直接抗病毒药物时代下丙型肝炎研究面临的挑战

HCV是全球范围内导致慢性病毒性肝炎的重要病原体之一。HCV长期隐匿性感染可能会引发肝纤维化、肝硬化和肝癌等晚期肝病。干扰素和利巴韦林联合用药广泛用于HCV感染的治疗,但这一疗法治疗效果有限,并且具有很强的副作用。HCV小分子直接抗病毒药物(DAA)的出现大大提高了治疗效果,并有望最终完全取代干扰素疗法。然而慢性丙型肝炎治疗进入DAA时代并不意味着丙型肝炎问题已经解决,丙型肝炎研究依然面对诸多挑战。     

丙型肝炎直接抗病毒药物治疗的临床应用及管理——2015年美国肝病学会丙型肝炎指南解读

<正>直接抗病毒药物(direct-acting antiviral agent,DAA)可有效清除患者体内的HCV,改善或减轻疾病进程,达到治愈目的。2015年6月30日美国肝病学会发布丙型肝炎诊治指南,为临床规范合理使用DAA提供依据,同时明确丙型肝炎患者治疗前、治疗中及治疗后的监测指标,实现真正意义上的治愈。随着临床上DAA已逐渐广泛开展应用,规范合理使用DAA及     

丙型肝炎发病机制、诊断与治疗

丙型肝炎病毒感染(HCV)是全球范围内慢性肝病的主要病因。据估计目前HCV慢性感染者约170000000人。慢性丙型肝炎是肝硬化、肝细胞癌的主要原因,在很多国家、肝细胞瘤与HCV相关的晚期肝病是肝移植的首要原因。 HCV感染具有向慢性转化的特点,由于具有较高遗传变异性,HCV能够逃逸宿主的免疫反应、     

丙型肝炎治疗的过去、现在和未来

丙型肝炎及其并发症是我国肝病防治的重点之一,从20年前的临床实践到现在近乎100%的治愈率,丙型肝炎诊疗的规范化、大量的科学研究以及药物的研发是HCV得以清除的根本。HCV的清除离不开直接抗病毒药物,HCV的清除并不等同于慢性丙型肝炎治愈,在当今直接抗病毒药物应用下取得高持续病毒学应答率的丙型肝炎患者仍应关注其长期预后,如何正确看待和合理应用丙型肝炎仍是目前需要探讨的热点问题。     

直接抗病毒药物未增加慢性HCV感染者肝细胞癌的发生率

2010年研究发现慢性HCV感染者经治疗获得持续病毒学应答意味着治愈,全球范围内IFN联合利巴韦林的总体治愈率为60%左右,中国的真实世界研究结果为71.1%。2013年以后,美国率先上市针对HCV的直接抗病毒药物(DAA),治愈率提高至接近100%。然而,近期有研究发现应用DAA后肝细胞癌的发生率有所升高,DAA是不是元凶目前仍有争议。笔者认为这主要是DAA的适应证覆盖了更多且疾病程度更重的终末期丙型肝炎患者所致,而这部分患者本身就是肝细胞癌的高危人群;亦不能完全排除DAA可导致机体抑癌免疫状态发生改变,未来需要从分子水平进行确证。     

《2016年欧洲肝病学会丙型肝炎治疗指南》解读及分析

鉴于抗HCV药物研制非常迅速,针对抗HCV治疗的指南更新也非常迅速.仅2016年日本、澳大利亚及亚太肝病学会均发布了HCV的最新指南[1-3].2016年9月23-24日在巴黎举行的欧洲肝病学会(EASL)年会发布了HCV感染新的展望-治愈的流程图及最新的丙型肝炎治疗指南,以往EASL更新指南发布通常在每年4月24日召开EASL会议前后数天,但今年之所以延迟更新指南,主要是等待2个新的直接抗病毒药物(DAA)在欧洲获批上市,即:grazoprevir/elbasvir(Zfpatier)和 sofosbuvir/velpatasvir (Epclusa).     

直接抗病毒药物在一般和特殊丙型肝炎患者中的应用

丙型肝炎是由丙型肝炎病毒(hepatitis C virus, HCV)引起的急性和慢性传染病，自1989年丙型肝炎病毒被发现命名至今，全世界有3.26亿HCV感染者，虽然丙肝没有疫苗可以防控，但因直接抗病毒药物(DAA)的出现，丙肝的治愈率得到极大的提高。本综述旨在阐述DAA药物对感染HCV的各类人群的治疗进展。     

中国丙型肝炎病毒感染的现状及清除进程

丙型肝炎可发展为肝硬化或者肝细胞癌,给患者家庭和社会造成沉重的疾病负担。丙型肝炎是人类面临的重大公共威胁之一,消除丙型肝炎是人类共同的目标。直接抗病毒药物（DAA）治疗是目前较为安全可达到较高的治愈率的丙型肝炎治疗方案,可以靶向不同HCV基因型,使得HCV感染消除成为可能。我国积极推广DAA临床应用,加快药物审批,提高DAA可及性,加强人群干预。国家医疗保障局逐步将DAA纳入国家医保目录,为消除HCV感染提供了有力保障。为响应世界卫生组织提出的2030年消除病毒性肝炎作为公共卫生危害的目标,近年来我国相继发布国家策略规划及行动计划,在HCV感染消除工作中取得了较大的成就,形成全社会多部门联合防治,积极迈向消除HCV感染的目标。本文着眼于国内HCV感染的现状和防治工作进展突出的防治消除策略,分析总结HCV感染防治微消除的实践进程,为我国开展HCV感染消除工作提供政策参考,助力实现全面消除HCV感染的目标。     

《2017年欧洲儿童胃肠病、肝病和营养学会肝病委员会意见书:儿童慢性HCV感染的治疗》摘译

欧洲儿科胃肠病、肝病和营养学会肝病委员会发布的本意见书对儿童慢性HCV感染治疗的系统回顾和荟萃分析进行研究,总结儿童慢性HCV感染治疗的科学证据;对直接抗病毒药物（direct-acting antiviral agents,DAA）在儿童患者中的应用前景进行系统阐述;在当前以及未来不断变化的临床环境下,     

干扰素治疗丙型肝炎的进展

丙型肝炎病毒(HCV)感染的临床过程和结局可能有很大的变化,大多数HCV病人会发生慢性肝病,约25％的慢性丙型肝炎(简称慢性丙肝)病人在3～20年内会发生肝硬化,出现晚期肝病的并发症,包括肝衰竭、门脉高压症和肝细胞癌。本文主要综述干扰素(IFN)治疗丙型肝炎的研究进展。 1.急性丙型肝炎的治疗 急性丙型肝炎(简称急性丙肝)的特点是70％以上会发展为慢性肝炎,在急性病变期间有效地治疗可以防止进展为慢性化。目前使用不同型和不同剂量的IFN治疗急性丙肝时,判断治疗反应的标准是检测HCV     

Management of hepatitis C in children and adolescents during COVID-19 pandemic

In recent years, significant progress in the antiviral treatment of chronic hepatitis C (CHC) has been made due to the development of interferon-free therapies. Three different highly effective, oral direct-acting antiviral (DAA) regimens have been approved for use in adolescents with CHC between the ages of 12-years-old and 17-years-old in Europe. According to the current recommendations, all treatment-naïve and treatment-experienced children with CHC virus infection should be considered for DAA therapy to prevent the possible progression of hepatitis C virus-related liver disease and its complications. However, the novel coronavirus disease 2019 outbreak, which was classified as a pandemic in March 2020, is currently spreading throughout the world, resulting in a disruption of the healthcare system. This disruption is having a negative impact on the care of patients with chronic diseases, including children with CHC. Thus, several efforts have to be made by pediatric hepatologists to prioritize patient care in children with CHC. These efforts include promoting telemedicine in the outpatient setting, using local laboratory testing for follow-up visits, and engaging in the home delivery of DAAs for patients under antiviral therapy whenever possible.     

Hepatitis C and lipid metabolism,hepatic steatosis,and NAFLD: still important in the era of direct acting antiviral therapy?

Chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) have an individual prevalence of 1.8–3% and at least 30%, respectively, in the United States. It is therefore not surprising that there is overlap between these two common chronic liver diseases, although the relationship appears to go beyond isolated co‐existence. Hepatic steatosis is a common feature of CHC infection and can be related to both metabolic and viral specific factors. Steatosis in the setting of nongenotype 3 CHC has been predictive of response to therapy prior to the advent of the direct acting antiviral medications (DAAs). Similarly, lipid metabolism appears important in response to CHC treatment. The pathways for both lipid homeostasis and NAFLD as it pertains to CHC infection as well as the utilization of statin therapy in CHC infection will be reviewed with a focus on the relevance of these topics in the era of DAA therapy.     

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。     

直接抗病毒药物治疗慢性丙型肝炎48周临床观察

背景慢性丙型肝炎(chronic hepatitis C,CHC)是全球公共卫生问题,随着直接抗病毒药(direct antiviral therapy,DAA)在中国的应用,DAA药物成为目前国内慢性丙型肝炎抗病毒一线方案,但目前真实世界DAA治疗后长期疗效数据尚少.目的观察慢性丙型肝炎患者接受直接抗病毒药物抗病毒治疗后48 wk病毒学应答及临床疗效.方法连续收集2018-04-01/2020-04-30在天津市第三中心医院接受DAA治疗的初治CHC患者,评估治疗基线、治疗结束、治疗后12 wk及48 wk的病毒学应答及肝肾功能、肝硬度、APRI及临床结局.结果共收集291例应用DAA治疗的CHC患者,纳入145例完成抗病毒治疗及随访的CHC患者进入本研究.其中肝硬化患者占28.3%,基因型1b、2a、3a、6a分别占78.0%、17.2%、2.8%、2.0%.DAA治疗结束、治疗后12 wk及48 wk获得持续病毒学应答(sustained virological response,SVR)比例分别为100%、97.9%和97.2%,其中基因型1b、2a、3a、6a的SVR48分别为97.3%、96%、100%、100%.治疗结束后48 wk与基线相比较,丙氨酸氨基转移酶、天冬氨酸氨基转移酶、总胆红素及白蛋白的复常率分别为93.2%、91.7%、73.3%及97.7%.治疗结束后48 wk肝硬度(liver stiffness measurement,LSM)及APRI与基线水平相比均明显下降(LSM 12.5 vs 10.2kpa P<0.01;APRI 0.34 vs 0.13 P<0.01),肝硬化组及非肝硬化组患者均有明显下降(P<0.05).48 wk随访期间,其中4例(2.8%)CHC患者进展为肝硬化,8例(5.6%)肝硬化患者进展为肝硬化失代偿,3例(2.1%)肝硬化患者发生新发肝细胞癌(hepatocellular carcinoma,HCC).结论本研究真实世界中慢性丙型肝炎患者应用DAA治疗后48 wk,总体病毒持续应答率较高,肝功能、肝硬度及APRI值均明显改善.2.1%患者出现新发HCC.     

Liver-related effects of chronic hepatitis C antiviral treatment

More than five years ago,the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral(DAA)drugs.They proved highly efficient in curing patients with chronic hepatitis C(CHC), including patients with cirrhosis.The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis,but the exact cause of the expected benefit was unclear.Further,little was known about how the underlying liver disease would be affected during and after viral clearance.In this review,we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects,such as macrophage activation,and the time-dependent effects of therapy,with specific emphasis on inflammation,structural liver changes,and liver function,as these factors are all related to morbidity and mortality in CHC patients.It seems clear that antiviral therapy,especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis.There seems to be a timedependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions.These improvements lead to favorable effects on liver function,followed by an improvement in cognitive dysfunction and portal hypertension.Overall,the data provide knowledge on the several beneficial effects of DAA therapy on liverrelated parameters in CHC patients suggesting short-and long-term improvements in the underlying disease with the promise of an improved longterm prognosis.     

Era of direct acting antivirals in chronic hepatitis C: Who will benefit?

In the era of highly effective direct acting antiviral(DAA) drugs for the treatment of chronic hepatitis C(CHC) infection, where eradication is almost ensured with minimal side effects, all hepatitis C carriers should benefit theoretically. In the real world setting however, only a small proportion will benefit at this time point due to the multiple barriers to accessing therapy. Given that universal treatment is unlikely, treatment with DAAs will likely be restricted to those with the highest health benefits, and for those who can afford the high expense of a treatment course. Those with the highest unmet needs include those who have failed previous interferon-based therapy or who are interferon-ineligible with evidence of active disease, those with advance liver disease, and those with recurrence of hepatitis C after liver transplantation. In the future, the focus should be on increasing access to treatment for those infected with CHC.     

Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response

Sustained virological response (SVR) results in reduced incidence of hepatocellular carcinoma (HCC) and mortality among chronic hepatitis C (CHC) patients with advanced fibrosis. Since both advanced fibrosis and liver steatosis (LS) may coexist in CHC patients, we evaluated their individual effects on a composite outcome of all‐cause mortality and HCC in CHC patients with SVR following direct‐acting antivirals (DAA) treatment. We retrospectively evaluated inception cohort of 515 CHC patients who achieved SVR following treatment with DAA, with a mean follow‐up of 24 months. Baseline liver fibrosis was assessed by transient elastography, and LS was validated by at least three independent ultrasonographic examinations. 211 of 515 patients (41%) had baseline LS. Patients with LS had a higher cumulative rate of all‐cause mortality and HCC at 2 years of follow‐up compared to patients without LS (15.75% and 2.79%, respectively, P < 0.001), although they did not have increased incidence of advanced fibrosis or cirrhosis. Consistently, multivariate analysis showed that LS was associated with a significant 7.5‐fold increased risk of all‐cause mortality and HCC (HR 7.51, 95% C.I 3.61‐13.36, P < 0.001) even upon adjustment to components of the metabolic syndrome, whereas advanced fibrosis showed only a trend towards statistical significance (HR 2.32, 95% C.I 0.97‐6.59, P = 0.06). In conclusion, LS is a major predictor of all‐cause mortality and HCC in patients who achieved SVR following DAA treatment regardless of fibrosis stage. These patients should be rigorously screened for HCC.     

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。     

Hepatitis C Therapy: Lessons of the Last Two Decades

Many important therapeutic lessons have been learned since the discovery of hepatitis C virus (HCV) in 1989. A sustained virological response (SVR) is now recognized to be considered tantamount to a cure and is the goal of therapy for chronic hepatitis C (CHC). Prior to the development of directly-acting antiviral therapies (DAA), SVR rates of between 50?% and 80?% were achievable using the previous standard of care for CHC, pegylated interferon and ribavirin. The mechanisms behind the inter-individual variation in response to interferon-based therapy had been elucidated by recent genome-wide association studies. The introduction of DAA therapy has resulted in a significant increase in SVR rate and given hope to patients with CHC in whom interferon is ineffective or contraindicated. The development of a therapeutic vaccine for HCV is, however, still in its infancy. This article will review the triumphs and tribulations of HCV therapy that have been witnessed over the last two decades.     

Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%‐8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long‐term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis‐related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow‐up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow‐up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow‐up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942‐2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407‐3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333‐1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.