A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben

2015 ◽  
Vol 156 (21) ◽  
pp. 849-854 ◽  
Author(s):  
István Tornai
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
First Generation ◽  
Pegylated Interferon ◽  
Direct Acting Antivirals ◽  
Direct Acting Antiviral ◽  
Genotype 1A ◽  
Direct Acting ◽  
Ns5b Polymerase

The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40–50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy. Orv. Hetil., 2015, 156(21), 849–854.

From first-generation hepatitis C virus protease inhibitors to direct-acting antivirals

2016 ◽  
Vol 28 (6) ◽  
pp. 733-734 ◽  
Author(s):  
Fabienne Marcellin ◽  
Isabelle Fournier ◽  
Maria P. Carrieri ◽  
Isabelle Poizot-Martin ◽  
Laurent Cotte
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
First Generation ◽  
Direct Acting Antivirals ◽  
Direct Acting

scholarly journals Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Stephen Ejeh ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Stephen E. Abechi
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Energy ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Antiviral Agents ◽  
High Potency ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Abstract Background Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. The conventional interferon-free treatment regimens are currently in use by a blend of direct-acting antiviral agents (DAAs) aiming at the viral NS3 protease. However, major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price. Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. This study aimed to use in-silico methods to identify high potent molecule as an NS3/4A protease inhibitor and investigating the binding energy of the identified molecule in comparison with approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) through molecular docking. Results The model obtained by in-silico method have the following statistical records, coefficient of determination (r2) of 0.7704, cross-validation (q2LOO = 0.6914); external test set (r2(pred) = 0.7049) and Y-randomization assessment (cR2p = 0.7025). The results from the model were used to identify 12 new potential human HCV NS3/4A protease inhibitors, and it was observed that the identified molecule is well-fixed when docked with the receptor and was found to have the lowest binding energy of − 10.7, compared to approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) with − 9.5, − 10.0, − 10.5 binding energy, respectively. Conclusion The binding affinity (− 10.7) of the newly identified molecule docked with 3D structures of HCV NS3/4a protease/helicase (PDB ID: 4A92) was found to be better than that of Telaprevir, Simeprevir, and Voxilaprevir (approved direct-acting antiviral agents) which are − 9.5, − 10.0, and − 10.5, respectively. Hence, a novel molecule was identified showing high potency as HCV NS3/4a protease inhibitors.

scholarly journals Hepatocellular Carcinoma Risk According to Regimens for Eradication of Hepatitis C Virus; Interferon or Direct Acting Antivirals

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3414
Author(s):  
Hye Won Lee ◽  
Dai Hoon Han ◽  
Hye Jung Shin ◽  
Jae Seung Lee ◽  
Seung Up Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Pegylated Interferon ◽  
Direct Acting Antivirals ◽  
Treatment Regimens ◽  
Direct Acting ◽  
Similar Risk ◽  
Carcinoma Risk

By pegylated interferon (PegIFN)-free direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection, a sustained virological response (SVR) rate >95% can be attained with a satisfactory tolerability and shorter treatment duration. However, it remains controversial whether there is any difference in prognosis depending on regimens—PegIFN or DAAs. We compared the probabilities of hepatocellular carcinoma (HCC) development between patients achieving an SVR by PegIFN/ribavirin (PegIFN group, n = 603) and DAAs (DAAs group, n = 479). The DAAs group was significantly older and had a higher proportion of cirrhosis than the PegIFN group. Before adjustment, the DAAs group had a higher HCC incidence than the PegIFN group (p < 0.001). However, by multivariate analyses, the DAAs (vs. PegIFN) group was not associated with HCC risk (adjusted hazard ratio 0.968, 95% confidence interval 0.380–2.468; p = 0.946). Old age, male, higher body mass index, cirrhosis, and lower platelet count were associated with increased HCC risk (all p < 0.05). After propensity score matching (PSM), a similar HCC risk between the two groups was observed (p = 0.372). We also compared HCC incidences according to sofosbuvir (SOF)-based and SOF-free DAAs, showing a similar risk in both groups before adjustment (p = 0.478) and after PSM (p = 0.855). In conclusion, post-SVR HCC risks were comparable according to treatment regimens; PegIFN- vs. DAA-based regimens and SOF-based vs. SOF-free DAA regimens. Further studies with a longer follow-up period are required.

scholarly journals Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

2020 ◽  
Vol 21 (7) ◽  
pp. 2583 ◽  
Author(s):  
Pil Soo Sung ◽  
Eui-Cheol Shin
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Virus ◽  
High Rate ◽  
Interferon Response ◽  
Direct Acting Antivirals ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Global Population ◽  
Open Issues

When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.

Inhibitory Effects of Amentoflavone and Orobol on Daclatasvir-Induced Resistance-Associated Variants of Hepatitis C Virus

2018 ◽  
Vol 46 (04) ◽  
pp. 835-852 ◽  
Author(s):  
Wei-Ping Lee ◽  
Keng-Li Lan ◽  
Shi-Xian Liao ◽  
Yi-Hsiang Huang ◽  
Ming-Chih Hou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Cost Effective ◽  
Pegylated Interferon ◽  
Chinese Herbs ◽  
Inhibitory Effects ◽  
Direct Acting Antiviral ◽  
Direct Acting

Hepatitis C virus (HCV) is recognized as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite rapid progress in the development of direct-acting antivirals (DAA) against HCV infection in recent years, cost-effective antiviral drugs with more affordable prices still need to be developed. In this study, we screened a library of natural compounds to identify natural HCV inhibitors. The library of the pure compounds extracted from Chinese herbs deposited in the chemical bank of National Research Institute of Chinese Medicine (NRICM), Taiwan was screened in the cell culture-derived HCV (HCVcc) system. We identified the flavone or flavan-based compounds amentoflavone, 7,4[Formula: see text]-dihydroxyflavanone, and orobol with the inhibition of viral entry, replication, and translation of the HCV life cycle. Amentoflavone and orobol also showed inhibitory effects on resistant-associated variants to the NS5A inhibitor daclatasvir. The results of this study have the potential to benefit patients who are intolerant to the adverse effect of pegylated interferon or who harbor resistant strains refractory to treatment by current direct-acting antiviral agents.

scholarly journals Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Kazi Abdus Salam ◽  
Nobuyoshi Akimitsu
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Standard Of Care ◽  
Pegylated Interferon ◽  
Virologic Response ◽  
Hcv Infection ◽  
Main Concern ◽  
Pegylated Interferon Plus Ribavirin ◽  
Direct Acting

Currently, hepatitis C virus (HCV) infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs) against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir) have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin). The new therapy has significantly improved sustained virologic response (SVR); however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

Viral Hepatitis C: Treatment

2018 ◽  
Author(s):  
Jay Luther ◽  
Raymond T. Chung ◽  
Anna Lidofsky ◽  
Jacinta A Holmes ◽  
Stephanie M Rutledge
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Pegylated Interferon ◽  
Direct Acting Antiviral ◽  
Hcv Therapy ◽  
Viral Hepatitis C ◽  
Pegylated Interferon Plus Ribavirin ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Infection with the hepatitis C virus (HCV) leads to chronic infection in the majority, and is associated with the development of complications including cirrhosis, end-stage liver failure, hepatocellular carcinoma and death. HCV is curable, and successful viral eradication is associated with a reduction in cirrhosis and liver-related mortality. However, previous HCV therapy, consisting of pegylated interferon plus ribavirin, was associated with poor cure rates and significant adverse events. The development of direct-acting antiviral agents (DAAs) that specifically target HCV replication has revolutionized the treatment of HCV. Current regimens are now highly potent, all-oral, interferon-free combinations of these DAAs. The Food and Drug Administration has now approved many of these regimens. The changing management of HCV infection, including recent advances in HCV therapy, are discussed. This review contains 1 figure, 5 tables and 59 references Key words: direct-acting antiviral agents, hepatitis C virus, interferon-free therapy, management, treatment

New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives

Gut ◽  
2012 ◽  
Vol 61 (Suppl 1) ◽  
pp. i36-i46 ◽  
Author(s):  
Christoph Welsch ◽  
Arun Jesudian ◽  
Stefan Zeuzem ◽  
Ira Jacobson
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Pegylated Interferon ◽  
The Novel ◽  
Genotype 1 ◽  
Direct Acting Antiviral ◽  
Hcv Therapy ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-N1 plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.

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