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<br>[1]. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect By Gao, Min; Nettles, Richard E.; Belema, Makonen; Snyder, Lawrence B.; Nguyen, Van N.; Fridell, Robert A.; Serrano-Wu, Michael H.; Langley, David R.; Sun, Jin-Hua; O/’Boyle, Donald R., II; et al From Nature (London, United Kingdom) (2010), 465(7294), 96-100.
Abstract
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200?million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3?log10 reduction in mean viral load measured 24?h post-dose that was sustained for an additional 120?h in two patients infected with genotype 1b virus….
<br>[2]. Pelosi LA, Voss S, Liu M, Gao M, Lemm JA. Effect on HCV Replication by Combinations of Direct Acting Antivirals Including NS5A Inhibitor Daclatasvir. Antimicrob Agents Chemother. 2012 Jul 30.
Abstract
Three Hepatitis C virus (HCV) inhibitors, asunaprevir (ASV, BMS-650032), daclatasvir (DCV, BMS-790052), and BMS-791325, each targeting a different non-structural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging pre-clinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed 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 demonstrate 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.
<br>[3]. Galmozzi E, Aghemo A, Colombo M. Low rates of naturally occurring resistant variants to the NS5A inhibitor daclatasvir in HCV-1 null responders. Hepatology. 2012 Jun 28. doi: 10.1002/hep.25924.
<br>[4]. Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA, Hézode C, Lim JK, Bronowicki JP, Abrams GA, Br?u N, Morris DW, Thuluvath PJ, Reindollar RW, Yin PD, Diva U, Hindes R, McPhee F, Hernandez D, Wind-Rotolo M, Hughes EA, Schnittman S. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis. 2012 Jun 15.
Abstract
BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV.METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770.FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups.INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection.FUNDING: Bristol-Myers Squibb.
<br>[5]. Fontana RJ, Hughes EA, Appelman H, Hindes R, Dimitrova D, Bifano M. A case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis c following liver retransplantation. Liver Transpl. 2012 Jun 18. doi: 10.1002/lt.23482.
Abstract
Recurrent hepatitis C virus infection following liver transplantation can lead to accelerated allograft injury and fibrosis. The aim of this study is to report the first ever use of daclatasvir (BMS-790052), a potent orally administered NS5A replication complex inhibitor, in combination with peginterferonα and ribavirin in a liver transplant recipient. A 49 year old female developed severe recurrent HCV genotype 1b infection 4 months after transplant with severe cholestasis on biopsy and an HCV RNA of 10,000,000 IU/ml, alk phos of 1525 IU/ml, and total bilirubin of 8.4 mg/dl. Despite partial virological suppression with peginterferonα and ribavirin, progressive allograft failure ensued culminating in retransplantation at 9 months. At 3 months after the second transplant, daclatasvir 20 mg per day, peginterferona2a 180 ug/ week and ribavirin 800 mg/ day were prescribed for early recurrent cholestatic HCV. Serum HCV RNA became undetectable at week 3 of treatment and remained undetectable during 24 weeks of triple therapy as well as during post-treatment follow-up. Daclatasvir was well-tolerated and the trough drug levels were within the targeted range throughout treatment. The cyclosporine trough levels were also stable during and after therapy. Conclusion: The lack of anticipated drug-drug interactions between daclatasvir and the calcineurin inhibitors coupled with its potent antiviral efficacy make this agent in combination with peginterferon and ribavirin an attractive antiviral regimen worthy of further study in liver transplant recipients with recurrent HCV. ? 2012 American Association for the Study of Liver Diseases.
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