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。     

Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response

The introduction of a direct-acting antiviral(DAA) for patients with hepatitis C virus(HCV) infection, could lead to higher sustained virologic response(SVR)rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma(HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.     

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。     

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.     

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     

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma

AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN- alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not signifi cant, the score was signifi cantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 ± 1.42 vs 5.81 ± 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrentHCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.     

Hepatitis C Virus and Antiviral Drug Resistance

Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.     

Hepatitis B reactivation in patients receiving direct-acting antiviral therapy or interferon-based therapy for hepatitis C:A systematic review and meta-analysis

AIM To assess the incidence of hepatitis B virus(HBV) reactivation in patients receiving direct-acting antiviral agent(DAA)-based therapy or interferon(IFN)-based therapy for hepatitis C and the effectiveness of preemptive antiHBV therapy for preventing HBV reactivation.METHODS The Pub Med, MEDLINE and EMBASE databases were searched, and 39 studies that reported HBV reactivation in HBV/hepatitis C virus coinfected patients receiving DAAbased therapy or IFN-based therapy were included. The primary outcome was the rate of HBV reactivation. The secondary outcomes included HBV reactivation-related hepatitis and the effectiveness of preemptive anti-HBV treatment with nucleos(t)ide analogues. The pooled effects were assessed using a random effects model. RESULTS The rate of HBV reactivation was 21.1% in hepatitis Bsurface antigen(HBs Ag)-positive patients receiving DAAbased therapy and 11.9% in those receiving IFN-based therapy. The incidence of hepatitis was lower in HBs Agpositive patients with undetectable HBV DNA compared to patients with detectable HBV DNA receiving DAA therapy(RR = 0.20, 95%CI: 0.06-0.64, P = 0.007). The pooled HBV reactivation rate in patients with previous HBV infection was 0.6% for those receiving DAA-based therapy and 0 for those receiving IFN-based therapy, and none of the patients experienced a hepatitis flare related to HBV reactivation. Preemptive anti-HBV treatment significantly reduced the potential risk of HBV reactivation in HBs Agpositive patients undergoing DAA-based therapy(RR = 0.31, 95%CI: 0.1-0.96, P = 0.042).CONCLUSION The rate of HBV reactivation and hepatitis flare occurrence is higher in HBs Ag-positive patients receiving DAA-based therapy than in those receiving IFN-based therapy, but these events occur less frequently in patients with previous HBV infection. Preemptive anti-HBV treatment is effective in preventing HBV reactivation.     

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...     

Hepatitis C virus NS5A inhibitors and drug resistance mutations

Some direct-acting antiviral agents for hepatitis C virus(HCV),such as telaprevir and boceprevir have been available since 2011.It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis.HCV NS5A inhibitors efficiently inhibited HCV replication in vitro.Human studies showed that dual,triple and quad regimens with HCV NS5A inhibitors,such as daclatasvir and ledipasvir,in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin,could efficiently inhibit HCV replication according to HCV genotypes.These combinations might be a powerful tool for"difficult-to-treat"HCV-infected patients."First generation"HCV NS5A inhibitors such as daclatasvir,ledipasvir and ABT-267,which are now in phaseⅢclinical trials,could result in resistance mutations."Second generation"NS5A inhibitors such as GS-5816,ACH-3102,and MK-8742,have displayed improvements in the genetic barrier while maintaining potency.HCV NS5A inhibitors are safe at low concentrations,which make them attractive for use despite low genetic barriers,although,in fact,HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors,HCV NS5B inhibitors or peginterferon plus ribavirin.This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.     

Prevention of cancer recurrence after treatment for hepatitis C virus-related hepatocellular carcinoma by interferon therapy

The outcome of treatment for hepatitis C virus-related hepatocellular carcinoma is still unsatisfactory because of the high rate of recurrence of cancer, including intrahepatic metastasis and multicentric carcinogenesis after treatment. The rate of recurrence, especially that of multicentric carcinogenesis, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis C. Interferon therapy improves the outcome after treatment of hepatocellular carcinoma by decreasing recurrence and preserving or improving liver function when treatment is successful. Radical treatment by anatomic resection and interferon therapy can markedly improve the outcome in patients with hepatitis C virus-related hepatocellular carcinoma.     

Impact of new treatment options for hepatitis c virus infection in liver transplantation

Liver transplant candidates and recipients with hepatitis C virus(HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens(e.g.,pegylated-interferon plus ribavirin with or without first generation protease inhibitors,boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents(DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir,daclatasvir,and combination of other DAA. Possible interactions should be monitored,especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.     

Hepatitis D virus and liver transplantation: Indications and outcomes

Hepatitis D virus(HDV) is a dependent virus that relies on hepatitis B virus for its replication and transmission. Chronic hepatitis D is a severe form of viral hepatitis that can result in end stage liver disease. Currently, pegylated interferon alpha is the only approved therapy for chronic HDV infection and is associated with significant side effects. Liver transplantation(LT) is the only treatment option for patients with end-stage liver disease, hepatocellular carcinoma, or fulminant hepatitis due to coinfection with HDV. As LT for HDV and hepatitis B virus coinfection is uncommon in the United States, most data on the long-term impact of LT on HDV are from international centers. In this review, we discuss the indications and results of LT with treatment options in HDV patients.     

Hepatitis C virus treatment failure: Clinical utility for testing resistance-associated substitutions

The hepatitis C virus has a high mutation capacity that leads to the emergence of resistance-associated substitutions(RAS). However, the consequence of resistance selection during new direct-acting antiviral drug(DAA) treatment is not necessarily the therapeutic failure. In fact, DAA treatment has shown a high rate( 95%) of sustained virological response even when high baseline RAS prevalence has been reported. In the context of RAS emergence and high rates of sustained viral response, the clinical relevance of variants harboring RAS is still controversial. Therefore, in order to summarize the data available in international guidelines, we have reviewed the clinical utility of testing RAS in the era of new pangenotypic DAA drugs.     

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.     

Hepatitis C virus infection,microRNA and liver disease progression

Hepatitis C virus (HCV) is a global health problem with an estimated 170-200 million peoples (approximately 3% of world population) are chronically infected worldwide and new infections are predicted to be on rise in coming years. HCV infection remains categorized as a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. There has been considerable improvement in our understanding of virus life cycle since, the discovery of HCV two-decades ago. MicroRNAs (miRNAs) are important players in establishment of HCV infection and their propagation in infected hepatocytes. They target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Very first anti-miRNA oligonucleotides, miravirsen has been tested in clinical trial and shown promising results as therapeutic agent in treatment against chronic HCV infection. Deregulated expression of miRNAs has been linked to the pathogenesis associated with HCV infection by controlling signaling pathways such as, proliferation, apoptosis and migration. Circulating miRNAs emerging as growing field in identification of biomarkers in disease progression and their potential as a means of communication between cells inside the liver is an exciting area of research in future. This review focuses on recent studies enforcing the contribution of miRNAs in HCV life cycle and coordinated regulation in HCV mediated liver disease progression.