Low Rates of Naturally Occurring Resistant Variants to the NS5A Inhibitor Daclatasvir in HCV-1 Null Responders

First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy. .
Hepatology (Impact Factor: 11.06). 05/2013; 57(5). DOI: 10.1002/hep.25924
Source: PubMed
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    ABSTRACT: Most direct-acting antivirals (DAAs) being developed against the hepatitis C virus target the NS3/4A protease, the NS5A protein and the NS5B polymerase. The latter enzyme offers different target sites: the catalytic domain for nucleoside/-tide analogues as well as a number of allosteric sites for non-nucleoside inhibitors. Two NS3/4A protease inhibitors have recently been approved and more than 40 new NS3/4A, NS5A or NS5B inhibitors are in the development pipeline. These agents can achieve very high cure rates when combined with pegylated-interferon-α and ribavirin and show promising clinical results when combined in all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small-molecule drug development are emerging, such as p7 or NS4B and viral entry. Future research will need to define well-tolerated and cost effective DAA combinations, providing the highest rates of viral eradication in all patients, including those with advanced liver disease, with broadest spectrum of action on viral genotypes, showing minimal or no clinical resistance and with the shortest treatment duration. (HEPATOLOGY 2013.).
    No preview · Article · Jul 2013 · Hepatology
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection is responsible for the development of liver cirrhosis and hepatocellular carcinoma. It has been a tremendous burden on global health care systems. With the advent of a number of new direct-acting and host-targeting antiviral agents, current interferon-α- and ribavirin-based HCV therapy has started to move towards an interferon-sparing or even interferon-free strategy. In this regard, a recently identified NS5A inhibitor, daclatasvir, showed a great promise in clinical trials as another new class of direct-acting anti-HCV therapeutics, with a distinct mechanism of action. In this review, a variety of preclinical as well as clinical proof-of-concept studies of daclatasvir, including the studies of its discovery, mechanism of action, viral resistance, and host polymorphism profiles are reviewed. In addition, a role of daclatasvir in the future therapy for HCV patients is discussed briefly.
    Full-text · Article · Oct 2013 · Drug Design, Development and Therapy
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    ABSTRACT: Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylated-interferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naïve patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.
    No preview · Article · Dec 2013 · Current Medicinal Chemistry
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