Current and future concepts in hepatitis C therapy

The goal of hepatitis C virus (HCV) therapy is permanent viral eradication. This requires the use of drug combinations with multiple modes of action. Steady-state HCV replication kinetics can be disrupted by drugs that inhibit virus production (antiviral molecules), inhibit de novo cell infection, and/or accelerate the clearance of infected cells. Pegylated interferon-alpha and ribavirin combine all of these mechanisms of action when used together, yet fail to clear HCV from a significant number of patients. New therapeutic approaches are needed. The next generation of anti-HCV therapeutic agents will fall into four main categories: new interferons and interferon inducers, alternatives to ribavirin, specific HCV inhibitors, and immune therapies. Ideally, these new treatments will increase the rate of sustained viral eradication and improve tolerability and acceptability. Drug combinations will be tailored to the individual patient, based on baseline parameters and viral kinetics during therapy.     

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。     

Management and treatment of chronic hepatitis C in HIV patients

Progression to cirrhosis occurs faster whereas response to peginterferon/ribavirin therapy is lower in patients with chronic hepatitis C coinfected with human immunodeficiency virus (HIV), as compared with hepatitis C virus (HCV) monoinfected individuals. The use of antiretroviral therapy may ameliorate poor outcomes in HIV/HCV coinfected patients. However, in the best scenario peginterferon/ribavirin therapy provides cure to 30% of patients harboring HCV genotypes 1 or 4 and to 70% of HCV genotypes 2 or 3 carriers, a rate lower than that seen in HCV monoinfection. Moreover, a substantial proportion of HIV/HCV coinfected patients are not treated due to contraindications, or do not complete therapy due to serious adverse events, or just do not wish to receive such a poorly tolerated medication. For these reasons, the advent of direct acting antivirals (DAA) has been eagerly awaited for treating HIV/HCV coinfected patients. However, new challenges have arisen, including the potential for harmful drug interactions with antiretroviral agents, poor drug adherence due to polymedication, increased risk for selection of drug-resistant HCV mutants, and unaffordable coverage in an environment of economic constraints. The use of noninvasive tools to measure liver fibrosis (i.e., elastometry) and pharmacogenomics (testing for IL28B and perhaps ITPA polymorphisms), along with consideration of early viral kinetics to guide length and drugs needed could help to individualize and improve the cost effectiveness of therapeutic decisions using DAA in HIV-infected patients with chronic hepatitis C.     

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。     

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。     

Peginterferon and ribavirin treatment for hepatitis C virus infection

Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, ...     

Understanding the interaction of hepatitis C virus with host DEAD-box RNA helicases

The current therapeutic regimen to combat chronic hepatitis C is not optimal due to substantial side effects and the failure of a significant proportion of patients to achieve a sustained virological response.Recently developed direct-acting antivirals targeting hepatitis C virus(HCV)enzymes reportedly increase the virologic response to therapy but may lead to a selection of drug-resistant variants.Besides directacting antivirals,another promising class of HCV drugs in development include host targeting agents that are responsible for interfering with the host factors crucia for the viral life cycle.A family of host proteins known as DEAD-box RNA helicases,characterized by nine conserved motifs,is known to play an important role in RNA metabolism.Several members of this family such as DDX3,DDX5 and DDX6 have been shown to play a role in HCV replication and this review will summarize our current knowledge on their interaction with HCV.As chronic hepatitis C is one of the leading causes of hepatocellular carcinoma,the involvement of DEADbox RNA helicases in the development of HCC will also be highlighted.Continuing research on the interaction of host DEAD-box proteins with HCV and the contribution to viral replication and pathogenesis could be the panacea for the development of novel therapeutics against HCV.     

Treatment of chronic hepatitis C]

Chronic infection with HCV represents second most common cause of end-stage liver diseases and hepatocellular carcinoma in Korea. The introduction of new agents and regimens for the treatment of chronic hepatitis C, such as pegylated forms of interferon-alpha (Peg-IFN) and combination with oral ribavirin has resulted in substantial improvement in sustained virologic response (SVR) rates. SVR rate of Peg-IFN and ribavirin combination therapy can be 40-46% of individuals infected with genotype 1 and approximately 75-85% with genotype 2 and 3. Peg-IFN/ribavirin combination therapy represents current standard therapy of chronic hepatitis C. This article reviews the treatment objectives, outcomes, optimal regimens, efficacy and predictors of response, monitoring during treatment, adverse events, retreatment of persons who failed to respond to previous treatments, and treatment of special patient groups in chronic hepatitis C.     

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.     

Interferon-based therapy for chronic hepatitis C: current and future perspectives

Pegylated interferon alpha (peginterferon alpha) plus ribavirin is the current mainstay of treatment for patients with chronic HCV infection. When peginterferon alpha plus ribavirin is administered for the standard duration, a sustained virological response is achieved in around 50% of patients infected with HCV genotype 1 and around 80% of patients infected with HCV genotype 2 or 3. Data now suggest that treatment duration can be shortened or lengthened depending on baseline viral load and/or early on-treatment viral kinetics, offering the prospect of individualizing therapy further to improve response or to prevent treatment from being unnecessarily extended. Further efforts to optimize therapy are likely to involve the use of new anti-HCV agents, several of which are currently in the early stages of development. These agents include HCV protease inhibitors (particularly those against NS3-4A protease), HCV polymerase inhibitors (including both nucleoside and non-nucleoside analogs) and cyclophilin inhibitors. These compounds will be used, at least initially, in combination with peginterferon alpha plus ribavirin, extending the pivotal role of interferon-based therapy in the management of chronic hepatitis C.     

Past, present, and future hepatitis C treatments

Conventional interferon (IFN) alfa has been used for many years in the treatment of chronic hepatitis C. However, few patients achieve sustained virological responses with IFN. Combining IFN with ribavirin improves efficacy considerably, but at the expense of diminished tolerability attributable to ribavirin. Pegylated interferons have improved pharmacokinetic profiles, may be administered once weekly, and are more effective than IFN is alone or in combination with ribavirin. In addition to enhanced efficacy, pegylated interferon alfa-2a (40 kD) also improves health-related quality of life during therapy compared with IFN-based therapy. New adjuvant agents have the potential to further improve sustained response rates and tolerability; however, pegylated interferons will likely remain the backbone of therapy in the foreseeable future. Therapies under development and evaluation for patients with HCV infection include adjunctive use of the antiviral agent amantadine and the immunomodulatory agent thymalfasin. Novel small molecules include the ribavirin analogues, viramidine and levovirin, and BILN 2061, an inhibitor of HCV serine protease. Other therapeutic strategies that have reached the clinic include antisense oligonucleotides (ISIS 14803), nuclease-resistant ribozymes targeting HCV RNA (Heptazyme), human monoclonal antibodie, and human antibody fragments directed at HCV helicase.     

丙型肝炎病毒感染与治疗药物

丙型肝炎病毒（HCV）通过在宿主细胞内持续复制,导致慢性感染。目前用于治疗慢性丙型肝炎（CHC）的药物主要是聚乙二醇干扰素（PEG-IFN）和利巴韦林的联合用药。本文将就HCV的细胞入侵、复制、逃避宿主的固有和获得性免疫,以及抗HCV临床试验药物的最新进展做一综述。     

How to Treat Patients with Chronic Hepatitis C Virus Infection and Decompensated Cirrhosis

Patients with chronic hepatitis C virus infection (HCV) and decompensated liver disease are not uncommon and present a considerable therapeutic challenge. Interferon-alfa-based regimens, standard therapy for HCV until recently, are plagued by worse tolerability and efficacy in patients with decompensated disease than others. Recent data have emerged with direct-acting anti-viral agents (DAAs) that are currently available including sofosbuvir, ledipasvir, and ribavirin; sofosbuvir, daclatasvir +/? ribavirin; and sofosbuvir, simeprevir +/? ribavirin that reveal excellent tolerability and efficacy in this patient population. In fact, sofosbuvir, ledipasvir, and ribavirin demonstrated sustained virologic response (SVR) rates of 87 and 89 % in CTP B and C patients, respectively, with a 12-week course. The current HCV guidance document from the AASLD/IDSA addresses treatment regimen recommendations for patients with decompensated disease. Ongoing long-term studies that assess quality of life, effect on the complications of ESLD, the rates of de-listing for liver transplantation, rates of development of hepatocellular carcinoma, and mortality after SVR in patients with decompensated disease will help address the question of who to treat when. Data should be forthcoming, including data on emerging therapies. The decision to treat patients with decompensated disease may be difficult, and such patients present complex clinical issues that dictate that experienced personnel administer therapy if at all possible.     

Actualización en la terapia de la hepatitis C. Nuevos fármacos,monitorización de la respuesta y resistencias

The development of novel direct antiviral agents (DAAs) against hepatitis C virus (HCV) has represented a breakthrough in the treatment of chronic hepatitis C. Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). In genotype 1 monoinfected patients, triple PI therapy has increased sustained viral response (SVR) rates by approximately 30% compared with conventional combination therapy. The introduction of these drugs into clinical practice will modify the timing of monitoring parameters in diagnostic laboratories, especially with regard to stopping rules and to faster delivery of results. In the near future, new DAAs, directed against different targets of the HCV cycle (polymerase inhibitors, viral replication complex inhibitors and cyclophilin inhibitors), which are currently in various stages of clinical development, will be available. Some of these DAAs have already reached advanced phases of development, both in combination with PEG-IFN and RBV and in interferon-free therapy, with very high rates of SVR.     

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.     

Tratamiento de la hepatitis C en grupos de pacientes especiales

The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects.These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy.     

A new era in the treatment of chronic hepatitis C infection

Treatment of chronic hepatitis C virus (HCV) infection has evolved over the past three decades. At the start, treatment involved interferon monotherapy followed by combination therapy using interferon and ribavirin, and subsequently evolved to pegylated interferon (Peg-IFN) and ribavirin. In genotype 1 infection, rates of sustained virological response (SVR) are approximately 45 % with Peg-IFN and ribavirin, whereas SVR rates in genotypes 2 and 3 infections are as high as 70 % to 80 %. Side effects and cost related to these drugs are important concerns, particularly in countries like India where patients have to bear their health expenses. In the recent past, there has been a significant change in course with the on-going search and the development of more effective drugs in the management of HCV infection. Telaprevir and Boceprevir are two new potent protease inhibitors (direct acting antiviral or DAA agents) which, when administered with Peg-IFN and ribavirin, have shown to result significantly higher SVR rates in phase 3 studies in patients with genotype 1 infection, both in treatment naïve patients (up to 75 %) and those with previously failed therapy. Several other new antiviral agents some in combination with Peg-IFN and ribavirin and some in combination without Peg-IFN (IFN-free regimens) are currently being tested in patients with genotype 1, 2 and 3 infections and are expected to dramatically change the armamentarium of HCV therapy in the coming years.     

The era of direct-acting antivirals has begun: the beginning of the end for HCV?

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.     

Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options

A significant proportion of chronic hepatitis C patients fails to achieve sustained virologic response even after treatment with the current, more potent, combination of pegylated interferon-alpha (IFNa) plus ribavirin. Such patients represent a rather heterogeneous group and may be divided initially into relapsers and nonresponders. Both the type of previous therapy and of previous response are very important factors for the indication and the type of re-treatment. The combination of pegylated IFNa and ribavirin seems to be a rational approach for patients who failed to respond to IFNa monotherapy. Pegylated IFNa-based regimens appear to induce sustained responses in 40-68% of relapsers but in only 11% of nonresponders to previous therapy with standard IFNa plus ribavirin. Thus, new therapeutic approaches are needed for the latter subgroup of patients as well as those who fail to respond to pegylated IFNa-based regimens. Such new approaches currently under evaluation include the triple combination of pegylated IFNa, ribavirin, and amantadine, alternative types of IFN, use of agents with ribavirin like activity but lesser degrees of side-effects, inhibitors of hepatitis C virus (HCV) replication, mainly inhibitors of NS3 protease or helicase, antisense oligonucleotides, and ribozymes, and several immunomodulators. Moreover, maintenance antifibrotic therapy, mostly with low doses of pegylated IFNa, are under evaluation in patients with advanced fibrosis. Thus, even in the current era of the potent pegylated IFNa-based regimens, the management of these difficult-to-treat patients represents an increasingly frequent problem and perhaps the most challenging therapeutic task in chronic hepatitis C.     

Antiviral strategies in hepatitis C virus infection

Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-na?ve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.