1134A AASLD ABSTRACTS HEPATOLOGY, October, 2014

1935Early Improvement in the HepQuant® (HQ)-SHUNT Function Test during Treatment with Ledipasvir/Sofosbu-vir in Liver Transplant Recipients with Allograft Fibrosis or Cirrhosis and Patients with Decompensated Cirrhosis who have not undergone TransplantationJacqueline G. O’Leary1, James R. Burton2, Steve M. Helmke2, Andrea Herman2, Michael W. Cookson2, Shannon Lauriski2, James F. Trotter1, Jill M. Denning3, Phillip S. Pang3, John G. McHutchison3, Gregory T. Everson2; 1Baylor University Medical Center, Dallas, TX; 2Gastroenterology and Hepatology, University of Colorado, Aurora, CO; 3Gilead Sciences, Inc., Foster City, CABackground and Aims: A primary goal of the treatment of advanced HCV is restoration of hepatic function. In SOLAR-1, recipients of liver transplantation (LTx) with either fibrosis or cir-rhosis, and patients with decompensated cirrhosis are treated with ledipasvir/sofosbuvir (LDV/SOF) and ribavirin. The HQ-SHUNT substudy is evaluating hepatic function with a test employing stable isotope labeled cholates administered orally and by IV. Results at baseline and at week 4 of treatment are presented. Methods: 31 patients from 2 centers, University of Colorado Denver (N=17) and Baylor University Medical Cen-ter Dallas (N=14), participated in the substudy. HQ-SHUNT was performed at baseline in 11 patients with LTx and F0-F3 fibrosis, 10 patients with LTx and cirrhosis (1 CTP A, 7 CTP B, 2 CTP C) and 10 pre-LTx patients with decompensated cirrhosis (4 CTP B, 6 CTP C). HQ-SHUNT was repeated at week 4 of treatment. The HQ-SHUNT test involves serum sampling prior to, and at 5, 20, 45, 60, and 90 minutes after administering the cholates, and yields Portal Hepatic Filtration Rate (HFR) from PO d4-cholate, Systemic HFR from IV 13C-cholate, SHUNT from the ratio of Systemic to Portal HFR, and disease severity index (DSI) from these 3 test results. Results (Table): At baseline, HFRs were higher and SHUNT and DSI were lower in non-cir-rhotic LTx recipients compared to cirrhotic LTx recipients, and in cirrhotic LTx recipients compared to the decompensated pre-LTx patients. Comparing the changes from baseline to week 4, SHUNT did not change in any group. HFRs and DSI improved more in non-cirrhotic LTx recipients than cirrhotic LTx recipi-ents, and did not improve in decompensated pre-LTx patients.Conclusions: Improvement in HFRs and DSI, without change in SHUNT, at week 4 of treatment is consistent with improved hepatic microcirculation. Improvement is inversely proportional to disease severity and patients with decompensated cirrho-sis will require longer follow-up to detect improvement. The HepQuant substudy will continue testing over a total of 48 weeks.

HQ-SHUNT TEST RESULTS

***all 3 groups different; **LTx groups not different; ^One patient in each group without W4 results.Disclosures:Jacqueline G. O’Leary - Consulting: Gilead, Jansen

James R. Burton - Grant/Research Support: Vertex pharaceuticals, Abbvie phar-maceuticals, Gilead pharmaceuticals, Janssen pharmaceuticalsSteve M. Helmke - Patent Held/Filed: University of ColoradoJames F. Trotter - Speaking and Teaching: Salix, NovartisJill M. Denning - Employment: Gilead Sciences, Inc.Phillip S. Pang - Employment: Gilead SciencesJohn G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead SciencesGregory T. Everson - Advisory Committees or Review Panels: Roche/Genen-tech, Abbvie, Galectin, Boehringer-Ingelheim, Eisai, Bristol-Myers Squibb, HepC Connection, BioTest, Gilead, Merck; Board Membership: HepQuant LLC, PSC Partners, HepQuant LLC; Consulting: Abbvie, BMS, Gilead, Bristol-Myers Squibb; Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, Abbvie, Bris-tol-Myers Squibb, Merck, Eisai, Conatus, PSC Partners, Vertex, Tibotec, GlobeIm-mune, Pfizer, Gilead, Conatus, Zymogenetics; Management Position: HepQuant LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado; Speaking and Teach-ing: Abbvie, GileadThe following people have nothing to disclose: Andrea Herman, Michael W. Cookson, Shannon Lauriski

1936Pooled analysis of resistance in patients treated with ombitasvir/ABT-450/r and dasabuvir with or without ribavirin in Phase 2 and Phase 3 clinical trialsPreethi Krishnan, Rakesh Tripathi, Gretja Schnell, Thomas Reisch, Jill Beyer, Michelle Irvin, Wangang Xie, Lois Larsen, Thomas Pod-sadecki, Tami Pilot-Matias, Christine Collins; Research and Devel-opment, AbbVie Inc., North Chicago, ILBackground: Over 2500 HCV genotype (GT) 1-infected patients have been treated with ombitasvir/ABT-450/r and dasabuvir (3D) ± ribavirin (RBV) in 2 Phase 2 (M13-386 and AVIATOR) and 6 Phase 3 (SAPPHIRE-I, SAPPHIRE-II, PEARL-II, PEARL-III, PEARL-IV, and TURQUOISE-II) clinical trials. Sev-enty-four patients experienced virologic failure (VF) in these studies, and were evaluated for the presence of resistance-as-sociated variants (RAVs) at baseline and at the time of VF. Methods: Baseline polymorphisms and treatment-emergent variants in HCV NS3, NS5A and NS5B from patients who experienced VF were analyzed by population sequencing. The number and percentage of subjects with baseline RAVs was compared between subjects experiencing VF and subjects who achieved sustained virologic response (SVR) by chi-square test. Results: Baseline sequencing was conducted on a subset of samples comprising over 700 GT1a and 1b-infected patients. Baseline RAVs in either GT1a or 1b in NS3 were rare (<1%); baseline RAVs in NS5A were observed in 12.5% of GT1a and 7.5% of the GT1b samples; baseline RAVs in NS5B were observed in 5.2% of GT1a and 28.6% of the GT1b samples; no subject had baseline RAVs in all 3 targets. The presence of baseline RAVs had no impact on treatment outcome. Among patients receiving the 3D ± RBV regimens in the Phase 2/3 clin-ical trials, 67 GT1a-infected patients experienced VF including 18 patients who experienced on-treatment breakthrough and 49 who relapsed; and 7 GT1b-infected patients experienced VF including 2 patients who experienced on-treatment break-through and 5 who relapsed. At the time of VF, the predomi-nant RAVs in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The predominant RAVs in GT1b were Y56H+D168V in NS3, Y93H in NS5A, and S556G in NS5B. Among patients who experienced VF, 39 GT1a- and 4 GT1b-infected patients had RAVs in all 3 targets; 15 GT1a- and 1 GT1b-infected patient had RAVs in any 2 targets; 4 GT1a-infected patients had RAVs in only 1 target; while 9 GT1a- and 2 GT1b-infected patients had no RAVs in any target. Long-term studies to monitor persistence of these variants are ongoing. Conclusions: In the 3D ± RBV regimens, the virologic failure rate was very low (3.0%). Of the