直接抗病毒药物对儿童慢性丙型肝炎的治疗进展

聚乙二醇干扰素α-2a或α-2b联合利巴韦林是目前治疗儿童慢性丙型肝炎的标准方案。该方案最早应用于成人,对HCV的有效率仅约50%,并且对于儿童HCV的治疗有效率最高也只达70%。近年来,直接作用于HCV基因靶点的抗病毒药物(direct-acting antiviral agents,DAAs)不断被研发出来,对HCV的治疗起到质的飞跃,但该类药物在儿童HCV治疗中的应用大多处在临床试验阶段。本文通过对目前DAAs在儿童慢性丙型肝炎中的研究进展作一综述,以期为HCV患儿的临床治疗提供参考依据。     

丙型肝炎肝硬化直接抗病毒药物治疗的临床结局

丙型肝炎（hepatitis C,简称丙肝）抗病毒治疗已经进入直接抗病毒药物（direct antiviral agents,DAAs）时代,即使是晚期肝硬化患者经DAAs治疗也可以获得较高的持续病毒学应答（sustained virological response,SVR）,但丙肝肝硬化患者经抗丙型肝炎病毒（hepatitis C virus,HCV）治疗后远期效益,如肝功能改善、失代偿肝硬化的再代偿、肝移植率、肝细胞癌（hepatocellular carcinoma,HCC）发生率等仍然值得探讨。文章对DAAs治疗丙肝肝硬化的长期随访结果进行探讨,为上述临床问题的解决提供更多依据,增强临床医生应用DAAs抗HCV治疗的信心。     

直接抗病毒药物对慢性丙型肝炎特殊人群的治疗进展

目前最新的口服直接抗病毒药物不再依赖于干扰素和利巴韦林,该类药对HCV治疗的有效率高达90%以上,这使得丙型肝炎(丙肝)成为可治愈的疾病。然而,在真实世界中,HCV感染的特殊人群(包括合并HIV、HBV共感染,肝移植、肝硬化、肾功能不全以及孕妇、儿童、老人等)的治疗有效率是偏低的,这对口服直接抗病毒药物提出挑战,解决这些挑战最好的办法是了解并掌握药物之间可能存在的风险,从而使更多丙肝特殊人群受益。     

直接抗病毒药物治疗后丙型肝炎相关肝细胞癌的发生与复发

丙型肝炎病毒（HCV）RNA可通过直接抗病毒药物治疗从血液循环中清除,达到持续病毒学应答（SVR）。研究表明,直接抗病毒药物治疗达到SVR后,可降低肝细胞癌（HCC）发病率,但仍需监测HCC的发生。现简要总结现有研究关于抗病毒治疗后丙型肝炎继发HCC可能原因的讨论,主要分为表观遗传学改变与DNA异常甲基化、HCV相关肝...     

慢性丙型肝炎抗病毒药物的新进展

目前全球丙型肝炎病毒(HCV)感染率约为3%,我国的抗-HCV抗体阳性率约3.2%,尚无预防疫苗,以基因Ⅰ型为主(占80%),其中又以Ⅰb型最为常见(占64%)。慢性丙型病毒性肝炎患者随着病情的发展进展为终末期肝硬化或肝癌,     

小分子化合物抗病毒治疗丙型肝炎肝硬化

正直接抗病毒药物(direct-acting antiviral agents,DAAs)对丙型肝炎的治疗效果已取得突破性进展,持续病毒学应答(sustained virologic response,SVR)高达90%~95%~([1])。目前,DAAs主要包括NS3/4A蛋白酶抑制剂、核苷类NS5B聚合酶抑制剂、非核苷类NS5B聚合酶抑制剂、NS5A抑制剂。自     

我国慢性丙型肝炎患者抗病毒治疗现状及药物选择策略分析

目的了解我国慢性丙型肝炎患者抗病毒治疗现状。方法选取2017年7月至2019年3月期间于瑞金医院感染科诊治的慢性丙肝患者,收集其临床及实验室数据,分析抗病毒药物选择的影响因素。结果共入组165例,未治疗者25例,聚乙二醇干扰素联合利巴韦林(PR)方案治疗者8例,基因型特异性直接抗病毒药物(DAA)方案者44例,泛基因型DAA方案者85例。除丙通沙是各基因型最常选择的方案以外,基因1b型患者中,选择基因型特异性DAA的比例(40%,44/111)明显高于其他泛基因型药物(7%,8/111)。结论泛基因型DAA治疗是首选,价格是可选范围内除疗效与安全性以外最重要的决定因素。     

直接抗病毒药物治愈的慢性丙型肝炎患者NK细胞的免疫学特点分析

目的探讨直接抗病毒药物(direct-acting antivirals, DAAs)治愈的慢性丙型肝炎(chronic hepatitis C, CHC)患者NK细胞的免疫学变化。方法入组13例经达拉他韦(daclatasvir, DCV)和阿舒瑞韦(asunaprevir, ASV)治疗24周的初治型HCV 1b型CHC患者,同时入组13例健康者为健康对照(healthy controls, HC)组。采用流式细胞术分析患者治疗前,治疗第24周,治疗结束后随访第12周、24周的外周血NK细胞表型和功能特点。结果 13例CHC患者经DCV/ASV抗病毒治疗均获得持续病毒学应答即临床治愈;与HC组相比,CHC患者抗病毒治疗前外周血NK细胞表达HLA-DR、NKP46、CD38的水平显著增高(P均<0.05),分泌CD107a和TNF-α的水平增高(P均<0.05),但产生IFN-γ的能力降低(P <0.05)。抗病毒治疗后,CHC患者外周血NK细胞活化程度降低,分泌IFN-γ的能力明显增强(P均<0.05)。结论经DAAs治愈的CHC患者外周血NK细胞的表型和功能显著改善。     

丙型肝炎直接抗病毒治疗研究进展

正目前,我国针对慢性丙型肝炎(chronic hepatitis C,CHC)的标准治疗方案(standard of care,SOC)仍然是聚乙二醇干扰素(pegylated interferon,PEGIFN)-α联合利巴韦林(ribavirin,RBV),简称PR治疗。但是近年来,针对HCV生活周期中病毒蛋白靶向特异性治疗的许多小分子化合物研究进展非常迅速,这些药物被统一命名为直接作用抗病毒药物     

直接抗病毒药物治疗慢性丙型肝炎肝硬化的研究进展

慢性丙型肝炎是由丙型肝炎病毒感染引起的一种病毒性肝炎, 可进一步进展为肝硬化、肝衰竭、肝细胞癌, 甚至死亡。目前尚未有预防性的疫苗, 因此, 预防感染及安全有效的药物治疗是目前应对丙型肝炎病毒感染最有效的应对策略。自2014年以来, 直接抗病毒药物的临床应用对慢性丙型肝炎的治疗带来了革命性的变化。直接抗病毒药物具有极佳的清除丙型肝炎病毒效果, 且耐受性、安全性良好, 可显著改善肝功能、代谢障碍及免疫功能障碍等。然而有研究指出, 直接抗病毒药物在治疗慢性丙型肝炎肝硬化时即使清除了丙型肝炎病毒, 仍有相当比例的患者出现严重肝衰竭、肝细胞癌甚至肝病相关死亡, 所以直接抗病毒药物治疗慢性丙型肝炎肝硬化仍有些问题需要进一步探讨。现综述直接抗病毒药物对慢性丙型肝炎肝硬化患者的研究进展, 为慢性丙型肝炎肝硬化患者的治疗提供有意义的参考。     

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.     

Serum Mac-2-binding protein glycosylation isomer predicts esophagogastric varices in cirrhotic patients with chronic hepatitis C virus infection treated with IFN-free direct-acting antiviral agent: M2BPGi levels predict varices in SVR patients

Introduction and objectivesWe examined whether Mac-2-binding protein glycosylation isomer (M2BPGi) levels could be a predictive marker for the presence of esophagogastric varices (EGV) in cirrhotic patients after hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs).Patients and methodsA total of 102 cirrhotic patients with HCV infection treated with DAAs were enrolled. Esophagogastroduodenoscopy was performed in 84 of the patients before treatment (Cohort A), in 66 after treatment (Cohort B), and in 48 at both time points (Cohort C). We examined factors associated with EGV before and after DAA treatment.ResultsIn Cohort A, M2BPGi levels and liver stiffness were significantly higher in the EGV-positive group than the EGV-negative group (p = 0.034, and p = 0.042, respectively). The proportion of EGV-positive patients with before-treatment levels of M2BPGi ≧ 7.3 C.O.I. was significantly higher than in patients with M2BPGi levels < 7.3 C.O.I. (p = 0.015). In Cohort B, M2BPGi levels were significantly higher in the EGV-positive group than EGV-negative group (p = 0.003). The proportion of EGV-positive patients with after-treatment levels of M2BPGi ≧ 3.4 C.O.I. was significantly higher than in patients with M2BPGi levels < 3.4 C.O.I. (p = 0.001). In Cohort C, M2BPGi levels decreased during DAA treatment regardless of EGV development, but there was no significant difference in the reduction of M2BPGi among the EGV-improvement, EGV-invariant, and EGV-exacerbation groups (p = 0.659).ConclusionsM2BPGi levels may be a novel serum marker for the presence of EGV before and after DAA treatment.     

乙型肝炎肝硬化失代偿期患者抗病毒治疗的疗效分析

乙型肝炎后肝硬化一旦肝功能发生失代偿,其预后极差,5年的病死率高达70%～86%.因此,急需寻求有效的治疗对策.本研究旨在观察乙型肝炎肝硬化失代偿期患者分别采用拉米夫定(LAM)、阿德福韦酯(ADV)、恩替卡韦(ETV)单药治疗和LAM联合ADV治疗的疗效及不良事件发生率,探讨乙型肝炎肝硬化失代偿期的治疗策略.     

我国丙型肝炎肝硬化患者DAA治疗现状及短期预后的研究

目的了解丙型肝炎肝硬化患者直接抗病毒药物(DAA)治疗现状、短期预后和影响因素。方法选取2015年1月至2019年11月期间于瑞金医院感染科诊治的丙型肝炎肝硬化患者,收集其数据,研究基线特征、DAA方案及疗效和预后的关系。结果共入组161例,DAA治疗者149例;代偿组122例,失代偿组27例;两组在年龄、性别、HCV基因型及干扰素治疗史等方面无显著性差别;两组疗效与安全性均良好,其中SVR12率(99.17%比96.25%,P=0.325)和SVR24率(96.64%比92.0%,P=0.614)均无明显差异;基线肝硬化失代偿期患者中发生肝病进展的比例明显高于代偿期患者(50%vs.13.75%,P=0.000);基线肝硬化失代偿是DAA治疗后短期预后的独立危险因素(HR 6.765,95%Cl:2.866~15.969,P=0.000)。结论基线肝硬化失代偿是DAA治疗后短期预后的独立预测因素。     

老年CHC临床特点及抗病毒治疗策略研究进展

由于患者老龄化和病程不断延长,老年慢性丙型肝炎（chronic hepatitis C,CHC）患者的治疗越来越受到关注。由于老年患者感染丙型肝炎病毒（HCV）的时间较长,罹患肝硬化和肝癌的风险较高。老年丙型肝炎患者可能还伴有多种肝外基础疾病,如恶性肿瘤、肾脏疾病、糖尿病、心血管疾病和神经认知障碍等。目前,新型直接抗病毒药物（DAA）对老年CHC患者的抗病毒治疗效果和相关并发症情况尚不明了。有限的有关DAA治疗老年CHC患者的研究资料表明,年龄不应成为DAA治疗的障碍。     

Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis

Recently, direct antiviral agents(DAAs) have been increasingly used for the treatment of chronic hepatitis C virus(HCV) infections, replacing interferon-based regimens that have severe adverse effects and low tolerability. The constant supply of new DAAs makes shorter treatment periods with enhanced safety possible. The efficacy of DAAs for treatment of compensated liver cirrhosis(LC) is not less than that for treatment of non-cirrhotic conditions. These clinical advantages have been useful in pre- and post-liver transplantation(LT) settings. Moreover, DAAs can be used to treat decompensated HCV-induced LC in elderly patients or those with severe complications otherwise having poor prognosis. Although encouraging clinical data are beginning to appear, the actual efficacy of DAAs for suppressing disease progression, allowing delisting for LT and, most importantly, improving prognosis of patients with decompensated HCV-LC remains unknown. Casecontrol studies to examine the short- or long-term effects of DAAs for treatment of decompensated HCV-LC are urgently need.     

HBV/HCV相关性肝细胞癌抗病毒治疗专家建议

乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染在肝细胞癌(HCC)的发生发展中起重要作用.我国近年发布的《慢性乙型肝炎防治指南(2010版)》和《原发性肝癌诊疗规范(2011版)》都强调了肝癌患者抗病毒治疗的重要性,但未作深入具体阐述.《丙型肝炎防治指南(2004版)》也注意到抗病毒治疗延缓HCC的发生.有鉴于此,中华医学会肝病学分会肝癌学组召开了三次专题讨论会,系统收集分析了现有HCC综合治疗中抗病毒治疗的临床研究文献,回顾了HCC治疗中抗病毒药物临床应用进展,依据现有病毒相关性HCC抗病毒治疗的循证医学临床资料,综合部分专家的意见,按照循证医学证据分级的GRADE系统(表1)进行细化和补充,针对这些患者抗病毒治疗的应用达成共识,提出如下具体建议,供国内同道参考,以期在临床实践过程中依据新的临床医学证据进行修改和更新,进一步完善《原发性肝癌诊疗规范》、《慢性乙型肝炎防治指南》和《丙型肝炎防治指南》的实施.     

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study

BACKGROUND Direct-acting antiviral agents(DAAs) are extremely effective in eradicating hepatitis C virus(HCV) in chronically infected patients. However, the protective role of the sustained virologic response(SVR) achieved by second-and thirdgeneration DAAs against the onset of hepatocellular carcinoma(HCC) and mortality is less well established.AIM To examine the occurrence of HCC or death from any cause in a retrospectiveprospective study of patients treated with DAAs.METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients(age: 60 ± 13 years, 224 males, 32% with cirrhosis)treated with DAAs with or without SVR(95/5%), with a median follow up of 58 wk(interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alphafetoprotein levels, and renal function were considered to be confounders.RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per100 person-years, respectively(incidence rate ratio: 44, 95%CI: 15-136, P 0.001).Considering the combined endpoint of HCC or death from any cause, the hazard ratio(HR) for the SVR patients was 0.070(95%CI: 0.025-0.194, P 0.001). Other independent predictors of HCC or death were low HCV viremia(HR: 0.808, P =0.030), low platelet count(HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia(HR: 3.460, P = 0.044). Considering SVR in a multi-state model,the independent predictors of SVR achievement were absence of cirrhosis(HR:0.521, P 0.001) and high platelet count(HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR(HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death.A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.     

Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C

Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.