Resistance to Direct Acting Antiviral Therapy

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Presentation transcript:

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-5885 3-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

ADVANCE Loss 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