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