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HCV Antiviral Activity and Resistance Analysis in Chronically Infected Chimpanzees Treated with Merck NS3/4A Protease and NS5B Polymerase Inhibitors
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Reported by Jules Levin
EASL, April 2007, Barcelona, Spain
D. B. Olsen1*, S. S. Carroll1, L. Handt2, S. Ludmerer1, D. Graham1, C. Fandozzi3, J. DeLuca4, N. Liverton5, J. Vacca5, D. Hazuda1
Antiviral Research Department1, Laboratory Animal Resources2, Drug Metabolism3, Safety Assessment4, Medicinal Chemistry5
Merck Research Laboratories, West Point PA USA
ABSTRACT
Background: Current standard of care treatment for chronic hepatitis C virus infection is combination therapy with pegylated interferon-_ and ribavirin, a regimen of limited efficacy and poor tolerability. Efforts to improve treatment include the development of direct antiviral agents targeting the virally encoded RNA polymerase, NS5B, and protease, NS3/4A enzymes. We have validated the in vivo efficacy of inhibitors for both targets in HCV-infected chimpanzees and characterized resistance with a novel, robust resistance assay.
Methods: Per protocol, two chronically infected chimpanzees were dosed by single, daily administration of inhibitors of NS5B (7d IV at 2mpk or 37d orally at 2 mpk) or NS3/4A (7d at 5mpk BID). Plasma vload was quantified using the HCV Taqman assay (Roche, LOQ=20 IU/ ml). Resistance was analyzed with sequencing of RT-PCR products and with an Allele-specific Ultrasensitive Genotyping assay for Enzyme Resistance (AUGER: LOD about 1 in 10,000 copies).
Results: Administration of either an NS5B or NS3/4a inhibitor resulted in rapid vload suppression to below the limit of quantitation (BLQ). Viral load rebounded postdose, but remained BLQ for several weeks following 37d dosing of the NS5B inhibitor. After NS3 PI treatment, rebound viral populations were enhanced for resistant virus, but there was no evidence for antiviral failure during dosing. Careful analysis showed a small population (<0.1%) of this resistant virus in pretreatment samples. WT virus eventually replaced resistant virus in the absence of further dosing, but the time course for reversion differed significantly between the 2 inhibitors. Virus resistant to the polymerase inhibitor (S282T) disappeared from circulating populations within days following the end of treatment, suggesting debilitated replication. Virus resistant to the protease inhibitor (R155K) diminished gradually and persisted as a minor species for several months.
CONCLUSIONS
The chimpanzee model of chronic HCV infection has provided crucial data to guide the clinical investigation of direct antiviral agents.
Robust efficacy was achieved with protease and polymerase inhibitors
- Viral load below LOD for >35d required for SVR
AUGER data suggests Nucleoside inhibitors offer advantages in terms of
- persistence of resistance mutations
NI _ short lived (days)
PI _ long lived (months)
The data support further investigation of all oral combination therapy consisting of direct antiviral agents to cure chronic HCV infection.
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