scholarly journals Challenge to overcome: Nonstructural protein 5A-P32 deletion in direct-acting antiviral-based therapy for hepatitis C virus

2018 ◽  
Vol 24 (38) ◽  
pp. 4304-4310 ◽  
Author(s):  
Ken Sato ◽  
Toshio Uraoka
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Nonstructural Protein 5A

scholarly journals Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

2012 ◽  
Vol 56 (10) ◽  
pp. 5230-5239 ◽  
Author(s):  
Lenore A. Pelosi ◽  
Stacey Voss ◽  
Mengping Liu ◽  
Min Gao ◽  
Julie A. Lemm
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Combination Treatment ◽  
Target Gene ◽  
Nonstructural Protein ◽  
Synergistic Effects ◽  
Antiviral Agents ◽  
Strong Support ◽  
Direct Acting Antiviral ◽  
Direct Acting

ABSTRACTThree hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.

New Epidemiologic Data Regarding Hepatitis C Virus Infection in Romania

2017 ◽  
Vol 26 (4) ◽  
pp. 381-386
Author(s):  
Mircea Manuc ◽  
Carmen M. Preda ◽  
Corneliu P. Popescu ◽  
Cristian Baicuș ◽  
Theodor Voiosu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Users ◽  
Antiviral Agent ◽  
Virologic Response ◽  
Advanced Fibrosis ◽  
Direct Acting Antiviral ◽  
Genotype 1B ◽  
Direct Acting ◽  
End Stage

Background & Aims: Literature data suggest that HCV genotype-1b is present in 93-99% of the Romanian patients infected with hepatitis C virus (HCV). We present the genotyping tests recently performed on patients with HCV and advanced fibrosis eligible for the Direct-Acting Antiviral (DAA) therapy, as well as the prevalence of these cases across Romania.Methods: The genotyping method was performed on 7,421 HCV patients with advanced fibrosis. The detection method was automatic real time PCR platform M2000 (Abbott). Every subject was introduced into a database including age, sex, county and address.Results: Genotype 1b was almost exclusively present: 7,392/7,421 (99.6%). Genotype 1b patients were 19.6% from Bucharest, 49% were males, with a median age of 60 years. Genotype non-1b was encountered in 29/7,421 subjects (0.4%), 62% were males, 69% from Bucharest and the median age was 52 years. Most of the subjects (75%) were in the 6th and 7th age decade. The prevalence of these cases varied significantly across Romanian counties: the highest was in Bucharest (61.3/105), Bihor (47/105), Iasi (46/105) and Constanța (43/105), and the lowest in Ilfov (2.8/105), Harghita (3.7/105), Covasna (5.4/105) and Maramureș (8.8/105) (p<0.001).Conclusions: Genotype 1b is encountered in 99.6% of patients with chronic hepatitis C and advanced fibrosis from Romania. The presence of genotypes non-1b is more common in Bucharest, in males and at a younger age. There are significant differences regarding the distribution of these cases across Romania: the highest rates are in Bucharest, Bihor, Iasi and Constanta.Abbreviations: BMI: body mass index; DAA: direct-acting antiviral agent; GT: genotype; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IDU: intravenous drug users; MELD: model for end stage liver disease; NASH: non-alcoholic steatohepatitis; SVR; sustained virologic response.

Efficacy of Direct-Acting Antiviral Combination Therapy in the Treat-ment of Hepatitis C Virus Among Kidney Transplant Patients

2020 ◽  
Vol 18 ◽  
Author(s):  
Mohammed Al Atbee ◽  
Saad Shaheen Al-Taher ◽  
Majid Alabbood
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Kidney Transplant ◽  
Virological Response ◽  
Hepatitis C Virus Infection ◽  
Direct Acting Antiviral ◽  
Transplant Patients ◽  
Kidney Transplant Patients ◽  
Direct Acting

Background: Up to date, there is no consensus on the best combination of direct-acting antiviral to treat hepatitis C virus in kidney transplant recipients. Objective: This study aims to analyze the efficacy of combination of sofosbuvir and ledipasvir regimen for treatment of hepatitis C virus infected kidney transplant patients. Method: A cross-sectional study conducted in a nephrology clinic and the Nephrology Center in Basrah Teaching Hospital from June 2015 to June 2018. Ledifos (90 mg Ledipasvir and 400 mg Sofosbuvir fixed-dose) was given as a single daily dose for all the participants for 12 weeks. Response for therapy was tested by follow up hepatitis C virus load at the end of 12 weeks and 24 weeks. The sustained virological response was defined as negative viral load of hepatitis C virus (aviremia) at the end of therapy. This study was done according to the Helsinki Congress. Results: A total of 60 (16 females) patients with renal transplantation and hepatitis C virus infection were included. Mean age was 40±6.2 years. A sustained virological response observed in all of the patients who received Ledifos after 12 and 24 weeks of therapy for all genotypes (1a, 1b and 4); p= 0.0001. Genotype 1a was more prevalent among males, 34 (56.6%); p= 0.0001, and it was the most common genotype tested negative serologically, 11 (18.3%). Conclusion: Ledifos therapy is effective and safe option for the treatment of hepatitis C virus infection in the post–renal transplant setting.

Effect on the adherence to concomitant medications after initiation of treatment with direct-acting antiviral agents against hepatitis C virus

2020 ◽  
Vol 43 (8) ◽  
pp. 418-425
Author(s):  
Maria Isabel Guzman Ramos ◽  
Mercedes Manzano-García ◽  
M. de las Aguas Robustillo-Cortés ◽  
Juan Antonio Pineda ◽  
Ramón Morillo-Verdugo
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Direct Acting Antiviral ◽  
Concomitant Medications ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

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.

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