rg-7128 and telaprevir

Mathematical modeling of hepatitis C viral kinetics has been an important tool in understanding hepatitis C virus (HCV) infection dynamics and in estimating crucial in vivo parameters characterizing the effectiveness of HCV therapy. Because of the introduction of direct-acting antiviral agents, there is a need to extend previous models so as to understand, characterize, and compare various new HCV treatment regimens. Here we review recent modeling efforts in this direction.

Topics: Antiviral Agents; Carbamates; Deoxycytidine; Hepacivirus; Hepatitis C; Humans; Imidazoles; Models, Biological; Oligopeptides; Protease Inhibitors; Pyrrolidines; Silybin; Silymarin; Valine

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.. ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.

Topics: Adult; Antibodies, Viral; Antimetabolites; Antiviral Agents; Deoxycytidine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Protease Inhibitors; Recombinant Proteins; Ribavirin; RNA, Viral; Treatment Outcome