Viral response to specifically targeted antiviral therapy for hepatitis C and the implications for treatment success

Currently, hepatitis C virus (HCV) antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C) molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.     

Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection

The estimated prevalence of hepatitis C virus infection in the US is approximately 1.8%. Although interferon monotherapy and combination therapy of interferon with ribavirin represent mainstay for treating HCV infection, the rate of sustained virologic response remains suboptimal. The growing evidence suggested that the clinical sequence and treatment response of chronic hepatitis C are determined by a dynamic, complex tripartite relationship among HCV infection, the host immune response, and the effect of different interferon regimens. The treatment response is associated with various viral factors including the pretreatment viral level, dynamic change of viral level during treatment, viral genotype quasispecies and nucleotide mutation in nonstructural protein 5A of hepatitis C virus. Host factors that may affect treatment response include age, gender, race, HLA alleles and the host immune responses. Interferon regimens, including type, dose, frequency and duration of treatment and combination of interferon with other anti-HCV agents also alter the therapeutic response. Understanding these complicated interaction may provide better insights into the mechanism(s) of interferon response, leading to more effective clinical application of interferon therapy.     

Treatment of chronic hepatitis C: Anticipated impact of resistance in patients treated with protease inhibitors

A main target of specifically targeted antiviral therapy for hepatitis C (STAT-C) is the NS3-protease, which has key functions in the hepatitis C virus (HCV) replication cycle. HCV/NS3-protease inhibitors have shown high antiviral activity in vitro and in patients with chronic hepatitis C. Protease-resistant HCV variants occurred rapidly in patients receiving protease-inhibitor monotherapy. The development of resistance can be best explained by selection of preexisting resistant variants, which grow out under selective pressure. Numerous mutations associated with resistance were identified. Clinical trials showed that protease-resistant strains are sensitive to interferon and that a triple combination of protease inhibitors, peginterferon, and ribavirin may improve the sustained virologic response rate compared with standard peginterferon/ribavirin combination therapy. Overall, it can be anticipated that successful treatment with protease inhibitors will require either combination therapy with peginterferon/ribavirin or a combination of STAT-C compounds with distinct modes of action and resistance patterns.     

Moving beyond interferon alfa: investigational drugs for hepatitis C virus infection

Numerous direct-acting drugs to treat hepatitis C virus (HCV) infection are in development, offering the potential for substantial improvement over current interferon alfa-based therapy and the possibility of effective interferon alfa-sparing regimens in achieving cure of HCV infection. Drugs furthest along in clinical development include HCV nonstructural protein 3 (NS3) protease inhibitors (eg, telaprevir, boceprevir), which have potent anti-HCV activity but low barriers to resistance and considerable likelihood of cross-resistance. Nucleoside analogue nonstructural protein 5B (NS5B) polymerase inhibitors exhibit a high barrier to resistance and cross-HCV genotype and subtype activity. Nonnucleoside analogue polymerase inhibitors have a low barrier to resistance and are characterized by a substantial frequency of preexisting resistance mutations. The initial use of direct-acting drugs will be as add-on treatment to interferon alfa and ribavirin regimens. The success of interferon alfa-sparing regimens will depend on presenting a sufficiently high barrier to resistance with direct-acting drugs and whether the immunomodulatory effects of interferon alfa are needed for cure of HCV infection.     

Hepatitis C virus infection in patients with HIV-1: epidemiology,natural history and management

Hepatitis C virus (HCV)-related liver diseases have contributed to increased morbidity and mortality in HIV-1-infected individuals in the era of effective antiretroviral therapy. HCV transmission patterns have changed among the HIV co-infected population during the last decade, with acute HCV infection emerging worldwide. HIV infection accelerates the progression of HCV-related liver diseases and consequently cirrhosis, liver failure, and hepatocellular carcinoma. However, the current standard treatment of HCV infection with pegylated interferon plus ribavirin results in only a limited viral response. Furthermore, cumbersome pill regimens, antiretroviral related hepatotoxicity, and drug interactions of HCV and HIV regimens complicate therapy strategies. Fortunately, in the near future, new direct-acting anti-HCV agents will widen therapeutic options for HCV/HIV co-infection. Liver transplantation is also gradually accepted as a therapeutic option for end stage liver disease of HCV/HIV co-infected patients.     

Progress in the development of vaccines for hepatitis C virus infection

The hepatitis C virus(HCV), first described in 1989, is now a leading cause of liver cirrhosis and hepatocellular carcinoma. With more than 170 million people infected globally, this virus is a major public health issue. The current standard therapy is based on interferon in combination with ribavirin. This costly therapy often fails to completely clear the infection and is associated with adverse side effects. Recent anti-HCV therapies are interferon-free direct-acting antiviral(DAA) regimens for HCV, including simeprevir, sofosbuvir, and ledipasvir, which have effects on non-structural proteins. DAA regimens have several advantages, such as specifically targeting HCV viral replication, accompanied by very high sustained virological response rates and lower side effects like flu-like syndrome. These facts plus the fact that most HCV cases progress to chronic infection suggest the potential need for an efficient HCV vaccine. Different innovative methods, including methods based on peptide, recombinant protein, DNA, vector-based, and virus-like particles, have been introduced for the development of HCV vaccines. An extensive number of studies have been published on these vaccines, and some vaccines were even tested in clinical trials. In the current review, progress in the development of preventive and therapeutic vaccines against the HCV is reviewed in the context of peptide vaccines, recombinant protein vaccines, HCV-like particle, DNA vaccines and viral vectors expressing HCV genes.     

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.     

New developments in the antiviral treatment of hepatitis C

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is endemic in most parts of the world, with an estimated 170 million people infected worldwide and 3–4 million new cases each year. HCV-related end-stage liver disease is now the main indication for liver transplantation in the USA and Western Europe. Unfortunately, no vaccine or immunoglobulin is available to prevent HCV infection. Currently, HCV treatment consists of the combined administration of pegylated interferon and ribavirin for a period of 24–48 weeks, resulting in complete viral eradication in 40–80% of patients, depending on genotype, viral load and patient characteristics. This therapy is often accompanied with side-effects that affect compliance and reduce treatment outcomes.
Recently, reliable in vitro culture systems have been developed which accelerated antiviral therapy research. Many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are evaluated in clinical trials. These new antiviral agents are expected to improve treatment significantly with potentially shorter treatment duration. The most promising antiviral agents will be reviewed.     

Hepatitis C treatment in the elderly: New possibilities and controversies towards interferon-free regimens

Due to the progressive aging of the hepatitis C virus (HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extra-hepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the well-known contraindications and side effects of interferon (IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn’t mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the “old” IFN-based regimens and with the newer drugs. We will conclude that the availability of IFN-free regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.     

Advances in the management of hepatitis C

Significant advances have recently been made in the management of hepatitis C virus (HCV) with many of the changes now part of routine clinical practice. These include the use of non‐invasive methods to assess liver fibrosis, interleukin 28B genotype testing to predict interferon responsiveness and the use of new anti‐viral regimens for HCV genotype 1. Two new antiviral agents (boceprevir and telaprevir) have recently become available in Australia. These protease inhibitors are used in combination with pegylated interferon and ribavirin as triple therapy for genotype 1 HCV. This combination increases sustained virological response from approximately 45–50% to 66–75% in treatment naïve patients. However, these new regimens present novel challenges including complicated treatment algorithms based on virological response, numerous drug interactions and additional side effects especially in patients with advanced fibrosis. The protease inhibitors are the first of many antiviral drugs to become available to treat HCV, heralding the arrival of new agents that will offer greater chances of cure with improved safety and tolerability compared with current therapies.     

Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B

More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far not everyone benefits from treatment. Recently, progress has been made in the development of specifically targeted antiviral therapy for HCV (STAT-C). A major target for such direct acting antivirals (DAAs) is the HCV RNA-dependent RNA polymerase or non-structural protein 5B (NS5B), which is essential for viral replication. This review will examine the current state of development of inhibitors targeting the polymerase and issues such as the emergence of antiviral resistance during treatment, as well as strategies to address this problem.     

Management of hepatitis C infection before and after liver transplantation

Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.     

New treatments for chronic hepatitis C: An overview for paediatricians

Pegylated interferon(IFN)α-2a or 2b in combination with ribavirin for children aged 3 years and older is the standard treatment for paediatric chronic hepatitis C.This treatment regimen was developed firstly in adults.In recent years,a number of direct-acting antiviral agents(DAAs)are under development for treatment of chronic hepatitis C virus(HCV)infection.These agents block viral replication inhibiting directly one of the several steps of HCV lifecycle.DAAs are classified into several categories based on their molecular target:HCV NS3/4A protease inhibitors,HCV NS5B polymerase inhibitors and HCV NS5A inhibitors.Other promising compounds are cyclophilin A inhibitors,mi-RNA122and IFN-λ.Several new drugs associations will be developed in the near future starting from the actual standard of care.IFN-based and IFN-free regimens are being studied in adults.In this constantly evolving scenario new drug regimens targeted and suitable for children would be possible in the next future.Especially for children,it is crucial to identify the right combination of drugs with the highest potency,barrier toresistance and the best safety profile.     

Hepatitis C virus:Is it time to say goodbye yet? Perspectives and challenges for the next decade

The majority of individuals exposed to hepatitis C virus(HCV) establish a persistent infection,which is a leading cause of chronic liver disease,cirrhosis and hepatocellular carcinoma.Major progress has been made during the past twenty-five years in understanding the HCV life cycle and immune responses against HCV infection.Increasing evidence indicates that host genetic factors can significantly influence the outcome of HCV infection and the response to interferon alpha-based antiviral therapy.The arrival of highly effective and convenient treatment regimens for patients chronically infected with HCV has improved prospects for the eradication of HCV worldwide.Clinical trials are evaluating the best anti-viral drug combination,treatment doses and duration.The new treatments are better-tolerated and have shown success rates of more than 95%.However,the recent breakthrough in HCV treatment raises new questions and challenges,including the identification of HCVinfected patients and to link them to appropriate health care,the high pricing of HCV drugs,the emergence of drug resistance or naturally occurring polymorphism in HCV sequences which can compromise HCV treatment response.Finally,we still do not have a vaccine against HCV.In this concise review,we will highlight the progress made in understanding HCV infection and therapy.We will focus on the most significant unsolved problems and the key future challenges in the management of HCV infection.     

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。     

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。     

STAT-C: New therapies cannot get here fast enough

The ability to culture hepatitis C virus (HCV) and the determination of the three-dimensional structure of the replication elements of the HCV genome allowed the rapid development of antiviral molecules directly targeting specific enzymes that allow HCV to reproduce itself. This new class of drugs, known as specifically targeted antiviral therapy for HCV (STAT-C), offers a new paradigm for the treatment of this elusive virus. During recent years, multiple STAT-C agents were introduced into clinical trials, but only a few have overcome the hurdles often associated with early clinical drug development. This article discusses the latest clinical trial findings on the emerging STAT-C agents for the treatment of HCV, particularly the agents that have progressed to phase 2 and phase 3 in clinical trials.     

Update on Specifically Targeted Antiviral Therapy for Hepatitis C Infection: Progress and Pitfalls on the Road to Viral Eradication

The global prevalence of hepatitis C virus (HCV) infection exceeds that of HIV but only has a 40% response rate to the currently available standard of care. In contrast to HIV infection, eradication of HCV is possible, with cure rather than viral suppression the goal of treatment. Specifically targeted antiviral therapy against hepatitis C (STAT-C) hopes to improve this low rate of response using small molecules designed to inhibit key viral processes. Protease and polymerase inhibitors are the most studied of the STAT-C small molecules with protease inhibitors being the closest to commercial availability. The most promising of these new approaches to therapy rely on a persistent need for pegylated interferon and ribavirin and may be limited by the development of viral resistance.     

丙型肝炎基因型定量检测及分型检测方法的研究进展

丙型肝炎病毒(hepatitis C virus,HCV)是一种RNA病毒,可以引发各种慢性肝病,其中包括肝硬化和肝细胞癌.全球每年HCV感染的患者数呈上升趋势,他已成为人类亟待解决的公共卫生难题.HCV可以分为6种主要的基因型以及70多种亚型,不同的基因型对抗病毒治疗的效果不同.如果在治疗前能通过准确灵敏的检测手段确定HCV的基因型,将会对临床治疗有重要的意义.本文对HCV基因型全球分布、临床表症与治疗、分型依据以及基因型与定量关系进行了概述,并重点阐述HCV基因分型的检测技术.     

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.