Specifically Targeted Antiviral Therapy For HCV Research Articles

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.

Recent Advances in Hepatitis C Virus Treatment: Review of HCV Protease Inhibitor Clinical Trials

Hepatitis C virus (HCV) infection affects millions of people world-wide, and chronic infection can result in end-stage liver disease and hepatocellular carcinoma. Conventional therapy to date has involved combination antiviral therapy including alpha-interferon and ribavirin; response rates with these drugs are variable based on both viral and host factors, such as HCV viral load, HCV genotype, HIV co-infection, host genetic polymorphisms (such as those in the IL28B region), and other factors. Recent advances in HCV treatment have included pegylated forms of alpha-interferon and, more recently, the development of specifically targeted antiviral therapy for HCV (STAT-C) with novel HCV protease inhibitors (PIs) for genotype 1 HCV. Although unlikely to be administered as monotherapy due to the potential for development of HCV PI drug resistance mutations, results of phase II trials of two PIs in development have recently been reported, demonstrating promising therapeutic efficacy of HCV PIs in combination with established conventional treatment. This review outlines the advances and the challenges in the development of these HCV PIs as effective HCV antiviral agents and their role in clinical practice.

Cyclophilin Inhibitors as a Novel HCV Therapy

A critical role of Cyclophilins, mostly Cyclophilin A (CyPA), in the replication of HCV is supported by a growing body of in vitro and in vivo evidence. CyPA probably interacts directly with nonstructural protein 5A to exert its effect, through its peptidyl-prolyl isomerase activity, on maintaining the proper structure and function of the HCV replicase. The major proline substrates are located in domain II of NS5A, centered around a “DY” dipeptide motif that regulates CyPA dependence and CsA resistance. Importantly, Cyclosporine A derivatives that lack immunosuppressive function efficiently block the CyPA-NS5A interaction and inhibit HCV in cell culture, an animal model, and human trials. Given the high genetic barrier to development of resistance and the distinctness of their mechanism from that of either the current standard of care or any specifically targeted antiviral therapy for HCV (STAT-C), CyP inhibitors hold promise as a novel class of anti-HCV therapy.

Safety of small molecules in combination with interferon-based therapy for hepatitis C virus

Importance of the field: HCV is a leading cause of liver disease in the US, where ∼ 3.4 million people are chronically infected. The standard of care (SOC) of pegylated IFN and ribavirin combination therapy has limited efficacy with ∼ 50% sustained viral response, and is associated with a considerable adverse event profile in many patients. New drugs that directly target the virus are in development, and promise more effective therapies for chronic HCV infection.Areas covered in this review: Patient sub-classes with poor prognosis with SOC are identified, as are their associated adverse event profiles. Novel drugs, known as specifically targeted antiviral therapy for HCV (STAT-C), are currently being evaluated in clinical trials in multidrug combinations. Emerging safety signals and strategies to identify and prevent viral resistance to STAT-C drugs are also addressed.What the reader will gain: How the multidrug combinations are being developed and tested, what their relative strengths and weakness are, and which patient groups will benefit the most.Take home message: The central questions to successful multidrug combination therapies including novel small molecules will be their composite safety and efficacy profiles. Carefully conducted clinical trials and timely updates will be needed for ongoing improvements in patient care.

Antiviral therapy for hepatitis C virus: beyond the standard of care.

Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.

Telaprevir: An Emerging Protease Inhibitor for the Treatment of Hepatitis C

Current standard anti-HCV therapy with peginterferon/ribavirin is effective in only half of the patients and limited by side-effects that often necessitate discontinuation. Therefore, new treatments are being developed including specifically targeted antiviral therapy for HCV (STAT-C). Clinical development is most advanced for telaprevir, a HCV NS3/4A protease inhibitor. Phase 1 trials demonstrated potent antiviral effect but rapid emergence of resistance mutations which could be controlled by simultaneous administration of peginterferon. Phase 2 clinical trials (the PROVE trials) demonstrated superior efficacy of a telaprevir-based triple combination regimen for 24 weeks as compared to standard of care at an acceptable safety profile in chronic HCV genotype 1 infection both in the treatment-naive (SVR 65% vs. 44%) and treatment-experienced (SVR 51% vs. 14%) setting. Phase 3 trials are currently ongoing in treatment-naive as well as treatment-experienced HCV genotype 1 patients and SVR data are expected for the second half of 2010.

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.

The role of new interferons in the era of STAT-C

More than 50% of patients infected with HCV genotype 1 fail respond to standard treatment with peginterferon plus ribavirin. potent treatment strategies are urgently needed to improve outcomes for such patients. novel interferons and specifically targeted antiviral therapy for HCV (STAT-C) represent promising strategies.

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.

Reply:

We appreciate the comments made by Carreno et al. because they reflect the complexity and controversy of data available on “occult” hepatitis C virus (HCV) infection, which were discussed in detail within our review article.1 If clinically significant replication of HCV takes place in patients with “occult” HCV infection and sustained virologic response (SVR) after interferon-alfa (IFN)–based antiviral therapy for chronic HCV infection, high rates of late virologic relapse may be expected. However, late virologic relapse rates are overall very low in patients with SVR, irrespective of whether their immune system is impaired or not.1 Carreno et al. argue that “cumulative evidence” strongly supports HCV replication in patients with “occult” HCV infection. Because this conclusion would have substantial consequences for patients considered cured of their HCV infection as well as for the healthcare system, data must be interpreted most carefully and differentiated. Indeed, MacParland et al. reported de novo infection of T cells exposed to plasma of patients with SVR after IFN-based antiviral treatment as demonstrated by detection of genomic and antigenomic HCV RNA as well as detection of HCV-like particles by immunoelectron microscopy.2 In contrast, other data indicate reasonable doubt whether HCV can replicate in peripheral blood mononuclear cells (PBMCs) at all.3 HCV cell entry receptors are CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin, of which claudin-1, SR-BI, and occludin are typically not expressed on PBMCs.3-5 Possible infection of PBMCs was investigated using the currently most robust and suitable in vitro system to fully recapitulate HCV entry, replication, and virus production.3, 6 Cell culture–produced HCV did not replicate in PBMCs, infection of PBMC subsets with HCV pseudoparticles (HCV-pp) failed, and even artificial expression of claudin-1 on a special B cell line also expressing CD81 and SR-BI did not enhance HCV-pp infectivity of PBMCs.3 Directly transfected HCV RNA was also not translated and did not replicate in PBMC subsets.3 Furthermore, Carreno et al. mention unpublished data reporting a higher incidence of serologic markers of HCV infection in family members of patients with “occult” HCV infection in comparison to patients with chronic hepatitis C.7 These data may be interpreted in detail after full publication, but prima facie it seems difficult to understand why immune responses to HCV in family members of subjects with undetectable HCV RNA in serum was more frequent than in family members of patients with detectable HCV RNA. Moreover, HCV-specific CD4+ T cell response may occur because of ongoing viral replication but also may reflect persistence of specific T cells after resolved HCV infection as discussed within our article.1 Similar considerations may be taken into account for other indirect markers of prior infection, such as anti-HCV core antibodies.8 We fully agree with Carreno et al. that the data of studies investigating the topic of “occult” HCV infection are heterogeneous.1, 10 However, it must be noted that several studies have failed to confirm “occult” HCV infection under various circumstances using particularly sensitive tests.1, 9, 11, 12 Reports on detection of HCV proteins in patients with “occult” HCV infection have been discussed within our review article but must be interpreted cautiously with respect to methods used and results of other studies.1, 13 In summary, data about the presence or absence of HCV RNA in liver and/or PBMCs despite negative HCV RNA in serum of patients with previous HCV infection are conflicting. Further well-designed, multicenter, prospective trials are necessary not only for current IFN-based therapies but also in the future for antiviral therapies based on specifically targeted antiviral therapy for HCV (STAT-C), with and without IFN, to finally resolve these conflicting data. Martin-Walter Welker*, Stefan Zeuzem*, * Medizinische Klinik 1, Klinikum der Johann-Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Review article: investigational agents for chronic hepatitis C

The need for effective treatment for chronic hepatitis C infection has driven the development of novel antiviral agents that target specific steps in the viral replication cycle. To evaluate the current literature concerning investigational agents for chronic hepatitis C virus infection. Resources used included PubMed, conference proceedings from the American and European Liver Associations' meetings 2005-2008 and the National Institute of Health's clinical trials website (http://www.clinicaltrials.gov). The focus was restricted to investigational agents that have progressed beyond preclinical development. Over 50 investigational agents for chronic hepatitis C infection are currently in clinical development. Specifically targeted anti-viral therapy for HCV (STAT-C) shows great promise with NS3/4a protease inhibitors now entering phase 3 programmes. New interferon-alpha and ribavirin formulations aim to optimize anti-viral efficacy yet limit toxicity. Other candidates include novel immunomodulators and therapeutic vaccines. A new era of therapy for chronic hepatitis C beckons, promising increased cure rates with shortened duration of therapy. However, the era will not be without challenges including viral resistance, drug toxicity and the need to optimize combination therapy in the face of a rapidly evolving therapeutic arsenal.

Protease and polymerase inhibitors for the treatment of hepatitis C

Chronic hepatitis C is among the leading causes of chronic liver disease worldwide, with approximately 170 million people infected. The severity of disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Recently,advances have been made, with the combination of pegylated interferon (PEG-IFN) and ribavirin leading to a sustained virological response (SVR) in approximately 55% of cases. In genotypes 2 or 3, SVR rates reach 80%; in genotype 1 SVR rates is 50%. Furthermore, SVR appears to be long lasting, associated probably with a reduction in the risk of cirrhosis and hepatocellular carcinoma. Despite this progress, treatment failure still occurs in about half of the patients. Furthermore, therapy results in several side effects and high costs. These limitations have led to important development of novel compounds under the name of specifically targeted antiviral therapy for HCV (STAT-C). Also, considering side effects and treatment cost, prediction of virological non-response is mandatory. The management of chronic hepatitis C must include better knowledge of viral cycle and mechanisms of non response. The development of new molecules such as HCV enzyme inhibitors is ongoing. The aim of this review is to summarize results obtained with STATC: protease and polymerase inhibitors.

Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) Inhibitors

Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log(10) units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log(10) units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 muM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.

Recent progress in the development of selected hepatitis C virus NS3·4A protease and NS5B polymerase inhibitors

Chronic hepatitis C virus (HCV) infection is a pressing medical problem worldwide. Current therapy with pegylated interferon plus ribavirin (Peg-IFN/RBV) is associated with a poor risk benefit profile, a long treatment duration (48 weeks) and inadequate success rate (approximately 40-50%) of SVR (sustained viral response) in patients infected with genotype 1 HCV. This review is focused on recent clinical trial results with specifically targeted antiviral therapy for HCV (STAT-C) protease and polymerase inhibitors. In the past decade, anti-HCV drug discovery has focused first on targeting host factors required for viral replication and second on multiple HCV antiviral agents. Owing to the large number of HCV inhibitors currently in pre-clinical and clinical development today, we have focused on the most advanced compounds in the HCV polymerase and HCV protease inhibitor classes. Within each class, compounds will be used to illustrate some of the properties associated with inhibitors that bind to the active site of HCV polymerase, the active site of HCV protease (macrocyclic and linear ketoamide inhibitors) and allosteric polymerase inhibitors.

Optimal dose of peginterferon and ribavirin for treatment of chronic hepatitis C

Chronic hepatitis C affects 170 million people worldwide, including up to 4 million people in the United States. The current standard of care therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) while highly successful in patients with genotype 2 and 3 infection, allows for sustained virologic response in 42-46% of treatment-naïve genotype 1 patients, comprising about 70% of cases of chronic hepatitis C in the USA. While awaiting approval of Specifically Targeted Antiviral Therapy for HCV (STAT-C) agents, which will require the completion of additional clinical trials, it is important to optimize the dose and duration of currently available treatment modalities, namely PEG-IFN and RBV, for treatment of CHC. Results of several recent trials evaluating optimal dosing of RBV and higher than standard dosing of PEG-IFN in treatment-naïve genotype 1 patients, as well as data from retreatment trials with "induction" doses of PEG-IFN or high-dose RBV in prior non-responders to IFN-based therapy will be reviewed here. The possibility of shorter duration of therapy for genotype 2 and 3 patients based on recent publications and presentations will be discussed as well.

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.