resistance to direct acting antiviral therapy
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Resistance to Direct Acting Antiviral Therapy. Resistance to HCV DAAs: What is the threat level?. HCV Biology is the basis for resistance. HCV biology is the basis for cure. Frequency of Protease Resistance Mutations Prior to Therapy. - PowerPoint PPT PresentationTRANSCRIPT
Resistance to Direct Acting Antiviral Therapy
Resistance to HCV DAAs: What is the threat level?
HCV Biology is the basis for resistance
HCV biology is the basis for cure
Frequency of Protease Resistance Mutations Prior to Therapy
Emergence of Pre-existing Resistant Variants During Treatment with DAA
Resistance Develops Rapidly During telaprevir monotherapy with Protease
Inhibitor
Barrier to resistance: Combination of DAAs with different mechanism of action
Multiple drugs target WT and resistant virus to prevent selection of resistant variants
Inhibitors of NS3/4A Protease
SVR with PegIFN/RBV + PI requires adequate IFN response to prevent
resistance
REALIZE: Resistance rates are higher in persons less responsive to PegIFN/RBV
Frequency of RAVs detected in Non-SVR Patients; Poor Interferon Responders and Interferon Responders
Barrier to resistance: Role of viral characteristics Telaprevir Resistance in patients who failed to achieve
SVR: Subtype 1a versus 1b
Barrier to resistance: Role of pharmacology Clonal sequence analysis from subjects dosed with ABT-450 for 3 days
Barrier to resistance: Combination therapy
Inhibitors of NS5A Replicase Protein
Daclatasvir: Emergence of resistance with 14 day
monotherapy
Potent antiviral activity of GS-58853-day monotherapy
Daclatasvir + Asunaprevir ± PegIFN/RBV in Previous PegIFN/RBV Null Responders
Inhibitors of NS5B polymersase: non-nucleoside inhibitors (NNIs)
Polymerase mutations in 89 treatment naïve HCV genotype 1 infected patients
PI (GS-9256) + NNI (Tegobuvir) with or without RBV for HCV genotype 1
Inhibitors of NS5B polymersase: nucleoside inhibitors (NIs)
Resistance to nucleos(t)ide inhibitors
Antiviral Activity of PSI-7977 alone or in combination with PSI-938
ELECTRON: SVR following GS-7977 ± RBV ± PegIFN x 12 weeks
INFORM-1: Combination of NI + PI may prevent emergence of PI resistant variants
Cyclophilin Antagonists: Target the host
Clinical implications of pre-existing mutations to DAAs – spontaneous
or selected
SVR Rates By Treatment Week 4 Response Among Patients With or Without Baseline RAVs Detected
Most Common RAVs†:Detectability Declines During
Follow-Up
ADVANCELoss of Resistance by NS3 Position
EXTEND Study: Long-term Follow-up of Patients Treated with Telaprevir
EXTEND study: Follow-up of TLV treated patients
C-219: Retreatment of 9 patients after TVR monotherapy with
resistance
Clinical implications of selection resistance to first generation HCV PIs
Resistance to Direct Acting Antiviral Therapy