepatitis B e antigen seroconversion with hepatitis B virus DNA levels just below 10⁵ copies/ml may not be sufficient. Patients with mild elevation of alanine aminotransferase levels are already at considerable risk of developing complications. Treatment strategy should aim at maximal and prolonged viral suppression to the lowest possible hepatitis B virus DNA levels. Nucleotide/nucleoside analogues will become the mainstay of treatment. Future treatment strategic plans should target maximising antiviral potency and minimising the chance of drug resistance.     

恩替卡韦治疗慢性乙型肝炎1年期疗效

目的分析恩替卡韦对慢性乙型肝炎患者的1年期疗效。方法44例慢性乙型肝炎患者分为HBeAg阳性组(24例)及HBeAg阴性组(20例),分别给予恩替卡韦0.5mg,1次/d,口服,共48周。在用药2、4、8、24及48周后检测血清HBVDNA水平(荧光定量-PCR法)及肝功能的变化。结果恩替卡韦在开始治疗2周后即有显著的抗病毒效果,患者HBVDNA的平均下降幅度,HBeAg阳性、阴性组分别为1.5522log10和1.6207log10,与用药前比较均P<0.01;同时两组AST、ALT也显著下降(P<0.01,其中HBeAg阴性组AST治疗前后P<0.05)。到第4周时HBeAg阳性组和HBeAg阴性组肝功复常率分别为14/24和14/20(P=0.4231);HBVDNA<1000拷贝/ml的比例分别为12/24和14/20(P=0.1791)。第8周时肝功几乎全部恢复正常;HBVDNA<1000拷贝/ml的比例也分别达到17/24和19/20(P=0.038)。24～48周,所有患者肝功均保持正常,HBVDNA<1000拷贝/ml。结论恩替卡韦治疗慢性乙型肝炎,疗效确切,且起效快,安全性较好。     

Emerging drugs for hepatitis B

Chronic hepatitis B remains a treatment challenge despite the availability of new nucleoside analogs. This is due to the persistence of viral infection during therapy, which exposes the patient to the risk of developing antiviral drug resistance. Therefore, new polymerase inhibitors are needed to manage resistance to existing drugs and new trials of combination therapy are required to delay drug resistance. In the future, antiviral agents targeting other steps of the viral life cycle will be needed to achieve antiviral synergy and prevent antiviral drug resistance. Immune modulators are also expected to enhance antiviral response and to achieve sustained response. Discovery of new antiviral drugs and design of new treatment strategies are, therefore, needed to manage this disease, which is still the main cause of cirrhosis and hepatocellular carcinoma worldwide.     

恩替卡韦治疗慢性乙型肝炎临床评价

目的：回顾恩替卡韦治疗慢性乙型肝炎临床疗效。方法：选取慢性乙型肝炎病人56例,其中28例使用恩替卡韦（治疗组）,28例使用拉米夫定（对照组）进行比较。治疗组与对照组的治疗剂量分别为0．5mg／d和100mg／d,观察两药在第4、8、12和24周共4个治疗阶段的ALT（丙氨酸氨基转移酶）、HBVDNA（乙肝病毒脱氧核糖核酸）及e抗原血清转换情况。结果：治疗组与对照组在治疗4周时AIJT复常率、HBVDNA转阴率及e抗原血清学转换率分别为25％和21％（P〉0．05）,50％和25％（P〉0．05）,0％和5％（P〉0．05）;8周时分别为36％和29％（P〉0．05）,71％和32％（P〈0．05）,19％和21％（P〉0．05）;12周时分别为54％和39％（P〉0．05）,75％和71％（P〉0．05）,31％和32％（P〉0．05）;24周时分别为75％和61％（P〉0．05）,89％和75％（P〉0．05）,44％和42％（P〉0．05）。结论：恩替卡韦相对于拉米夫定能更早、更有效的抑制乙肝病毒复制,伴随着HBVDNA的下降,两组间Au、复常率及e抗原血清转换率差异无显著性。     

观察恩替卡韦联合苦参素胶囊治疗慢性乙型肝炎的疗效

目的观察恩替卡韦(抗病毒药)联合苦参素胶囊(抗病毒植物提取药物)治疗慢性乙型肝炎患者的临床近期疗效。方法选65例慢性乙型肝炎患者,随机分为2组,30例为对照组,单用恩替卡韦(每次0.5 mg,1次/天);另35例为治疗组,给予恩替卡韦(每次0.5 mg,1次/天)联合苦参素胶囊(每次0.2 g,3次/天),2组疗程均为24周。观察治疗后患者肝功能、乙肝病毒血清学指标、HBV-DNA定量的变化。结果治疗组与对照组相比,HBV-DNA阴转率的差异无显著性意义;ALT复常率和HBeAg阴转率,治疗组明显优于对照组(94.2%vs 80%)和(40%vs 16.7%)。结论恩替卡韦联合苦参素胶囊治疗慢性乙型肝炎有效并安全。     

核苷类药物在乙型肝炎后肝硬化治疗中的疗效分析

目的观察核苷类抗病毒药物拉米夫定(LAM)、阿德福韦酯(ADV)、恩替卡韦(ETV)在失代偿期乙型肝炎肝硬化患者中的疗效。方法失代偿期乙肝后肝硬化患者120名随机分为A、B、C三组,在内科综合治疗的基础上,A组单用LAM(100 mg/d),B组单用ADV(10 mg/d),C组单用ETV(O.5 mg/d)治疗,观察患者3,6,9及12个月时血清生化指标及病毒载量变化。结果经过核苷类似物抗病毒治疗后,各组HBV DNA载量在3,6,9和12个月后均有大幅度下降,ETV组患者HBV DNA载量下降及HBeAg阴转率显著高于LAM组和ADV组。结论 ETV更适合于失代偿期乙肝后肝硬化患者中的抗病毒治疗。     

Targets of emerging therapies for viral hepatitis B and C

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow’s treatment approaches.     

慢性重型乙肝患者血乳酸水平变化及核苷类抗病毒治疗的疗效分析

目的 探讨慢性重型乙肝患者血乳酸水平变化及核苷类抗病毒治疗的疗效.方法 回顾性分析30例慢性重症肝炎患者的临床资料,检测血乳酸并计算MELD评分.将患者按照入院顺序分两组,分别采用拉米夫定（LAM）、恩替卡韦（ETV）治疗,观察血乳酸和MELD评分的变化.结果 慢性重症肝炎患者随着MELD评分的增加,血乳酸浓度逐渐增加（P＜0.05）;治疗后,两组血乳酸值稍高于治疗前,但组间治疗后比较无统计学意义（P〉0.05）,同时在MELD评分上也无明显改善（P〉0.05）;个例初步分析以乳酸水平轻度升高为多,但无乳酸中毒.结论 MELD评分与血乳酸具有良好相关性,二者联合应用对于病情判断具有重要意义;应用核苷类抗病毒药物的严重肝病患者以血乳酸轻度升高为主,临床上应权衡利弊选择使用并注意监测.     

Pharmacoeconomics of entecavir treatment for chronic hepatitis B

Background: Entecavir is a new antiviral agent for chronic hepatitis B virus (HBV) infection with potent HBV suppression and a low rate of viral resistance. Objective: To review published studies on the pharmacoeconomics of entecavir for treatment of chronic HBV. Methods: A literature search on Medline and Embase over the period of 1998 – 2008 was performed in April 2008 using keywords ‘entecavir’ and ‘cost’. Results/conclusion: Four studies comparing the cost effectiveness of entecavir with lamivudine and/or adefovir for treatment with chronic HBV infection using either decision tree or Markov modeling were reviewed. All four studies showed that entecavir was cost-effective in the treatment of chronic HBV with the incremental cost per QALY (quality-adjusted life-year) gained below the commonly accepted benchmark. The results are mainly due to the lower complication rates and better quality of life of patients using entecavir which can offset the higher acquisition cost of the drug. Patient characteristics, comparing agents and model assumptions were different among the four studies and they should be taken into account when applying the results to real life situations.