In addition we have recently shown that viral variants with in vitro reduced dependency on SR-BI can still be successfully blocked in vivo by our mAb. These observations suggested that anti-SR-BI mAb1671 efficiently prevents intrahepatic viral spread. Therefore we hypothesized that mAb1671 could prevent on-therapy breakthrough of DAA-RAVs, by restricting DAA-RAVs to the hepatocytes in which they are selected,

thereby improving Proteases inhibitor virologic response. Thirteen gt1b-infected mice were randomized over two study groups. Seven mice received BILN-2061 monotherapy, while the six remaining ones received a combination consisting of BILN-2061 and mAb1671. During a six-week period BILN-2061 was administered (10 mg/kg, BID, oral gavage) with or without additional injections of mAb1671 (400 Lig per injection) at day 0, 2, 4, 7, 10, 13, 16, 20, 23, 27, 30, 34, 37, 41. Results: In this study, we observed that human-liver chimeric mice receiving monotherapy of the protease inhibitor (PI) Ciluprevir (BILN-2061) rapidly experience on-therapy virologic breakthrough. Deep sequencing analysis of the HCV protease domain confirmed the dominant manifestation of PI-RAVs upon viral rebound. In contrast, such on-treat-ment breakthrough was

completely absent in mice treated with a combination of the PI with BMN673 mAb1671. Our data suggest that mAb1671 precludes the emergence and dissemination of PI-RAVs during combination therapy. Conclusion: We provide preclinical in vivo evidence that the addition of an entry inhibitor to a DAA regimen is an excellent strategy to prevent therapeutic failure due to the selection and rebound of DAA-RAVs. Disclosures: Riccardo Cortese – Patent Held/Filed: JVBIO srl Thomas Pietschmann – Advisory Committees or Review Panels: Janssen GmbH, Biotest AG; Speaking

and Teaching: MSD Sharp & Dohme GmbH, Essex Pharma GmbH Alfredo Nicosia – Patent Held/Filed: JVBIO srl The following people have nothing to disclose: Koen Vercauteren, Ahmed A. Mesalam, Richard Brown, Fulvia Troise, Juliane Doerrbecker, Naomi Van Den Eede, Ali Farhoudi, Geert Leroux-Roels, Philip Meuleman Background selleck chemicals and Aims: The uridine-analog nucleotide prodrug ACH-3422 is a potent, pan-genotypic NS5B inhibitor currently in clinical development for the treatment of chronic hepatitis C. In this report, we present the antiviral activity and effect on the emergence of resistant variants in vitro of ACH-3422 alone and when combined with ribavirin (RBV), a Phase 2 NS5A inhibitor (ACH-3102), and/or one of two clinical investigational NS3 protease inhibitors (sovaprevir or ACH-2684) to understand the clinical potential of various combination regimens. Methods: Short-term combination assays were performed to assess antiviral efficacy in genotype-1b replicon cells.