Just released to the public domain: Results from use of HepQuant technology in a study of Ledipasvir/Sofosbuvir HCV antivirals.. “Early Improvement in the HepQuant®(HQ)-SHUNT Function Test during Treatment with Ledipasvir/Sofosbuvir in Liver Transplant Recipients with Allograft Fibrosis or Cirrhosis and Patients with Decompensated Cirrhosis who have not undergone Transplantation. O’Leary JG, Burton JR, Helmke SM, Herman A, Cookson MW, Lauriski S, Trotter JF, Denning JM, Pang PS, McHutchison JG, Everson GT. Hepatology 2014;60:1134A.”

1. 1134A AASLD ABSTRACTS HEPATOLOGY, October, 2014
1935
Early 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 Transplantation
Jacqueline 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, CA
Background 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 pharmaceuticals
Steve M. Helmke - Patent Held/Filed: University of Colorado
James F. Trotter - Speaking and Teaching: Salix, Novartis
Jill M. Denning - Employment: Gilead Sciences, Inc.
Phillip S. Pang - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Gregory 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, Gilead
The following people have nothing to disclose: Andrea Herman, Michael W.
Cookson, Shannon Lauriski
1936
Pooled analysis of resistance in patients treated with
ombitasvir/ABT-450/r and dasabuvir with or without
ribavirin in Phase 2 and Phase 3 clinical trials
Preethi 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, IL
Background: 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