4--azidocytidine and telaprevir

Specifically Targeted Antiviral Therapy against hepatitis C virus (STAT-C) stands for a new era in the treatment of patients with chronic hepatitis C. Results from recent trials with protease and polymerase inhibitors indicate that therapy with a single HCV specific compound will not be sufficient to eradicate hepatitis C virus infection and that combination therapy will be necessary to improve sustained virologic response rates. The search for the optimal combination of STAT-C compounds with peginterferon alfa with or without ribavirin is currently under investigation in several clinical trials. Overall the current studies indicate that peginterferon alfa and ribavirin remain the backbone of antiviral therapy of chronic hepatitis C even in the era of STAT-C. Nevertheless, it can be anticipated that combination of STAT-C compounds with non-overlapping resistance profiles could improve response to antiviral therapy. Promising combinations are protease inhibitors plus nucleoside analogue and non-nucleoside analogue polymerase inhibitors.

Topics: Antiviral Agents; Cytidine; DNA-Directed RNA Polymerases; Drug Delivery Systems; Drug Resistance, Viral; Drug Therapy, Combination; Forecasting; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Nucleosides; Oligopeptides; Polyethylene Glycols; Prodrugs; Proline; Protease Inhibitors; Pyrimidine Nucleosides; Recombinant Proteins; Ribavirin

Specific inhibitors of hepatitis C virus (HCV) replication that target the NS3/4A protease (e.g., VX-950) or the NS5B polymerase (e.g., R1479/R1626, PSI-6130/R7128, NM107/NM283, and HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug-resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and nonnucleoside inhibitors during clinical trials and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine whether nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors at 10 and 15 times the 50% effective concentration resulted in clearance of the replicon, while treatment with a nonnucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors. Furthermore, the combination of a nonnucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.

Topics: Antiviral Agents; Cytidine; Deoxycytidine; Drug Resistance, Viral; Hepacivirus; Nucleosides; Oligopeptides; Protease Inhibitors; Replicon; Serine Endopeptidases; Viral Nonstructural Proteins; Virus Replication