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Direct Acting Antivirals for the Treatment of Chronic Viral Hepatitis  [PDF]
Peter Karayiannis
Scientifica , 2012, DOI: 10.6064/2012/478631
Abstract: The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives. 1. Introduction Conservative estimates of the number of individuals worldwide who are thought to be chronically infected with either HBV or HCV are placed at over 350 [1] and 200 [2] million, respectively. It has long been established through epidemiological surveys that these patients are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). About 1 million people die per year as a result of HBV-related liver pathologies [3]. In resource-limited countries, HBV infection accounts for 30% of cirrhotic patients and 53% of those with HCC [4]. On the other hand, HCV is responsible for approximately 350000 deaths every year [5]. The only means of preventing these un-necessary deaths is therapeutic intervention through the use of immune modulators and direct acting antivirals (DDAs). The ultimate goals of treatment are to achieve a sustainable suppression of replication and remission of liver disease in the case of HBV, and complete eradication of the virus from the liver in the case of HCV. For many years, the only choice for treatment was interferon alpha (IFNα), lymphoblastoid initially and recombinant subsequently, both of which have more recently been superceded by the pegylated form (PegIFN), which requires intramuscular injection only once a week as opposed to three times a week with the previous forms. Interferon has not only immunomodulatory, but also antiproliferative and antiviral effects. It acts by promoting cytotoxic T-cell activity for lysis of infected hepatocytes and by stimulating cytokine production for control of viral replication. DDAs on the other hand constitute a more recent development based on increasing
New strategies for the treatment of hepatitis C virus infection and implications of resistance to new direct-acting antiviral agents
Josep Quer, Maria Buti, Maria Cubero, et al
Infection and Drug Resistance , 2010, DOI: http://dx.doi.org/10.2147/IDR.S7136
Abstract: trategies for the treatment of hepatitis C virus infection and implications of resistance to new direct-acting antiviral agents Review (3570) Total Article Views Authors: Josep Quer, Maria Buti, Maria Cubero, et al Published Date November 2010 Volume 2010:3 Pages 133 - 145 DOI: http://dx.doi.org/10.2147/IDR.S7136 Josep Quer1–3, Maria Buti1–3, Maria Cubero1–3, Jaume Guardia1–3, Rafael Esteban1–3, Juan Ignacio Esteban1–3 1Liver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Barcelona, Spain; 2Universitat Autònoma de Barcelona, Barcelona, Spain; 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain Abstract: Persistent hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and the major indication for liver transplantation in adults. Current standard of care treatment (SOC) with pegylated-interferon-a 2 and ribavirin (RBV) has a limited efficacy and is associated with significant side effects frequently associated with poor compliance or treatment discontinuation, requiring specialized and frequent monitoring. To overcome the limited efficacy of SOC, more than 50 direct-acting antiviral agents (DAA) designed to target viral-encoded proteins essential in the HCV life cycle are currently under development. The rapid selection of resistant mutants associated with the quasispecies nature of HCV with high mutation and replication rates is one of the main challenges for the new HCV therapies. Predictive host and viral factors together with combination of DAAs with or without IFN and/or RBV need to be accurately evaluated to design the most effective individualized treatment strategy within the shortest time interval and with minimum side effects.
Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents  [PDF]
Fei Xiao equal contributor,Isabel Fofana equal contributor,Laura Heydmann,Heidi Barth,Eric Soulier,Fran?ois Habersetzer,Michel Doffo?l,Jens Bukh,Arvind H. Patel,Mirjam B. Zeisel,Thomas F. Baumert
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004128
Abstract: Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.
New strategies for the treatment of hepatitis C virus infection and implications of resistance to new direct-acting antiviral agents  [cached]
Josep Quer,Maria Buti,Maria Cubero,et al
Infection and Drug Resistance , 2010,
Abstract: Josep Quer1–3, Maria Buti1–3, Maria Cubero1–3, Jaume Guardia1–3, Rafael Esteban1–3, Juan Ignacio Esteban1–31Liver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Barcelona, Spain; 2Universitat Autònoma de Barcelona, Barcelona, Spain; 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, SpainAbstract: Persistent hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and the major indication for liver transplantation in adults. Current standard of care treatment (SOC) with pegylated-interferon-a 2 and ribavirin (RBV) has a limited efficacy and is associated with significant side effects frequently associated with poor compliance or treatment discontinuation, requiring specialized and frequent monitoring. To overcome the limited efficacy of SOC, more than 50 direct-acting antiviral agents (DAA) designed to target viral-encoded proteins essential in the HCV life cycle are currently under development. The rapid selection of resistant mutants associated with the quasispecies nature of HCV with high mutation and replication rates is one of the main challenges for the new HCV therapies. Predictive host and viral factors together with combination of DAAs with or without IFN and/or RBV need to be accurately evaluated to design the most effective individualized treatment strategy within the shortest time interval and with minimum side effects.Keywords: HCV, treatment, quasispecies, resistance
Human Subtilase SKI-1/S1P Is a Master Regulator of the HCV Lifecycle and a Potential Host Cell Target for Developing Indirect-Acting Antiviral Agents  [PDF]
Andrea D. Olmstead,Wolfgang Knecht,Ina Lazarov,Surjit B. Dixit,Fran?ois Jean
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002468
Abstract: HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1) – or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care.
Recent progress in research of hepatitis B viruses with precore and basic core promoter mutations  [cached]
LI Jin′e
Journal of Clinical Hepatology , 2013,
Abstract: Mutations in the precore and basic core promoter of hepatitis B virus (HBV) can reduce synthesis and secretion of the HBV e antigen (HBeAg), increase viral replication, and cause HBeAg-negative chronic hepatitis B (CHB). Therefore, these mutations are likely to have important impacts on the clinical progression of the hepatitis B disease. In this review, the recent progress in research on HBV precore and basic core promoter mutations is discussed, including but not limited to insights into the related molecular mechanisms and their biological significance for established and new laboratory tests and antiviral therapies.
A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection  [PDF]
Bambang S. Adiwijaya ,Tara L. Kieffer,Joshua Henshaw,Karen Eisenhauer,Holly Kimko,John J. Alam,Robert S. Kauffman,Varun Garg
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002339
Abstract: We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-na?ve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-na?ve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.
The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents  [PDF]
Christina Gavegnano,Edward M. Kennedy,Baek Kim,Raymond F. Schinazi
Molecular Biology International , 2012, DOI: 10.1155/2012/625983
Abstract: Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2′-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells. 1. Introduction Macrophages are a key reservoir for HIV-1, and their ubiquitous nature, multiple, and often independent microenvironments in which they are contained, coupled with their susceptibility to HIV-1 infection [1–3], dictate that further understanding must be garnered about the distinctive characteristics of macrophages and the subsequent impact on the dynamics of HIV-1 infection in these cells. Despite these factors, most of the attention on reservoirs for latent HIV-1 has focused on cells of lymphoid origin, most notably CD4+/CD45RO+ memory lymphocytes [4]. Consequently, the interplay between HIV-1 infection in macrophages and macrophage-like cells is markedly less defined. Additionally, the relationship between in vitro observations and in vivo dynamics is not fully elucidated. Much evidence exists to support the existence of HIV-1 replication in macrophage/macrophage-like cells in vivo [5–11], including a recent report from Deleage et al., and confirmed the presence of HIV-1 in macrophages within seminal vesicles of patients on effective highly active antiretroviral therapy (HAART) [12]. Correspondingly, a variety of studies have presented evidence that monocytes harbor productive viral replication in patients receiving HAART [13, 14], with
Silver Nanoparticles as Potential Antiviral Agents  [PDF]
Stefania Galdiero,Annarita Falanga,Mariateresa Vitiello,Marco Cantisani,Veronica Marra,Massimiliano Galdiero
Molecules , 2011, DOI: 10.3390/molecules16108894
Abstract: Virus infections pose significant global health challenges, especially in view of the fact that the emergence of resistant viral strains and the adverse side effects associated with prolonged use continue to slow down the application of effective antiviral therapies. This makes imperative the need for the development of safe and potent alternatives to conventional antiviral drugs. In the present scenario, nanoscale materials have emerged as novel antiviral agents for the possibilities offered by their unique chemical and physical properties. Silver nanoparticles have mainly been studied for their antimicrobial potential against bacteria, but have also proven to be active against several types of viruses including human imunodeficiency virus, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkey pox virus. The use of metal nanoparticles provides an interesting opportunity for novel antiviral therapies. Since metals may attack a broad range of targets in the virus there is a lower possibility to develop resistance as compared to conventional antivirals. The present review focuses on the development of methods for the production of silver nanoparticles and on their use as antiviral therapeutics against pathogenic viruses.
Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B  [PDF]
Megan H. Powdrill,Jean A. Bernatchez,Matthias G?tte
Viruses , 2010, DOI: 10.3390/v2102169
Abstract: 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.
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