直接抗病毒药物治疗慢性丙型肝炎的作用机制

近年来随着直接抗病毒药物(DAAs)在全球的研发上市,慢性丙型肝炎的治疗方案不断演化,DAAs在我国也即将上市。DAAs主要作用于HCV的非结构蛋白,抑制HCV RNA的复制。介绍了各类DAAs的作用靶位、作用机制、耐药特性以及在中国的研发现状和临床Ⅲ期试验结果,旨在为慢性丙型肝炎DAAs联合其他抗病毒治疗方案提供临床参考。     

慢性丙型肝炎直接抗病毒药物应用现状及存在问题

慢性丙型肝炎可导致肝硬化、肝细胞癌等终末期肝病的发生,及时抗病毒治疗是改善预后的关键。直接抗病毒药物(DAAs)的诞生及发展使慢性丙型肝炎治疗发生了划时代的改变。当下世界各国正逐渐或已经步入DAAs时代,我国DAAs获批上市较晚,药物应用于临床时间短,临床数据有限。主要从国外相关研究出发,对适合我国患者的DAAs代表药物、治疗方案及存在的问题进行综述。     

慢性丙型肝炎抗病毒药物及其治疗方案研究进展

慢性丙型肝炎成为全球严重的公共卫生问题,近年来随着丙型肝炎的药物治疗不断发展,使丙型肝炎治愈成为可能。从丙型肝炎的流行现状,传统的标准治疗方案(聚乙二醇干扰素+利巴韦林)以及不同的口服小分子直接抗病毒药物(DAAs)的优势及副作用,总结了不同DAAs药物组合对于不同慢性丙型肝炎基因型治疗的利弊,并简要介绍了世界卫生组织对于丙型肝炎治疗的推荐意见。相信未来慢性丙型肝炎的药物治疗会不断飞跃,消灭丙型肝炎指日可待。     

慢性丙型肝炎病毒感染的治疗:热点、难点和希望

2011年3月欧洲肝病年会发布新版《欧洲临床实践指南:丙型肝炎病毒感染的处理》的时候,聚乙二醇干扰素α(PEG-IFNα)联合利巴韦林(RBV)仍然是慢性丙型肝炎的标准治疗方案.但紧随其后,2011年5月两种直接抗HCV药物(direct acting antivirals,DAAs)在美国和欧洲陆续批准上市,即telaprevir和boceprevir两个蛋白酶抑制剂.2011年8月8日,JHepatol在线发表了法国Beaujon医院Asselah[1]撰写的述评,提出DAAs的迅速发展使在PEG-IFNα联合RBV的基础上加用DAAs(三联治疗)成为新的标准治疗方案.这一最新的进展显示了目前慢性HCV感染治疗的热点和随之带来的难点和希望.     

直接抗病毒药物抗HCV治疗进展

聚乙二醇干扰素α联合利巴韦林是慢性丙型肝炎的标准抗病毒方案,但其疗效有限,且不良反应明显。直接抗病毒药物(direct-acting antiviral agents,DAAs)的出现为慢性丙型肝炎的治疗提供了更多选择。DAAs包括NS3/4A蛋白酶抑制剂、NS5B多聚酶抑制剂及NS5A抑制剂等。目前已有多种药物完成了临床前研究,部分完成了Ⅲ期临床试验。结果显示使用DAAs可明显提高持续病毒学应答获得率。但DAAs的临床使用经验有限,一些问题如对药物的耐受性、联合使用及耐药等仍须进一步研究。     

丙型肝炎直接抗病毒药物应用中的药物相互作用管理专家共识

正直接抗病毒药物(direct-acting antiviral agents,DAAs)治疗慢性丙型肝炎具有持续病毒学应答率高、疗程短、不良反应发生率低等优点,已广泛用于慢性丙型肝炎抗病毒治疗[1-3]。但是,大部分DAAs经过多种药物代谢酶代谢和不同的药物转     

丙型肝炎抗病毒治疗:口服药物改变了什么?

正慢性丙型肝炎抗病毒治疗的革命性变化是近几年来直接抗病毒药物(direct-acting antiviral agents,DAAs)进入临床,开辟了慢性丙型肝炎抗病毒治疗的新纪元。以DAA为基础的抗病毒方案包括1个DAA联合聚乙二醇干扰素alpha和利巴韦林(PR)、DAAs联合RBV,以及不同DAA联合或复合制剂的应用~([1])。三种方案基本可以涵盖所有类     

丙型肝炎直接抗病毒药物耐药相关变异的研究

直接抗病毒药物(direct-acting antiviral agents,DAAs)的应用使慢性丙型肝炎(chronic hepatitis C,CHC)抗病毒治疗进入了新的时代,全口服的DAAs联合治疗方案抗病毒活性强、安全性好且不良反应少。耐药相关变异(resistanceassociated variants,RAV)的出现削弱了DAAs的抗病毒活性,给DAAs的临床应用带来了巨大的挑战。本文将对临床试验和体外研究中检测到的DAAs RAV及其在CHC患者中的自然发生率进行系统的阐述,以期为DAAs治疗效果的预测和治疗方案的选择提供有用的信息。     

迎接慢性丙型肝炎治疗的春天——DAAs时代的到来

正对于慢性丙型肝炎(chronic hepatitis C,CHC)的抗病毒治疗,直接抗病毒药物(direct-acting antiviral agents,DAAs)无疑是主角和焦点。DAAs自2011年问世以来,使CHC的治疗领域发生了翻天覆地的变化。人们用里程碑、新时代和革命性等词语来评价和期待DAAs对CHC治疗即将带来的影响。是的,就像HAART使AIDS不再是令人绝望的致死性疾病一样,DAAs的应用使得CHC的治愈变得触手可及,     

达拉他韦联合阿舒瑞韦治疗基因1b型慢性丙型肝炎13例报告

正据统计[1],我国一般人群中约有560万HCV感染者,感染率为0. 43%;高危人群和高发地区的HCV感染者约1000万例,每年丙型肝炎新发病例数超过20万。作为肝细胞癌的重要原发病之一,慢性丙型肝炎一直以来都是我国严重的疾病负担。直接抗病毒药物(DAAs)的问世开创了丙型肝炎治疗新时代[1],使丙型肝炎的临床治愈成为可能。现笔者报道应用达拉他韦联合阿舒瑞韦治疗13例慢性丙型肝炎患者的效果及安     

小分子化合物抗丙型肝炎治疗新方案

2015年6月30日Hepatology发布由美国肝病研究学会和美国感染病学会更新的相对完善的丙型肝炎诊治指南推荐意见,就成人丙型肝炎患者的治疗方案达成共识。直接抗病毒药物(direct-acting antiviral agents,DAAs)的类型选择基于HCV基因分型、既往治疗应答情况以及是否存在DAAs相关耐药位点等问题的综合考虑,以便优化治疗,提高抗病毒疗效。同时规范临床合理使用DAAs,可以防止耐药发生,降低治疗成本。     

Challenges and opportunities for hepatitis C drug development in HIV-hepatitis C virus-co-infected patients

The approval of the first direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) has been eagerly expected for treating chronic hepatitis C in HIV individuals given that progression to cirrhosis and end-stage liver disease occurs faster in the co-infected population. The appropriate and judicious use of DAAs may provide cure to a large number of HIV-HCV patients. On the contrary, the widespread use of DAAs will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance in HCV. As a result of using first-generation DAAs in HIV-HCV-co-infected patients, a growing proportion of the remaining hepatitis C individuals will be those harboring non-HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will accumulate in resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.     

Hepatitis C in injection drug users:It is time to treat

Injection drug users(IDUs)are at risk of hepatitis C virus(HCV)infection,due to needle and syringe sharing.Chronic HCV infection is a major cause of liver-related morbidity and mortality but can be cured with antiviral treatment leading to sustained viral response(SVR).It is well demonstrated that,when close cooperation between specialists in drug addiction and psychiatrists is assured,patients on maintenance treatment with methadone/buprenorphine can be treated for HCV with response rate,tolerability and side effects similar to those reported in non-IDUs.Current guidelines recommend that active injection drug use should not exclude patients from HCV treatment,but many services remain reluctant to treat IDUs.No significant pharmacodynamic interactions were reported between approved direct anti-viral agents(DAAs)and buprenorphine or methadone.Dose adjustments are not recommended;therefore DAAs appear to be the"perfect"therapy for patients taking opiate substitutive therapy.These suggestions have been recently recognized by the European Association for the Study of the Liver(EASL)and included in EASL Recommendations on Treatment of Hepatitis C 2016.Guidelines confirm that HCV treatment for IDUs should be considered on an individualized basis and delivered within a multidisciplinary team setting;a history of intravenous drug use and recent drug use at treatment initiation are not associated with reduced SVR and decisions to treat must be made on a case-by-case basis.     

抗HCV小分子化合物的研究

目前抗HCV治疗的标准疗法是聚乙二醇干扰素(PEG-IFN)联合利巴韦林(RBV),但仍有部分患者不能达到治愈。近年来,靶向针对HCV生活周期中病毒蛋白的小分子化合物的研究得到了迅速发展,小分子化合物联合PEG-IFN、RBV三联治疗可以提高持续病毒学应答率。而对于不能应用/耐受干扰素治疗的慢性丙型肝炎患者,各类小分子化合物之间的联合抗病毒治疗也可取得较好的疗效。因此,认为小分子化合物给今后慢性丙型肝炎治疗带来新的希望。     

New treatment strategies for hepatitis c infection

Hepatitis C infection can lead to cirrhosis and hepatocellular carcinoma and it is an important cause of mortality and morbidity. Achieving a sustained virological response has been the major aim for decades. Interferon treatment was the primarily developed therapy against the infection. Addition of the guanosine analog ribavirin to stop viral RNA synthesis increased the response rates as well as the adverse effects of the treatment. The increasing demands for alternative regimens led to the development of direct-acting antivirals(DAAs). The approval of sofosbuvir and simeprevir signaled a new era of antiviral treatment for hepatitis C infection. Although the majority of studies have been performed with DAAs in combination with interferon and resulted in a decrease in treatment duration and increase in response rates, the response rates achieved with interferon-free regimens provided hope for patients ineligible for therapy with interferon. Most DAA studies are in phase Ⅱ leading to phase Ⅲ. In the near future more DAAs are expected to be approved. The main disadvantage of the therapy remains the cost of the drugs. Here, we focus on new treatment strategies for hepatitis C infection as well as agents targeting hepatitis C virus replication that are in clinical development.     

HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy

Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.     

A new standard of care for the treatment of chronic HCV infection

The introduction of direct acting antiviral agents (DAAs) will markedly change treatment options for individuals who have a chronic HCV infection. Within the next few months, licensing of two HCV protease inhibitors (boceprevir and telaprevir) for the treatment of patients with chronic hepatitis C as part of a triple therapy with PEG-IFN-α and ribavirin is anticipated in the USA, Europe and many other countries. Final results of pivotal phase III clinical trials in previously untreated and treatment-experienced patients with HCV genotype 1 infection were presented at the Annual Meeting of the American Association for the Study of the Liver 2010 held in Boston, MA, USA, and at the Annual Conference of the Asian Pacific Association for the Study of the Liver 2011, held in Bangkok, Thailand. This article summarizes the results of these phase III trials in consideration of accumulating data on important baseline and on-treatment predictive factors for treatment response, such as the host IL28B genotype and the rapid virologic response; the introduction of these new therapies into clinical practice is also covered. Furthermore, preliminary data on the combination of different classes of DAAs, such as HCV protease inhibitors and HCV polymerase inhibitors, without interferon α are discussed.     

2012年亚太肝病学会慢性乙型肝炎治疗指南解读

在对乙型肝炎病毒(HBV)感染的深入研究和新的抗病毒药物治疗研究的基础上,2012年亚太肝病学会(APASL)对慢性乙型肝炎防治指南进行了更新。本文对指南推荐意见中关于治疗前评估、治疗的目标和治疗终点以及抗病毒药物的应用策略,包括怎样选择药物及治疗监测、如何停药、如何治疗肝硬化及失代偿的患者、如何防止肝移植患者的复发、如何治疗人类免疫缺陷病毒(HIV)和(或)丙型肝炎病毒(HCV)与HBV重叠感染的患者、如何治疗妊娠患者及如何治疗应用免疫抑制剂及化疗药物的患者等进行解读。     

Treatment of hepatitis C virus infection with direct‐acting antiviral drugs is safe and effective in patients with hemoglobinopathies

Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon‐free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct‐acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow‐up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.     

无干扰素抗HCV方案的研究进展

当前,全球约有1.5亿慢性HCV感染者,其中20%会进展为肝硬化并最终死于终末期肝病和肝癌。干扰素(IFN)长期作为慢性丙型肝炎治疗的基石,在维持持续病毒学应答以及阻止病情进展方面有重要作用,但其疗效有限、不良反应多。近年来,直接抗病毒药物(DAAs)呈现出良好的疗效,在DAAs的基础上,介绍了无IFN抗HCV方案的最新研究进展,认为随着DAAs的出现,无IFN抗HCV方案发展迅速,前景较好。