核苷类抗乙肝药物新进展

近年来核苷类抗乙型肝炎病毒药物的研究趋热。本文总结了近年来应用于临床的核苷类抗乙型肝炎病毒药物,供同道参考。1拉米夫定(L am ivud ine)为一L型双脱氧核苷类似物。该药95年首次在美国上市,99年在我国上市,能有效抑制HBV的DNA。2阿德福韦(A defov ir)为腺嘌呤核苷类似物。     

抗乙型肝炎病毒核苷类似物耐药机制的研究进展

核苷类似物是目前临床上治疗乙型肝炎的重要抗病毒药物,然而由于长期用药,很容易产生耐药性,药物疗效不是很理想。本文就目前抗乙型肝炎病毒(HBV)核苷类似物进行比较并分析其耐药机制。     

乙型肝炎病毒拉米夫定耐药的监测

随着抗HBV核苷类似物的临床应用，如何组织和开展核苷类似物HBV耐药性监测计划并指导各级医院和国家的抗HBV耐药监测的规范和管理，正确认识核苷类似物的耐药性，这些问题已成为临床医师关注的焦点，研究HBV耐药性对治疗效果的影响可能有重要的临床价值/     

2006—2008年我院门诊抗乙型肝炎病毒药物使用分析

慢性乙型肝炎（CHB）是由乙型肝炎病毒（HBV）感染引起的病死率较高的一种传染性疾病。在CHB治疗原则上,认为抗病毒治疗是其中最主要、最根本的治疗措施。目前国内外公认的抗HBV药物主要有干扰素类和核苷（酸）类似物两大类。为了解我院这两大类抗病毒药使用情况,现将我院2006-2008年度干扰素和核苷（酸）类似物抗病毒药的使用情况及用药趋势进行汇总分析。     

基于病毒靶点的乙型肝炎的抗病毒药物研究进展

乙型肝炎病毒(HBV)感染是导致肝硬化和肝癌的主要原因,抗病毒是治疗慢性乙型肝炎的关键.目前用于治疗HBV感染的药物主要集中于干扰素和核苷类似物,但效果并不十分令人满意.因此,寻找具有新的靶点和作用机制的抗HBV药物至关重要.文中对近年来发展的部分抗HBV药物的作用靶点和作用机制进行综述.     

以核衣壳为靶点的抗乙型肝炎病毒药物研究进展

乙型肝炎病毒(HBV)感染是导致肝癌和肝硬化的主要原因,HBV的流行严重危害人民健康,对社会经济发展具有不容忽视的制约作用。目前用于治疗HBV感染的药物主要为干扰素和核苷类DNA聚合酶抑制剂,但干扰素的低应答率,核苷类药物的耐药性及停药后反弹的问题一直没有得到很好的解决。因此,寻找具有新作用机制的抗HBV药物一直受到人们的重视。本文对以核衣壳为靶点的新型抗HBV药物的研究进行了综述,这种新作用机制药物的发现对于延缓甚至阻止耐药病毒株的出现具有特殊的意义。     

核苷类似物在慢性乙型肝炎抗病毒治疗中的效果评价

<正>国内外公认有效的治疗慢性乙型肝炎病毒(HBV)药物主要包括干扰素和核苷类似物,核苷类似物主要通过作用于HBV的聚合酶区发挥抗HBV疗效,药物进入体内后首先磷酸化为三磷酸盐或二磷酸盐形式,然后取代HBV复制过程中聚合酶链延长所需的结构相似的核苷,从而终止链     

慢性乙型肝炎病毒感染的治疗策略

慢性乙型肝炎病毒（HBV）感染可导致肝硬化和肝细胞癌，在高发地区它的流行性可达10％，在美国也有125万人被感染。在出现核苷类似物以前，α干扰素一度是惟一治疗途径，干扰素治疗需要严格选择病人。拉米夫定是研究最多的一种核苷类药物，对大多数病人来说，拉米夫定会都会产生对HBV DNA的抑制，但长期用拉米夫定会产生在DNA聚合酶的YMDD区域有碱基对取代的特异性拉米夫定耐药病毒。新的核苷类似物和免疫调节治疗正在研究之中。     

拉米夫定抗乙型肝炎病毒的耐药性及对策

乙型肝炎病毒 (HBV)感染严重危害人类健康 ,WHO估计 ,至 2 0 0 0年全球范围内HBV携带者达 4亿人口[1] 。我国估计有 1 3亿慢性HBV感染者 ,其中 2 0 0 0万左右是需抗病毒治疗的慢性进展性肝病患者。近年抗病毒药物的发展使有效、系统地治疗慢性乙型肝炎成为可能。新一代抗病毒药物核苷类似物对HBV有很强的抑制作用 ,且不良反应少 ,是治疗慢性乙肝的一大突破。新近发展的核苷类似物主要包括两类 :一类是嘌呤类 ,如泛昔洛韦 (famci clovir,FCV)、喷昔洛韦 (penciclovir ,PCV)、更昔洛韦(ganciclovir,GCV)、阿德福韦 (adefovir,ADV)…     

乙型肝炎病毒的耐药和耐药管理

抗病毒治疗是慢性乙型肝炎(以下简称乙肝)最根本的治疗方法,目前公认有效的抗乙型肝炎病毒(HBV)药物主要包括干扰素(IFN)类和核苷(酸)类似物.自1998年拉米夫定在全球上市以来,迄今已有拉米夫定(LAM)、阿德福韦酯(ADV)、恩替卡韦(ETV)和替比夫定(LdT)共4种核苷(酸)类似物获国家食品药品监督管理局(SFDA)批准用于抗HBV治疗.相对于干扰素,口服核苷(酸)类似物治疗具有方便有效的优点,但该类药物只有长期治疗才有望实现持久应答,使得HBV产生耐药性的风险大大增加.     

Emerging pipeline drugs for hepatitis B infection

INTRODUCTION: Chronic hepatitis B virus (HBV) infection continues to represent a global health concern with an estimated 350 - 400 million people infected worldwide. Current treatment options are either of two IFN-based therapies or either of five oral nucleos(t)ide analogs which are used as monotherapy or in combination. Control of viral replication can be achieved basically in all patients today. However, despite the clinical efficacy of antivirals, long-term management remains a clinical challenge mainly due to the slow kinetics of HBsAg clearance. Emergence of viral resistance has been a challenge in the past with some but not all oral therapies. The development of novel therapeutic agents with different mechanisms of action might provide new opportunities to clear HBsAg and achieve HBsAg seroconversion which could be maintained off therapy. The long-term efficacy of combinations of IFN and/or nucleos(t)ide analogs might achieve antiviral synergy, preventing drug resistance and clearing viral covalently close circular DNA and infected cells. AREAS COVERED: This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of chronic hepatitis B infection. EXPERT OPINION: Currently, entecavir and tenofovir offer a safe and effective treatment option for patients with chronic HBV with minimal to no resistance. Although entecavir and tenofovir are able to suppress replication in essentially all patients, achieving HBsAg seroconversion remains suboptimal among all antiviral therapy. There are a number of new therapies in the pipeline for the treatment of chronic HBV infection as well as revisiting IFN combined or sequential to antiviral therapy.     

Review article: chronic hepatitis B – anti‐viral or immunomodulatory therapy?

Aliment Pharmacol Ther 2011; 33: 501–513

Summary

Background First‐line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG‐IFN). The optimal choice for individual patients remains controversial. Aim To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG‐IFN. Methods A comprehensive literature search was undertaken. Results Long‐lasting, treatment‐maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off‐treatment response is, however, unlikely and long‐term therapy must be anticipated. PEG‐IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre‐treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG‐IFN therapy. Furthermore, on‐treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG‐IFN treatment course, thereby preventing unnecessary treatment. Conclusions Both nucleos(t)ide analogues and PEG‐IFN can be prescribed as first‐line treatment options for CHB. However, PEG‐IFN should only be considered for patients with a high chance of response based on pre‐treatment and on‐treatment factors.     

Systematic review: combination therapies for treatment-naïve chronic hepatitis B

Background  There is a renewed interest in use of combination therapies in treatment-naïve chronic hepatitis B (CHB) because of limitations of monotherapies.
Aim  To discuss the current status of combination therapies in treatment-naïve CHB.
Methods  PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms.
Results  The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons.
Conclusions  The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.     

乙型肝炎肝硬化抗病毒治疗研究进展

乙型肝炎病毒（HBV）感染是全世界主要的公共卫生问题之一。HBV感染后易进展为肝硬化,核苷（酸）类似物是乙型肝炎肝硬化患者重要的抗病毒治疗药物,本文综述核苷（酸）类似物对乙型肝炎肝硬化的治疗进展。     

慢性乙型肝炎抗病毒治疗方案探讨

慢性乙型肝炎（CHB）的治疗药物主要包括两大类即聚乙二醇化干扰素α和核苷（酸）类似物,临床一直致力于寻找最佳治疗方案以期提高抗病毒疗效。本文主要综述两类药物的优势与局限,探讨聚乙二醇化干扰素α联合核苷（酸）类似物治疗CHB的策略。     

抗肿瘤药物和免疫抑制剂相关的乙型肝炎病毒再激活

肿瘤患者接受抗肿瘤联合化疗方案和免疫抑制剂治疗时可导致潜伏或静止状态的乙型肝炎病毒（HBV）发生再激活,出现肝炎症状,伴随HBV DNA水平高于基线10倍以上或绝对值大于20 000 IU/ml。HBV再激活可致4.5%～8.1%的患者死于肝病,23.3%～71.0%的患者中断或改变肿瘤化疗方案。肿瘤患者化疗后HBV 再激活的机制可能是抗肿瘤药物及免疫抑制剂抑制了机体对HBV起免疫作用的T细胞和自然杀伤细胞,导致HBV大量复制。肿瘤患者HBV再激活与患者的HBV感染状况、肿瘤类型和化疗方案有关。拉米夫定等核苷（酸）类药物可有效预防和治疗肿瘤患者的HBV再激活。肿瘤患者接受化疗前应常规进行HBV筛查,对高风险患者预防性使用核苷（酸）类药物可明显降低HBV再激活的发生率和严重程度。     

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.     

Design, synthesis, and biological evaluation of triazolo-pyrimidine derivatives as novel inhibitors of hepatitis B virus surface antigen (HBsAg) secretion

The high levels of hepatitis B virus (HBV) surface antigen (HBsAg)-bearing subviral particles in the serum of chronically infected individuals play an important role in suppressing HBV-specific immune response and are only mildly affected by the current small molecule therapies. Thus, a therapy that specifically reduces HBsAg serum levels could be used in combination therapy with nucleos(t)ide drugs or permit therapeutic vaccination for the treatment of HBV infection. Herein, we report the design, synthesis, and evaluation of novel triazolo-pyrimidine inhibitors (1, 3, and 4) of HBsAg cellular secretion, with activity against drug-resistant HBV variants. Extensive SAR led to substantial improvements in the EC(50) of the parent compound, 5 (HBF-0259), with the best being 3c, with EC(50) = 1.4 ± 0.4 μM, SI ≥ 36. The lead candidates, both 1a (PBHBV-001) and 3c (PBHBV-2-15), were well-tolerated in both normal and HBV-transgenic mice and exhibited acceptable pharmacokinetics and bioavailability in Sprague-Dawley rats.     

Emerging drugs for the treatment of hepatitis B

Introduction: Nucleos(t)ide analogs and interferon-based compounds are currently approved for the treatment of chronic hepatitis B (CHB). Although these treatments are effective in suppressing viral replication, it is unable to completely eradicate the virus from the host. Therefore, CHB patients are at a life-long risk of developing complications, including hepatocellular carcinoma.

Areas covered: Drugs targeting novel sites of the hepatitis B virus (HBV) replication cycle and the host immune response in development are discussed. As current available drugs only target a small segment of the HBV life cycle, the development of new agents targeting different sites is an important step in eradicating HBV. The host immunological response is also vital in viral clearance. Newer agents in development include immunomodulatory agents and therapeutic vaccines.

Expert opinion: For any chance of eradication, a combination of drugs targeting both the host factors and different sites of the viral life cycle will be required. Two key components to achieving this goal include the removal of covalently closed circular DNA (cccDNA) together with restoration of the immune control against HBV.