valopicitabine and 4--azidocytidine

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

To characterize the effect of hepatitis C virus (HCV) polymerase intrinsic genetic heterogeneity on the inhibitory activity of nucleoside and non-nucleoside HCV polymerase inhibitors.. The sensitivity of genotype (GT) 1 HCV NS5B clinical isolates from treatment-naive patients to nucleoside and non-nucleoside polymerase inhibitors was assessed. The genetic diversity at the population level, as well as that of their quasispecies, was correlated with the observed reduced sensitivity to inhibitors.. R1479 and NM107 (nucleoside analogues that have entered Phase 2 clinical trials as prodrugs R1626 and NM283, respectively) were similarly active across the tested clinical isolates. Resistance mutations to nucleoside analogues were not observed in any of the isolates. However, the activity of the non-nucleoside thumb II inhibitor NNI-1, palm I inhibitors NNI-2 and NNI-3, and palm II inhibitor HCV-796 was reduced across different isolates. This reduction in inhibitory activity for non-nucleoside inhibitors (NNIs) was, in most cases, correlated with the existence of known NNI resistance mutations in the NS5B polymerase population of the clinical isolates, as detected by population sequencing. Resistance mutations to NNIs were also observed at a low frequency within the clinical isolates' viral quasispecies that allowed for their rapid selection upon drug selective pressure.. The higher frequency of known NNI resistance mutations or polymorphisms known to affect their antiviral potency when compared with the lack of detection of resistance mutations to the nucleoside analogues suggests a potential for primary reduced responsiveness as well as faster development of clinically significant resistance.

Topics: Amino Acid Sequence; Amino Acid Substitution; Antiviral Agents; Cytidine; Drug Resistance, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Pyrimidine Nucleosides; Sequence Analysis, DNA; Viral Nonstructural Proteins; Virus Replication