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Resistance-associated variants (RAVs) have been shown to influence treatment response to direct-acting antivirals (DAAs) and first generation NS3/4A protease inhibitors (PIs) in particular. Interpretation of hepatitis C virus (HCV) genotypic drug resistance remains a challenge, especially in patients who previously failed DAA therapy and need to be retreated with a second DAA based regimen. Bayesian network (BN) learning on HCV sequence data from patients treated with DAAs could provide insight in resistance pathways against PIs for HCV subtypes 1a and 1b, in a similar way as applied before for HIV. The publicly available ‘Rega-BN’ tool chain was developed to study associative analyses for various pathogens. Our first analysis, comparing sequences from PI-naïve and PI-experienced patients, determined that NS3 substitutions R155K and V36M arise with PI-exposure in HCV1a infected patients, and were defined as major and minor resistance-associated variants respectively. NS3 variant 174H was newly identified as potentially related to PI resistance. In a second analysis, NS3 sequences from PI-naïve patients who cleared the virus during PI therapy and from PI-naïve patients who failed PI therapy were compared, showing that NS3 baseline variant 67S predisposes to treatment-failure and variant 72I to treatment success. This approach has the potential to better characterize the role of more RAVs, if sufficient therapy annotated sequence data becomes available in curated public databases. In addition, polymorphisms present in baseline sequences that predispose patients to therapy failure can be identified using this approach. [ABSTRACT FROM AUTHOR]

Use of direct-acting antiviral drugs (DAAs) greatly improves management of adults infected with hepatitis C virus (HCV) whether patients are treatment-naive or unsuccessfully pre-treated. Several inhibitors of viral nonstructural proteins (NS3/4A protease, NS5A and NS5B polymerase) allow a rapid HCV clearance and increase rates of sustained virological response. Both the EASL and AASLD guidelines have recently published up-to-date recommendations for their use, addressing each HCV genotype and particular situations. However, management of patients coinfected with hepatitis B virus (HBV) has been developed by these guidelines with reference to cases of HBV reactivation reported during previous anti-HCV regimens containing interferon known active against both HBV and HCV. In the setting of the interferon-free HCV therapies with DAAs only, the possibility of HBV reactivation during treatment of hepatitis C is raised due to viral interferences in HCV/HBV coinfected persons. Herein, we report a case of early HBV reactivation during DAAs-based anti-HCV treatment (ledipasvir/sofosbuvir) in a patient having a resolved HBV infection and chronically infected with HCV genotype 4 and HIV. Moreover, we review similar recent cases of HBV reactivation in patients infected with HBV and HCV genotype 1 during treatment of hepatitis C by regimen incorporating other combination of DAAs (sofosbuvir/simeprevir or daclatasvir/asunaprevir). Due to the potential risk of early HBV reactivation in HCV/HBV-coinfected patients during interferon-free DAAs-based HCV therapies, altogether these cases highlight the necessity to closely monitor HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAAs used. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a major cause of chronic hepatitis in 170 million people worldwide and can progress to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, a disease process accelerated in HIV co-infection. Approximately 25% of HIV infected people are co-infected with HCV (worldwide prevalence 4-5 million) and up to 16.7% of deaths in this population are attributable to HCV co-infection. Previous treatment options for HCV were limited to pegylated interferon and ribavirin (PEG-IFN/RBV), a combination that demonstrated lower successful cure rates in genotype 1 HCV mono-infection and HIV/HCV co-infection, and is also associated with a considerable adverse side-effect profile. The development of directly acting antivirals (DAAs) offers the first class of drug to achieve good viral suppression in previously hard-to-treat patient groups. We review the benefits, tolerability and drug interactions with concomitant drugs of the DAA simeprevir for patients who have HCV mono-infection and hep C/HIV co-infection. [ABSTRACT FROM AUTHOR]

The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease. [ABSTRACT FROM AUTHOR]

The identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The goal to omit pegylated interferon due to its unfavorable side-effect profile from novel HCV therapeutic approaches led to an expedited design and competitive conduct of DAA combination trials striving for easily applicable, all-oral HCV treatments. Approval of several interferon-free regimens is awaited in the near future (2014/2015). Results of different DAA combination trials (without nucleos(t)ide polymerase inhibitors) and trials involving HTAs are reviewed herein. [ABSTRACT FROM AUTHOR]

In the United States, chronic hepatitis C virus (HCV) infection is the leading cause of blood-borne, virus-associated death related to advanced liver disease and the leading indication for liver transplantation. Although the diagnostic test for HCV has been available for more than 20 years, the majority of persons with HCV infection still have not received a diagnosis. This has led to a recent change in screening recommendations by the Centers for Disease Control and Prevention. Moreover, new medications were approved in 2011 after nearly a decade of minimal progress in the development of treatments for HCV infection. This was followed by the highly anticipated approval of sofosbuvir and simeprevir in 2013. In the past 3 years, there has been an explosion of reports on medications from different classes, promising a dramatic expansion to an all-oral regimen for the treatment of HCV genotype 1 infection within the next few years. This article reviews the current screening recommendations and standard of care for treatment of HCV infection and highlights specific agents in the pipeline that should change the landscape of how HCV infection is treated in the near future. [ABSTRACT FROM AUTHOR]

Boceprevir (BOC or B) and telaprevir (TVR or T), two newly approved NS3/4A protease inhibitors, have revolutionized hepatitis C therapy for genotype 1 since their availability in 2011. The new regimens are highly effective in treatment naive and treatment experienced patients. They are administered three times daily, and have an extensive list of drug-drug interactions that require vigilance with drug co-administration. The phase 3 clinical trials that led to the drugs' approval are reviewed in detail with regard to the clinical trial design, efficacy and safety data. Both drugs utilize response guided therapy (RGT) based upon rapid virological response (RVR) and extended rapid virological response, (eRVR) and depend upon defined stopping rules to minimize the risk of resistance development and prolonged treatment with unavoidable treatment futility. Although both drugs depend upon a framework of pegylated IFN alfa (PEG) and ribavirin (RBV), with the expected adverse events, telaprevir adds an additional risk of rash, anorectal symptoms and worsened anemia. Boceprevir is associated with worsened anemia and dysgeusia. Although these two medical regimens are compared and contrasted in this paper, it must be recognized that comparisons are limited because there have been no direct, head-to-head comparison studies. The hope that the next generation of direct acting anti-viral agents (DAAs) will afford the development of safe and effective therapy for HCV, including all genotypes, fuels ongoing research development of HCV therapy. [ABSTRACT FROM AUTHOR]

The addition of NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (Peg-IFN)-α and ribavirin for the treatment of hepatitis C virus (HCV) genotype 1-infected patients has led to higher rates of virological response and adverse events. Among the several side effects of interferon, neuropsychiatric symptoms have been described, particularly depression and anxiety, occurring in about 25% of patients. Although seizures have been reported in interferon-treated patients with multiple sclerosis and in a variety of malignancies, the epileptogenic potential of interferon-α in the treatment of HCV infection is considered minimal. In this report we present a new onset of seizures occurring in 2 patients during anti-HCV therapy in association with Peg-IFN, ribavirin and HCV protease inhibitors. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN- α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have been approved or are in clinical development, the majority of currently available PIs have significant limitations related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing schedules, and shorter treatment durations., Methods: The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using a fluorescence-based enzymatic assay., Results: We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a., Conclusion: The two compounds presented in this study may be promising inhibitors against NS3/4A protease of HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of chronic HCV infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)