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.     

Entecavir: new drug. Chronic hepatitis B: a last resort

(1) For patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a is the standard treatment used to prevent clinical complications and death. Lamivudine and adefovir dipivoxil, both taken orally, are second-line options. They can also be used as first-line treatments in patients with HBeAg-negative chronic hepatitis B if the adverse effects of prolonged peginterferon therapy are likely to pose a major problem. (2) Entecavir, a nucleoside analogue, is now marketed for oral treatment of chronic hepatitis B in adults. (3) Entecavir has not been compared with adefovir in clinical trials. Its evaluation is based mainly on three 48-week trials versus lamivudine. When given at a dose of 0.5 mg/day to patients who had not yet received antiviral treatment, and at a dose of 1 mg/day to patients in whom lamivudine had failed, entecavir was significantly more effective than lamivudine, in terms of effects on liver histology and viral load. The possible clinical implications of these effects are not known. (4) In these trials, similar types and frequencies of adverse effects occurred with entecavir and lamivudine, mainly consisting of headache (about 20% of patients) and other neurological disorders. Hepatitis rebound occurred in less than 10% of patients during or after both treatments but at slightly different times. (5) Entecavir was carcinogenic in experimental animals. No increase in the frequency of cancer has been seen in clinical trial participants thus far, but follow-up is limited. (6) Given the uncertainties concerning the potential adverse effects of entecavir and the fact that it affects viral load in patients in whom lamivudine fails, entecavir should only be used when lamivudine and adefovir have failed.     

Entecavir for chronic hepatitis B: a review

Three nucleotide/nucleoside analogs are currently used for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are beneficial for oral administration and safety, but only a few of the patients treated experience a sustained response after therapy withdrawal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of chronic hepatitis B virus DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. In phase II and phase III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients as well as being effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown evidence of cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day.     

Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B

Infection with hepatitis B virus (HBV) is extremely widespread - it infects two billion people out of the six billion world population. It is estimated that between 350 and 400 million people are chronically infected with HBV. Chronic HBV infection leads to development of complications, such as cirrhosis and hepatocellular carcinoma (HCC), which arise in 15-40% of patients. HBV-related liver disease and its complications result in approximately one million deaths each year. The ultimate goals of chronic hepatitis B (CHB) therapy are decreases in the incidence of cirrhosis, end-stage liver disease and HCC. The following six medications are currently approved by the U.S. Food and Drug Administration for the treatment of CHB: interferon (INF)-alpha2b, pegylated INF-alpha2a, lamivudine, adefovir dipivoxil, entecavir and, recently, telbivudine. Interferon therapy has many contraindications and commonly causes multiple intolerable adverse effects. Lamivudine therapy leads to increased development of resistant mutations with each year of use. Entecavir, a new guanosine nucleoside analogue with specific activity against HBV DNA polymerase, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class. It has distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects and has a limited potential for resistance. In clinical trials, entecavir was superior to lamivudine in all primary endpoints in both nucleoside-naive and lamivudine-refractory hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Preliminary data support entecavir efficacy in patients with cirrhosis and HIV/HBV coinfected patients. No resistance occurred after two years of entecavir therapy in nucleoside-naive patients. Up to 9% resistance developed in patients with documented prior lamivudine resistance during 96 weeks of entecavir therapy. Currently, entecavir should be considered a first- or second-line treatment option for the management of HBeAg-positive or -negative nucleoside-naive or lamivudine-refractory CHB patients.     

Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection

BACKGROUND: Chronic hepatitis B infection carries considerable risk for the development of cirrhosis and hepatocellular carcinoma. Treatment options are increasing but are limited to interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir dipivoxil, and entecavir. Entecavir, a nucleoside analog, is the newest oral antiviral approved in the United States for treatment of chronic hepatitis B. OBJECTIVE. To review the available data for entecavir regarding its pharmacology, pharmacokinetics, safety, efficacy, and clinical use. METHODS. A MEDLINE, EMBASE, and Cochrane search of the English-language literature from January 1997-May 2006 was performed. Preapproval studies provided by the manufacturer and abstracts from recent scientific meetings on infectious disease and hepatology were also reviewed. RESULTS. Three phase III clinical trials representing more than 1600 subjects established the superior efficacy and equivalent safety of entecavir compared with lamivudine for treating patients who are hepatitis B early antigen (HBeAg) positive, HBeAg negative, or refractory to lamivudine. Entecavir resistance has not occurred in nucleoside-na?ve patients but may develop in those who already possess lamivudine resistance mutations. CONCLUSION. Trial results, along with previously published response rates for adefovir dipivoxil and interferon monotherapy, make entecavir the preferred first-line treatment option for patients with chronic hepatitis B who are nucleoside na?ve, HBeAg positive or negative, and have compensated liver disease. Both entecavir and adefovir dipivoxil maintain activity against hepatitis B virus in patients with chronic hepatitis B who are refractory to lamivudine, and both agents are reasonable first-line treatment options. Longer trials involving nucleoside-na?ve, lamivudine-refractory patients are needed to determine entecavir's optimal treatment duration, long-term safety, and durability of response, including rate of resistance.     

Entecavir: a step forward in combating hepatitis B disease

Background: Entecavir (ETV) is a potent deoxyguanosine nucleoside analog with a very good safety record. Objectives/methods: This review provides a comprehensive overview on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of entecavir obtained through an extensive literature search. Results/conclusion: ETV inhibits all three steps of hepatitis B virus replication via entecavir – triphosphate, its intracellular active form, by dose-dependently competing with deoxyguanosine triphosphate for incorporation into DNA. Superior efficacy of ETV over lamivudine (LVD) has been shown in four double-blind, randomized controlled clinical trials encompassing a large cohort of treatment naive HBeAg-positive and HBeAg-negative patients and LVD-refractory HBeAg-positive patients. Prolongation of ETV treatment is associated with further improvement of efficacy. In treatment-naive patients, cumulative probability of ETV resistance and viral breakthrough after 5 years of treatment has been reported as 1.2 and 0.8%, respectively. ETV displays low cytotoxicity in proliferating cultured liver cell and has an excellent safety in clinical use.     

Entecavir: a review of its use in chronic hepatitis B

Entecavir (Baraclude) is a novel nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus (HBV). In large, randomised, double-blind, phase III clinical trials in patients with chronic HBV infection, oral entecavir 0.5 or 1.0mg once daily for up to 96 weeks was superior to lamivudine 100 mg/day in improving hepatic histology, normalising aminotransferase levels and suppressing viraemia to levels undetectable by polymerase chain reaction (PCR) assay in nucleoside-naive hepatitis B e antigen (HBeAg)-negative (precore or core promoter mutants) and/or HBeAg-positive patients, and in lamivudine-refractory (persistent viraemia during lamivudine therapy) HBeAg-positive patients. In addition, the tolerability profile of entecavir was generally similar to that of lamivudine. Thus, entecavir is a primary option in the treatment of chronic HBV infection in both nucleoside-naive and lamivudine-refractory patients.     

Recent advances in antiviral agents: antiviral drug discovery for hepatitis viruses

Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated liver diseases are now one of the important health problems in the world because of the high numbers of patients and the serious consequences. Recently, however, relatively effective treatments with antiviral agents have become available. Interferon (IFN), lamivudine and adefovir are now approved for treatment of HBV-associated liver diseases and they have been shown to be fairly effective. The goal of treatments for HBV-associated liver disease is to achieve a clinical cure in as short a period as possible without producing resistance mutation of the virus. Several nucleotide analogues with more potent antiviral activities are now in clinical trials. In the case of HCV-associated liver diseases, Pegylated IFN (Peg IFN) + ribavirin combination therapy is the standard and most effective treatment with a sustained response of 60-70%. The goal of the treatments for these liver diseases is to induce the complete eradication of the infected virus and at present new anti HCV drugs targeting the molecular segments of the virus are under development. It is expected that the complete eradication of infected virus will be possible in most cases in the near future.     

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.     

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。     

The current status and future directions of hepatitis B antiviral drug discovery

Introduction: The current standard care of chronic hepatitis B fails to induce a durable off-drug control of hepatitis B virus (HBV) replication in the majority of treated patients. The primary reasons are its inability to eliminate the covalently closed circular (ccc) DNA, the nuclear form of HBV genome, and restoration of the dysfunctional host antiviral immune response against the virus. Accordingly, discovery and development of therapeutics to completely stop HBV replication, eliminate or functionally inactivate cccDNA as well as activate a functional antiviral immune response against HBV are the primary efforts for finding a cure for chronic hepatitis B.

Area covered: Herein, the authors highlight the current efforts of HBV drug discovery and offer their opinions for the future directions of this research.

Expert opinion: The authors believe that through a consecutive or overlapping three-stage antiviral and immunotherapy program to: (i) completely stop HBV replication and cccDNA amplification; (ii) reduce viral antigen load and induce HBV surface antigen (HBsAg) seroclearance through eradication or inactivation of cccDNA and RNA interference-mediated degradation of viral mRNA and (iii) activate a functional antiviral immune response against HBV through therapeutic immunization or immunotherapy, a functional cure of chronic HBV infection can be achieved in the majority of chronic HBV carriers.     

拉米夫定治疗乙型肝炎的抗病毒疗效和耐药性

拉米夫定是第1个正式进入临床治疗慢性乙型肝炎病毒(HBV)感染的口服核苷类药物。现对拉米夫定治疗乙型肝炎病毒感染的作用特点、临床应用、病毒变异以及对疗效的影响进行综述。     

恩替卡韦与替比夫定治疗慢性乙型肝炎的临床效果对比分析

目的 对比恩替卡韦与替比夫定治疗慢性乙型肝炎(CHB)的临床效果.方法 选取2013年3月至2015年3月本院感染科收治的120例CHB患者,根据随机数字表法将患者随机分为恩替卡韦组(ETV组,60例)与替比夫定组(LDT组,60例).治疗周期为72周.比较两组丙氨酸转氨酶(GTP)转复率、HBeAg阴转率、HBV-DNA阴转率及HBeAg血清学转换率等应答情况,并分析治疗24周后患者HBV-DNA转阴情况对其治疗72周后疗效的影响.结果 治疗后12周、24周、48周、72周,两组GTP转复率、HBeAg阴转率、HBeAg血清学转换率比较,差异均无统计学意义(P＞0.05);治疗24周时,ETV组HBV-DNA水平明显低于LDT组(P＜0.05),但在治疗12周、48周、72周时两组HBV-DNA水平比较,差异均无统计学意义(P＞0.05).无论是ETV组还是LDT组,HBV-DNA＜31g拷贝/ml组在72周时的GTP转复率、HBeAg阴转率均明显高于HBV-DNA≥31 g拷贝/ml组.结论 CHB患者治疗24周后HBV-DNA水平能有效预测患者的长期疗效,在治疗CHB方面,恩替卡韦与替比夫定的疗效、耐药率、不良反应等效果相当,但恩替卡韦的早期抗HBV-DNA效果明显优于替比夫定.     

Dasabuvir: a new direct antiviral agent for the treatment of hepatitis C

Introduction: Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) has revolutionized the care of infected patients. Among these novel compounds are non-nucleoside analogs, which bind viral RNA-dependent RNA polymerase resulting in a conformational change inhibiting RNA synthesis.

Areas covered: Efficacy and tolerability of treatment regimens containing the non-nucleoside analog polymerase inhibitor dasabuvir (ABT-333).

Expert opinion: Dasabuvir-containing regimens achieve high rates of sustained virologic response in HCV genotype 1a and 1b–infected patients when combined with other DAAs, namely paritaprevir (ABT-450), ritonavir and ombitasvir (ABT-267). In the populations studied, dasabuvir seems to be well tolerated and safe. The major limitations of this novel drug are its genotype-restricted activity, the necessity to include ribavirin for HCV genotype 1a and the emergence of resistance if not combined with other DDAs.     

Telbivudine: new drug. Chronic hepatitis B: similar to lamivudine

Telbivudine does not offer any tangible advantage over existing treatments. It is better to continue to use lamivudine, which is known to prevent clinical complications and has been in use for many years.     

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.     

恩替卡韦治疗HBeAg阳性慢性重度乙型肝炎临床疗效

目的评估恩替卡韦治疗HBeAg阳性慢性重度乙型肝炎临床疗效。方法将HBeAg阳性慢性重度乙型肝炎患者58例随机分为治疗组29例和对照组29例,治疗组用恩替卡韦0.5 mg/天治疗,疗程为48周,前4周加用保肝药物治疗。对照组患者保肝治疗,疗程为48周。结果治疗组ALT复常率（93.1%）、HBeAg阴转率（44.8%）、HBeAg/抗HBe转换率（41.4%）、HBV DNA阴转率93.1%均显著高于对照组（P值〈0.05）,且治疗组肝组织病理炎症活动度好转率（93.1%）和纤维化好转率（72.4%）也显著高于对照组（P值〈0.05）,对照组有13.8%发生重型肝炎和13.8%发生肝硬化,而治疗组无病人发生重型肝炎和肝硬化（P值〈0.05）。结论恩替卡韦对HBeAg阳性慢性重度乙型肝炎有较好的临床疗效,能阻止重型肝炎和肝硬化的发生。     

恩替卡韦在治疗乙型肝炎病毒相关肝病中的应用

恩替卡韦(entecavir,ETV)是新一代核苷酸类抗病毒药物,具有强效抗病毒作用和极低耐药性的特点,被广泛用于治疗乙型肝炎病毒(hepatitis B virus,HBV)相关的慢性肝炎、肝硬化和急慢性重型肝炎等疾病.此文就ETV在HBV相关肝病的临床治疗中的应用作一综述.