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.     

Clevudine: a promising therapy for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection, affecting ～ 350 million people worldwide, is associated with significant morbidity and mortality. In the past 10 years, hepatitis B therapy research has led to a multitude of available antiviral therapies: IFN-α, pegylated IFN-α_2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir. To further improve reductions in viral load and resistance profiles, development of new HBV therapeutic strategies has been an important focus. One such therapy is clevudine, an analogue of the β-L configuration. Clevudine is already licensed in Korea for anti-HBV therapy (Bukwang Pharmaceuticals, Seoul, Korea). Unique to clevudine is its ability to maintain antiviral activity following discontinuation of therapy. Typically, hepatitis B treatment requires continuous therapy to prevent reactivation. Sustained response is uncommon except in hepatitis B antigen (HBeAg)-positive patients who developed HBeAg seroconversion. This article reviews chronic HBV and its therapy options. Specifically, it describes clevudine's potent and sustained antiviral activity as observed in vitro and in vivo.     

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。     

Lamivudine for the treatment of chronic hepatitis B

Lamivudine (Zeffix^®, Epivir^®, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-α. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.     

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.     

Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients

The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-α and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.     

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.     

Natural products as promising drug candidates for the treatment of hepatitis B and C

Hepatitis B virus （HBV） or hepatitis C virus （HCV） infections are a major threat worldwide. Combination therapy of interferon-α and ribavirin is currently the treatment of choice for HCV-infected patients. However, this regimen is only effective in approximately 50% of patients and provokes severe side-effects. Numerous natural alternatives for treating HCV have been suggested. Deoxynojirimycin and its derivatives are iminosugars which exert anti-HCV activity by inhibiting α-glucosidases. A non-immunosuppressive derivate of cyclosporine A, NIM811, exerts anti-HCV activity by binding to cyclophilin. Other natural products with promising anti-HCV activity are 2-arylbenzofuran derivatives, Mellein, and pseudoguaianolides. For HBV treatment, several drugs are available, specifically targeting the virus polymerase （lamivudine, entecavir, telbivudine, and adefovir dipivoxil）. The efficacy of these drugs is hampered by the development of resistance due to point mutations in the HBV polymerase. Due to drug resistance and adverse side-effects, the search for novel drugs is mandatory. Wogonin, ellagic acid, artemisinin and artesunate, chrysophanol 8-O-β-D-glucoside, saikosaponin C, and protostane triterpenes are active against HBV. Natural products need to be investigated in more detail to explore their potential as novel adjuncts to established HBV or HCV therapy.     

益乐治疗慢性乙型肝炎临床观察

目的 探讨门冬氨酸钾镁葡萄糖注射液(益乐)治疗慢性乙型肝炎的临床疗效。方法 将60例慢性乙型肝炎患者随机分为治疗组30例和对照组30例。治疗组应用益乐250mi。静脉滴注,同时联合应用甘利欣注射液30mL 10％葡萄糖注射液250m静脉滴注,每日一次。对照组给予甘利欣治疗,两组疗程均为一个月。治疗前后各检测肝功能,HBsAg,HBeAg及HBV-DNA。结果 治疗组疗效显著高于对照组。结论 益乐治疗慢性乙型肝炎退黄疗效显著.     

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.     

Recent advances in the treatment of chronic hepatitis B

Introduction: At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial.

Areas covered: The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed.

Expert opinion: The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited.     

双环醇治疗慢性乙型肝炎患者52例

目的:对比双环醇及拉米夫定治疗慢性乙型肝炎的疗效.方法:慢性乙型肝炎患者随机分成双环醇组(52例)和拉米夫定组(30例),分别服用双环醇25 mg,tid或拉米夫定100 mg,qd,共24周.结果:治疗结束时,e抗原转阴率两组分别为7.4%与8.8%(P>0.05),总有效率两组分别为83.3%及67.3%(P>0.05).HBV DNA阳性但e抗原阴性或ALT正常的患者亦适合双环醇治疗.疗前病毒定量的高低、性别及年龄并不影响疗效.结论:双环醇对乙型肝炎患者降低转氨酶及抗病毒疗效与拉米夫定类似,无明显不良反应.     

水飞蓟素治疗慢性乙型肝炎肝功能异常40例

目的：观察水飞蓟素胶囊治疗肝功能异常的慢性乙型肝炎疗效.方法：80例肝功能异常的慢性乙肝患者,随机分为对照组和试验组各40例.对照组口服葡醛内酯200 mg,tid;试验组在此基础上加用口服水飞蓟素胶囊140mg,bid,疗程均为12周,并评价患者临床症状与肝功能变化.结果：试验组总有效率80%,对照组60%,两组比较差异有显著性（P＜0.05）,且无明显的不良反应.结论：水飞蓟素胶囊治疗慢性乙型肝炎肝功能异常安全、有效.     

促肝细胞生长素肠溶胶囊治疗慢性乙型病毒性肝炎72例疗效观察

目的观察促肝细胞生长素肠溶胶囊治疗慢性乙型病毒性肝炎的疗效。方法144例患者随机分为两组,72例常规治疗加促肝细胞生长素肠溶胶囊作为试验组,每日服2粒,每日3次,疗程12周;另72例常规治疗加促肝细胞生长素颗粒剂作为对照组,每次2袋,每日3次,疗程12周。服药前及服药时4、8、12周及治疗结束后4、8、12周测定肝功能、症状与体征变化。结果两组治疗后肝功能的多项指标均有明显改善,且治疗结束后12周肝功能尚持续改善;临床症状和体征也有明显改善,治疗组总有效率达76.57%。结论促肝细胞生长素肠溶胶囊能有效改善慢性乙型病毒性肝炎患者症状、体征与肝功能,且未见明显不良反应,使用安全。     

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.     

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。     

硫普罗宁治疗慢性乙型肝炎的临床疗效评价

目的探讨硫普罗宁对慢性乙型肝炎的治疗效果及安全性。方法将慢性乙型肝炎84例,随机分为两组。对照组42例,以肌苷0.6g,维生素C2.0g,维生素B60.2g加入5%葡萄糖溶液250ml中静脉滴注,1次/d,连续治疗4周;治疗组42例,以硫普罗宁0.2g加入5%葡萄糖溶液250ml中静滴,1次/d,连续治疗4周,同时分别监测肝功能指标：丙氨酸氨基转移酶（ALT）,天冬氨酸转移酶（AST）、总蛋白（TP）、总胆红素（TBI）、总胆汁酸（TBA）等,并进行比较。结果硫普罗宁治疗组较对照组在肝功能复常方面显示良好的治疗效应,使转氨酶明显下降,两组显效率分别为50%（21/42）和30%（13/42）,总有效率为84%（35/42）和50%（21/42）,两组比较差异有显著性（P〈0.01）。结论短期临床研究提示硫普罗宁治疗慢性乙型肝炎,可明显改善肝功能,且不良反应少,疗效显著。     

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.     

恩替卡韦分散片治疗乙型肝炎E抗原阴性代偿期慢性乙型病毒性肝炎的临床研究

目的观察恩替卡韦分散片治疗乙型肝炎E抗原(HBe Ag)阴性的代偿期慢性乙型病毒性肝炎(CHB)患者的临床疗效及安全性。方法将95例HBe Ag阴性代偿期CHB患者按血清HBV DNA水平分为对照组42例(低病毒载量,HBV DNA<7.00 log10U·m L^-1)和试验组53例(高病毒载量,HBV DNA≧7.00log10U·m L^-1)。2组患者均给予恩替卡韦0.5 mg,qd,空腹口服,连续48周。比较2组患者治疗48周后临床有效率以及药物不良反应(ADR)的发生情况;治疗前和治疗后12周,用放射免疫法检测血清HBV DNA、III型前胶原肽(PCIII);用生化分析仪测定谷丙转氨酶(ALT)水平。结果治疗48周后,试验组和对照组的总有效率分别为83.02%,85.71%,差异无统计学意义(P>0.05)。治疗12周后,试验组和对照组血清HBV DNA、PCIII和ALT水平分别为(4.92±0.78)log10U·m L^-1,(162.34±13.28)μg·L^-1,(95.31±12.19)U·L^-1;(3.89±0.75)log10U·m L^-1,(140.56±10.42)μg·L^-1,(79.62±11.91)U·L^-1,差异均有统计学有意义(均P<0.05)。治疗24,48周后,试验组和对照组的以上指标差异均无统计学意义(均P>0.05)。试验组和对照组ADR发生率分别为7.55%,7.14%,组间差异无统计学意义(P>0.05)。结论恩替卡韦分散片能降低患者HBV DNA水平,减缓肝纤维化进程和改善肝功能,其对不同病毒载量患者在24周以后的远期效果无明显差异,且较为安全。