valopicitabine and telaprevir

Antiviral therapy for chronic hepatitis C has advanced dramatically since the discovery of the hepatitis C virus and the introduction of interferon in early 1990's. An initial treatment regimen, 24 weeks of interferon monotherapy, achieved sustained virologic response, which is formally defined at 24 weeks after completion of the treatment, only for 5% of patients with genotype 1 high-viral load belonging to a difficult-to-treat group. Current standard therapy is a combination of pegylated interferon and ribavirin. Forty eight weeks of the combination therapy achieves successful viral eradication for 40-50% of genotype 1 patients while 24 weeks of that do so for 80% of genotype 2 patients. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response for genotype 1 patients, serving as recommendation criteria for extended duration, 72 weeks, of combination therapy. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for patients that do not respond to combination therapy. Hepatitis C is not just an infectious disease, but a potentially serious liver disease progressing to end-stage liver cirrhosis and hepatocellular carcinoma. Antiviral therapy should be considered from the view point of suppressing liver-related death in hepatitis C virus-infected patients.

Topics: Antiviral Agents; DNA-Directed RNA Polymerases; Drug Administration Schedule; Drug Discovery; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Nitro Compounds; Oligopeptides; Polyethylene Glycols; Protease Inhibitors; Pyrimidine Nucleosides; Recombinant Proteins; Ribavirin; Thiazoles

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

Hepatitis C infection (HCV) remains a global problem and the current anti-HCV therapies available in the clinic have sustained virologic response rates (SVR) of only about 50%, especially in HCV genotype 1-infected subjects. The SVR is even lower in HIV-HCV co-infected patients, estimated at only about 30-40%. However, exciting new research is under way to find new anti-HCV therapies. Presently, efforts to develop new anti-HCV agents for HCV-infected persons who fail pegylated interferon and ribavirin-based therapies have focused on inhibitors of key HCV enzymes such as the HCV NS3 protease and the NS5B polymerase. There are two protease inhibitors, telaprevir (VX-950, Vertex) and boceprevir (SCH 503034, Schering-Plough); and three polymerase inhibitors, valopicitabine (NM283, Idenix), R1626 (Roche), and HCV-796 (Viropharma) that have advanced to late-stage clinical trials. Of these aforementioned agents, telaprevir is the most advanced in clinical development. Early trial results on efficacy, safety, and HCV drug-resistance profiles of these novel agents will be discussed in this review paper.

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; HIV Infections; Humans; Multicenter Studies as Topic; Oligopeptides; Proline; Protease Inhibitors; Pyrimidine Nucleosides; Randomized Controlled Trials as Topic

Several new classes of antiviral drugs are undergoing development and should change the way that hepatitis C virus infection is treated in the future. It is likely that combinations of drugs that target different points in the viral replication and disease processes will prove most successful. It is hoped that such combinations will improve the efficacy, tolerability, and duration of antiviral treatment for this disease.

Topics: Antibodies, Viral; Antiviral Agents; Enzyme Inhibitors; Hepacivirus; Hepatitis C, Chronic; Humans; Immunologic Factors; Oligopeptides; Pentanoic Acids; Pyrimidine Nucleosides

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

Topics: Antiviral Agents; Biomedical Research; Drug Design; Hepatitis C; Humans; Oligopeptides; Pyrimidine Nucleosides; Recombinant Fusion Proteins; Ribavirin; Toll-Like Receptors