Prevention and management of drug resistant hepatitis B virus infections

肝胆速递

Prevention and management of drug resistant hepatitis B virus infections

    Cheng Wang,
    Rong Fan,
    Jian Sun,
    Jinlin Hou*
Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
*Professor Jinlin Hou, Hepatology Unit and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, No 1838 North Guangzhou Avenue, Guangzhou 510515, China. Email address: [email protected]

Article first published online: 21 AUG 2012
Journal of Gastroenterology and Hepatology
DOI: 10.1111/j.1440-1746.2012.07198.x

Abstract
In the past decade, broadened therapeutic options of oral direct antiviral agents for the treatment of chronic hepatitis B infection include: Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir and Tenofovir Disoproxil Fumarate. These direct oral antiviral agents effectively suppress the replication of the virus and reduce the risk of potential liver-related complications. However, prolonged use of these nucleos(t)ide analogues has been associated with drug resistance that compromises the initial clinical benefits. Moreover, the oncogenic risk of mutations due to prolonged nucleos(t)ide analogue therapy needs to be further investigated by in vitro and in vivo studies. In the current era of potent nucleotide analogues, new data are emerging, we are still facing the pool of patients who have developed resistance to the prior generation of nucleos(t)ide analogues. This paper aims to focus on incidence of antiviral drug resistance and virological breakthrough, prudent selection of initial therapy, on-treatment monitoring for drug resistance and revise treatment strategies for patients with resistant virus.

Background
Hepatitis B virus (HBV) infects 400 million people worldwide; more than 75% of those reside in the Asia-Pacific area.1 Chronic hepatitis B (CHB) infection is the major risk factor for cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC).2,3 Increasing serum HBV DNA level is a strong predictor associated with progression to cirrhosis and HCC.4,5 Substantial advances have been made during the last decade with the worldwide clinical use of nucleos(t)ide analogues (NA). Since 1998, five NA have been licensed: Lamivudine (LAM), Adefovir dipivoxil (ADV), Telbivudine (LdT), Entecavir (ETV) and Tenofovir Disoproxil fumarate (TDF). These direct oral antiviral agents effectively suppress the replication of HBV and reduce the risk of potential liver-related complications. Sustained and profound suppression of viral replication together with reversal of fibrosis and cirrhosis are achievable.6 Based on specific viral kinetics and low sustaining off-treatment response, long-term NAs treatment is necessary.7,8 However, the major concern of prolonged NA treatment of CHB can result in development of antiviral resistance with reduced sensitivity to the antiviral agents, thus compromising the initial clinical benefits.

Perspectives
While major advances in the treatment of CHB has been made in the past decade, the prevention and management of drug resistance is still very challenging. The role of periodical monitoring of quantitative HBsAg level and HBV genotypes remains controversial. Oncogenic potential of drug resistance needs further investigation. To ultimately overcome the cross-resistance and multiple resistances, the development of drugs with distinct antiviral mechanism of NA is essential. Chinese scientists recently indicated that combination of NA with Oxymatrine, a natural drug extracted from a Chinese herb (Kushen), could reduce the chance of developing drug resistance.105 Such agents provide complementary treatment options. In this era of potent NA treatment, options have been expanded; various combination regimens including interferon-based therapies are available. However, the efficacy of the best combination, best timing of initiation, duration of therapy, potential add-on side effects due to drug interaction are uncertain. Although theoretically attractive, these combinations and applications from bench to bedsides still await justification from larger scale clinical studies and cost–benefit analyses.

肝胆速递

预防和管理耐药的乙肝病毒感染

    成王，
    樊荣，
    孙立坚，
    侯金林*
部传染病和肝病学单位，南方医科大学，南方医院，广州，中国
侯金林教授，肝病单位和器官衰竭的研究重点实验室，南方医科大学南方医院，南方医科大学，1838年北广州大道，广州510515，中国。电邮地址：[email protected]

在网上公布：2012年8月21日

DOI：10.1111/j.1440-1746.2012.07198.x

抽象
在过去的十年中，扩大的口服直接抗病毒的药物用于治疗慢性B型肝炎感染，包括拉米夫定，阿德福韦酯，替比夫定，恩替卡韦和替诺福韦富马酸的治疗方案。这些直接口服抗病毒药物有效地抑制病毒的复制，并减少潜在的肝脏相关并发症的风险。然而，长时间使用一直伴随着这些核苷（酸）类似物耐药性，损害了初步的临床益处。此外，由于长期的核苷突变的致癌风险（T）类似物治疗需要进一步研究在体外和体内研究。在当前的时代强效的核苷类似物，新的数据不断涌现，我们仍然面临着池已与前一代的核苷（酸）类似物耐药性的患者。本文旨在集中在抗病毒耐药性的发生率和病毒学突破，审慎选择初始治疗，对治疗耐药性的监测和修改患者抗病毒治疗策略。

背景
乙型肝炎病毒（HBV）感染全球400万人，超过75％的人居住在的亚太area.1慢性乙型肝炎（CHB）感染是肝硬化，终末期肝病和肝癌的主要危险因素。 （HCC）。2,3增加血清HBV DNA水平与进展为肝硬化和HCC.4是一个强有力的预测，5重大进展，已在过去十年中，全球临床使用核苷（酸）类似物（NA ）。自1998年以来，NA已被授权：拉米夫定（LAM），阿德福韦酯（ADV），替比夫定（LDT），恩替卡韦（ETV）和富马酸替诺福韦酯（TDF）。这些直接口服抗病毒药物有效地抑制乙肝病毒的复制，并减少潜在的肝脏相关并发症的风险。持续而深刻的抑制病毒复制，逆转纤维化和肝硬化的achievable.6基于特定的病毒动力学和低维持治疗反应，长期NAS治疗是必要，8过，主要关注长期NA治疗慢性乙型肝炎可导致发展的抗病毒药物耐药的抗病毒药物的敏感性降低，从而影响了最初的临床利益。

在过去的十年中，虽然在慢性乙型肝炎的治疗已经取得了重大进展，预防和管理耐药性仍然是非常具有挑战性的。 HBsAg定量水平的定期监测和HBV基因型的作用仍存在争议。致癌潜在的耐药性，需要进一步调查。为了最终克服交叉耐药性和多个电阻，发展的药物具有明显的抗病毒机制的NA是必不可少的。中国科学家日前表示，组合的NA，氧化苦参碱（苦参）从中国草药中提取的一种天然的药物，可减少开发药物的机会resistance.105这些代理商提供互补的治疗方案。在这个时代的强效NA治疗，可一直在扩大，各种组合方案包括干扰素为基础的治疗。然而，疗效的最佳组合，最佳时机，治疗时间开始，潜在的附加的副作用，由于药物的相互作用是不确定的。虽然理论上是有吸引力的，这些组合和应用从实验室到床边，仍有待于更大规模的临床研究和成本效益分析的理由。

StephenW

这是侯金林教授，广州南方医科大学南方医院的医生写的评论文章.
整篇文章的链接：
http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2012.07198.x/full