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。     

直接抗病毒药物时代特殊人群HCV感染的管理和治疗

慢性丙型肝炎呈全球性流行,不同性别、年龄、种族、民族人群均易感染HCV。分别阐述了儿童丙型肝炎患者、合并肾损伤患者、肝移植患者、合并肝硬化患者、合并HIV感染者、急性丙型肝炎患者等不同特殊人群HCV感染的管理方法和个体化治疗方案。     

丙型肝炎相关直接抗病毒药物耐药的研究现状

近年来,靶向针对HCV生活周期中病毒蛋白的直接抗病毒药物(DAA)的研究得到了迅速发展,但是各种DAA均存在特异的耐药位点,且与基因型/亚型相关。依据DAA的作用机制概述各类药物的耐药位点及其对治疗方案的影响,指出某些天然变异位点的存在使得部分HCV基因亚型患者在治疗中耐药,故在治疗前需要谨慎评估以选择适当方案;而对于既往干扰素治疗失败的患者,如需联合DAA或直接采用无干扰素的DAA联合治疗方案,还需要就预存耐药等问题作进一步研究。     

丙型肝炎直接抗病毒药物的代谢及药物相互作用

直接抗病毒药物(direct-acting antiviral agents,DAAs)的抗HCV疗效显著,但须关注DAAs的不良反应、安全性检测以及与其他药物的相互作用。本文对DAAs的代谢及其与其他药物的相互作用进行综述。     

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。     

与直接抗病毒药物应用相关的HCV/HBV双重感染的特点及其诊治管理

HCV和HBV的双重感染(DI)具有不同于单一HCV或HBV感染的特殊临床、免疫学和病毒学特点,为临床诊治和管理带来了诸多挑战。在应用直接抗病毒药物(DAA)有效控制HCV感染的同时,可能导致HBV的激活和乙型肝炎的发作甚至肝衰竭。在抗HCV治疗的同时,根据不同的HCV/HBV-DI状态选用合适的抗HBV治疗和随访管理策略至关重要。     

Treatment of chronic genotype-3 hepatitis C virus infection using direct-acting antiviral agents: An Indian experience

Background

Direct-acting antiviral drugs (DAAs) are favored for the treatment of hepatitis C virus (HCV) infection. However, the experience with the DAAs currently available in India in the treatment of genotype-3 HCV is limited. We therefore reviewed our experience with these drugs in treating patients with chronic genotype-3 HCV infection, including those with cirrhosis.

Methods

We prospectively followed adult patients with genotype-3 HCV infection who had received treatment regimens containing sofosbuvir with/without daclatasvir. Patients were categorized as chronic hepatitis C (CHC), compensated cirrhosis (CC), and decompensated cirrhosis (DC). They received either (i) sofosbuvir and ribavirin, with or without pegylated interferon (Peg-IFN) for 12 or 24 weeks, or (ii) sofosbuvir and daclatasvir, with or without ribavirin for 12 or 24 weeks. Response was assessed using HCV RNA testing after 2 or 4 weeks of treatment (rapid virological response [RVR]), at treatment completion (end-of-treatment response [ETR]) or 12 weeks after treatment completion (sustained virological response [SVR12]).

Results

Of the 160 patients (90% treatment-naïve; CHC 49%, CC 32%, and DC 19%), 39 (24%) received Peg-IFN, sofosbuvir and ribavirin, 21 (13%) received sofosbuvir and ribavirin, and 100 (63%) received sofosbuvir and daclatasvir, with or without ribavirin. On intention-to-treat basis, RVR, ETR, and SVR12 in the entire cohort were 146/160 (91.3%), 151/160 (94.4%), and 147/160 (91.9%), respectively. Seven patients died (CC 2, DC 5) during treatment; four (2 CHC, 2 DC) patients discontinued treatment; and two patients with CC relapsed.

Conclusions

Dual-DAA-based regimens were safe and highly effective in treating genotype-3 HCV infection in CHC and CC patients.

     

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。     

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。     

直接抗病毒药物治疗丙型肝炎肝硬化早期抗病毒疗效及安全性临床实践研究

目的评价直接抗病毒药物(direct-acting antiviral agents,DAAs)治疗丙型肝炎肝硬化的早期抗病毒疗效及安全性。方法给予基因1b型丙型肝炎肝硬化患者DAAs抗病毒治疗。方案1:sofosbuvir+ribavirin(RBV);方案2:sofosbuvir+ledipasvir+RBV;方案3:sofosbuvir+daclatasvir+RBV,疗程均为24周。观察不同治疗时间点的病毒学和生物化学指标变化以及患者的不良反应。本研究先期分析24例患者12周的数据。结果完成12周治疗的24例患者中,方案1组12例,方案2组和方案3组均为6例。24例应用DAAs治疗1、2、4和12周HCV转阴率分别是25.00%(6/24)、45.83%(11/24)、66.67%(16/24)和70.83%(17/24),随着治疗时间的延长,HCV转阴率逐渐上升。方案1组中,初治和经治患者治疗12周时HCV转阴例数分别为4例和1例;方案2和3组中,初治和经治患者治疗12周时HCV转阴例数均为3例。截至2016年1月,有3例随访至停药12周,1例在方案1组,该患者停药12周后复发,HCV RNA为1.8×106 IU/ml;2例在方案2组,达到治疗12周持续病毒学应答,HCV RNA未检测到。DAAs治疗2周后ALT降到正常值范围,12周时仍在正常值范围。治疗1周时CK和CK-MB稍有上升,但差异无统计学意义,2周后降到正常值范围,12周时仍在正常值范围。在DAAs治疗过程中,BUN和CRE无显著性升高,无须调整DAA剂量。DAAs常见的不良反应是恶心(58.83%)。结论基因1b型丙型肝炎肝硬化患者应用DAAs抗病毒治疗早期疗效好,安全性高。对于经治患者应用sofosbuvir联合ledipasvir或daclatasvir。     

慢性丙型肝炎直接抗病毒药物的研究进展和应用前景

针对HCV感染的标准治疗方案是聚乙二醇干扰素α联合利巴韦林。按此治疗方案部分HCV感染者是可治愈的。但仍有一小部分患者不能治愈。随着分子生物学的进展,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的研究得到了迅速发展,提高了抗病毒的疗效。这些药物统一命名为抗HCV的直接抗病毒药物(direct-acting antiviralagents,DAAs),包括非结构蛋白(non-structural protein,NS)3/4A蛋白酶抑制剂、NS5B聚合酶抑制剂和NS5A蛋白抑制剂等。本文对慢性丙型肝炎DAAs的研究进展、临床应用、应用中的问题及应用前景进行概述。     

Effect on the adherence to concomitant medications after initiation of treatment with direct-acting antiviral agents against hepatitis C virus

IntroductionMany patients with hepatitis C virus (HCV) have associated comorbidities that require complex treatments. We sought to determine the impact of treatment with direct-acting antiviral agents (DAAs) for HCV on adherence to prescribed concomitant medications for associated comorbidities and to identify predictors of non-adherence to comedications.Patients and methodsHCV-infected patients treated with DAAs in a Spanish hospital between January 2015 and December 2016 and followed-up by the pharmacy unit were included in the study. Adherence to concomitant comedication prescribed before and during HCV therapy with DAAs was compared to adherence during the same number of weeks before DAA initiation. Demographic, clinical and pharmacotherapy variables were analyzed to determine factors associated with non-adherence. A multivariate regression model was created for prediction of non-adherence to concomitant medication.ResultsData from 214 patients using prescribed concomitant therapies were analyzed. Significant reduction on adherence to comedications was observed after initiation of DAA treatment compared with a similar period before therapy initiation (29.9% vs. 36.9%, p = 0.032). The univariate analysis showed that polypharmacy and presence of vascular disease were associated negatively with adherence to concomitant medications (87.8%, p = 0.006 and 84.7%, p < 0.001, respectively). Multivariate analysis indicated that HIV/HBV coinfection was associated with adherence (OR 0.19; 95% CI 0.09–0.39), while polypharmacy was a predictor for non-adherence (OR 4.54; 95% CI 1.48–13.92).DiscussionAdherence to concomitant medications decreases in HCV-infected patients when DAA therapy is initiated. Polypharmacy is a predictor for non-adherence, while HIV/HBV coinfection reduce non-adherence rates. Polymedicated patients on DAAs might benefit from close follow-up and educational programmes to improve their adherence.     

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.     

New perspectives in occult hepatitis C virus infection

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases.     

慢性丙型肝炎合并肾功能不全患者直接抗病毒药物治疗的选择

HCV感染在肾功能不全(RD)患者中较常见,尤其是在终末期肾病进行血液透析(HD)的患者中,感染率明显高于普通人群,肝脏疾病的发生率及病死率升高。直接抗病毒药物在慢性丙型肝炎的治疗中取得了超过90%的持续病毒学应答和较少的不良事件。在合并RD和HD患者中推荐应用grazoprevir/elbasvir、paritaprevir/ritonavir+ombitasvir+dasabuvir、glecaprevir/pibrentasvir或daclartasvir+asunaprevir等治疗方案,不建议推荐以sofosbuvir为基础的治疗方案。     

宿主基因和直接抗病毒药物:丙型肝炎个体化治疗的新时代

宿主白细胞介素(interleukin,IL)-28B基因型的发现和直接抗病毒药物的发展将改变对慢性丙型肝炎的治疗,但最重要的是明确易发生肝硬化和肝癌的患者.个体化治疗应该考虑抗病毒治疗的时机、不同药物的特定目标人群、药物和疗程.亚洲人群由于IL-28B的宿主基因大多为CC型,治疗的个体化明显不同于高加索人.     

直接抗病毒药物治疗慢性丙型肝炎合并血小板减少患者的效果分析

目的探讨慢性丙型肝炎（CHC）合并血小板（PLT）减少患者应用直接抗病毒药物（DAA）的临床疗效及对PLT的影响。方法回顾分析2018年4月—2019年3月在天津市第三中心医院接受DAA治疗合并PLT减少（PLT<150×10⁹/L）的CHC患者83例,应用无干扰素方案的DAA治疗12～24周,评估治疗结束（EOT）及结束后第12周患者病毒学应答、肝功能指标、PLT、肝硬度（LSM）的变化。正态分布的计量资料组间比较采用重复测量资料的方差分析。非正态分布的计量资料组间比较前进行正态转换,后行重复测量资料的方差分析。logistic回归分析影响PLT升高的预测因素。绘制受试者工作特征曲线（ROC曲线）评价基线LSM对治疗后PLT升高的预测价值。结果 83例CHC合并PLT减少的患者中,肝硬化患者占61.4%,治疗结束后12周持续病毒学应答（SVR12）率为98.8%。与基线相比较,EOT及SVR12时,患者血清AST、ALT、GGT、TBil、Glo水平下降,Alb水平升高,LSM明显下降,差异均有统计学意义（P值均<0.05）。患者PLT在EOT[（1...     

Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents

Summary. During the late 1990s and early 2000s, major advances were made in the treatment of patients with chronic hepatitis C virus (HCV) infection. Interferon, combination interferon plus ribavirin (RBV) and pegylated interferon plus RBV increased sustained virologic response (SVR) rates from ~5% to ~40-80%, depending on the genotype of HCV infection. Advances in molecular biology have allowed investigators to begin to understand the mechanisms of HCV infection and replication. Advances in understanding of viral kinetics have provided tools to identify patients who are most likely to attain SVR. With the advances in the science of HCV infection, the first part of the 21st century has seen the development and early introduction of a number of direct-acting antiviral (DAA) drugs. These novel medications interfere with critical steps in HCV replication and have the potential to significantly increase SVR rates. This article will review the key elements of HCV replication and evaluate the various classes of new and investigational DAA that have the potential to create a revolution in the management of patients with chronic hepatitis C.