valopicitabine and Hepatitis-C--Chronic

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

New drug therapies to treat hepatitis C (HCV) and HIV infection are being developed with improved understanding of the molecular structures of the viruses themselves, the pathogenesis of infection and the specific immune responses needed to eradicate or control these infections. Interferon and ribavirin based therapies will continue to be a component of HCV therapy for the near future combined with other novel compounds directed at targets of viral replication, immunomodulation or cell entry. The goals of anti-HCV therapy are viral eradication for differing genotypes and prevention of hepatic morbidity such as hepatocellular carcinoma and cirrhosis. Future antiretroviral therapies for HIV will include agents that focus on new classes of inhibitors of viral replication and cell binding. The new treatment choices in HIV will need to ensure effective and durable viral suppression especially against highly resistant virus strains, regimen tolerability and improved toxicity.

Topics: Anti-Retroviral Agents; Antiviral Agents; Comorbidity; Hepatitis C, Chronic; HIV Infections; Humans; Pyrimidine Nucleosides; Pyrrolidinones; Quinolones; Raltegravir Potassium; Substance Abuse, Intravenous

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

Currently available anti-HCV therapy is effective in only half of the patients and limited by side effects that often necessitate discontinuation. Therefore, new treatment strategies are being developed including (i) the optimization of current regimens, (ii) the use of additional agents working via novel mechanisms, and (iii) anti-fibrotic strategies. Many new antiviral compounds are now being studied in preclinical and clinical trials. This review will focus on drugs that have already entered the stage of phase 2 or phase 3 studies.

Topics: Antidepressive Agents; Antiviral Agents; Clinical Trials as Topic; Erythropoietin; Genome, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Liver Cirrhosis; Protease Inhibitors; Purine-Nucleoside Phosphorylase; Pyrimidine Nucleosides; Ribavirin; Viral Hepatitis Vaccines

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

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