studies

558A AASLD ABSTRACTS HEPATOLOGY, October, 2015
Disclosures:
Parvez S. Mantry - Consulting: Salix, Gilead, Janssen, Abbvie, BMS; Grant/
Research Support: Salix, Merck, Gilead, Boehringer-Ingelheim, Mass Biologics,
Vital Therapies, Santaris, mass biologics, Bristol-Myers Squibb, Abbive, Bayer-Onyx,
Shinogi, Tacere, Intercept; Speaking and Teaching: Gilead, Janssen,
Salix
Heidi L. Smith - Employment: MassBiologics of UMass Medical School
Raymond T. Chung - Grant/Research Support: Gilead, Mass Biologics, Abbvie,
Merck, BMS
Michael P. Curry - Advisory Committees or Review Panels: Bristol Meyers Squib,
Abbvie; Grant/Research Support: Gilead Sciences, Mass Biologics, Merck,
Salix, Conatus; Stock Shareholder: Achilion
Deborah C. Molrine - Employment: MassBiologics of Univ of Massachusetts
Medical School
The following authors have nothing to disclose: William C. Chapman, Thomas
D. Schiano, Yang Wang
705
Analysis of HCV Genotype 1 Variants Detected During
Monotherapy and Combination Therapy with Next Generation
HCV Direct-Acting Antiviral Agents ABT-493 and
ABT-530
Teresa Ng, Tami Pilot-Matias, Rakesh Tripathi, Gretja Schnell,
Thomas Reisch, Jill Beyer, Tanya Dekhtyar, Armen Asatryan, Federico
J. Mensa, Andrew L. Campbell, Jens Kort, Christine Collins;
AbbVie, North Chicago, IL
Background: ABT-530 (NS5A inhibitor) and ABT-493 (NS3/4A
protease inhibitor identified by AbbVie and Enanta) are next
generation HCV direct-acting antiviral agents (DAAs). Each
has demonstrated potent anti-HCV activity in genotype (GT)
1-infected patients in 3-day monotherapy (Study M13-595) as
well as in combination therapy for 12 weeks (Phase 2 study
M14-867). In this report we present the characterization of HCV
GT1 variants detected in samples from these 2 studies. Methods:
Population sequencing was performed on the NS3/4A
and NS5A genes from all available baseline (BL) samples from
both studies, last available samples with HCV RNA ≥ 1000 IU/
mL during monotherapy in study M13-595, and first available
sample after virologic failure with HCV RNA ≥1000 IU/mL in
the combination study M14-867. Sequences were examined
for the presence of resistance-associated variants (RAVs) at
positions where variants have been shown to confer resistance
to HCV protease or NS5A inhibitors. NS3 or NS5A RAVs were
introduced into appropriate subgenomic HCV GT1 replicons
and their susceptibility to ABT-493 or ABT-530 was evaluated
in a transient transfection assay. Results: In ABT-493 monotherapy
study (n=49), none of the BL samples had NS3 RAVs. A
single NS3 RAV (GT1a A156T) emerged in 1 subject during
therapy. In ABT-530 monotherapy study (n=40), NS5A RAVs
(M28V, Q30R, L31M, H/P58 variants, and Y93 variants)
were present in 8 subjects at BL. Most of these were present as
NS5A single RAVs that do not confer resistance to ABT-530.
During monotherapy, additional RAVs emerged in 3 of these
8 subjects, producing double RAVs that conferred a higher
level of resistance (27- to >300-fold) to ABT-530 than either
RAV alone. In the M14-867 combination study of ABT-493 +
ABT-530 (n=79), 2 subjects had NS3 RAVs (R155K) and 13
subjects had NS5A RAVs (M28V, Q30 variants, L31M, H/P58
variants, and Y93H) at BL. To date, 78 subjects have achieved
SVR 4
(99% SVR 4
) and 1 subject relapsed at post treatment
week 4. In the relapse subject, no BL RAVs were detected,
but a double NS5A RAV (Q30K+H58D) emerged at failure.
Conclusions: Variants resistant to ABT-493 were not detected
in subjects at BL, and a single NS3 RAV (A156T) emerged
in 1 subject during ABT-493 monotherapy. During ABT-530
monotherapy, additional NS5A variants emerged in 3 of the 8
subjects who already had variants present at BL. These double
RAVs conferred medium to high resistance to ABT-530. In the
combination study, a treatment-emergent double NS5A RAV
was detected at failure in the subject who relapsed. All other
subjects from this study have achieved SVR 4
, regardless of the
presence of BL NS3 and/or NS5A variants.
Disclosures:
Teresa Ng - Employment: AbbVie; Patent Held/Filed: AbbVie; Stock Shareholder:
AbbVie
Tami Pilot-Matias - Employment: AbbVie; Stock Shareholder: AbbVie
Rakesh Tripathi - Employment: AbbVie Inc.; Stock Shareholder: AbbVie Inc.
Gretja Schnell - Employment: AbbVie Inc.; Stock Shareholder: AbbVie Inc.
Thomas Reisch - Employment: Abbvie; Stock Shareholder: Abbvie
Jill Beyer - Employment: Abbvie; Stock Shareholder: Abbvie
Tanya Dekhtyar - Employment: Abbvie; Stock Shareholder: Abbvie
Armen Asatryan - Employment: AbbVie
Federico J. Mensa - Employment: Abbvie Inc.; Stock Shareholder: Abbvie Inc.
Andrew L. Campbell - Employment: AbbVie; Stock Shareholder: AbbVie
Jens Kort - Employment: AbbVie Inc.; Stock Shareholder: AbbVie Inc.
Christine Collins - Employment: AbbVie, Inc.
706
Improvement in liver disease parameters following
treatment with daclatasvir + sofosbuvir and ribavirin
in patients with chronic HCV infection and advanced
cirrhosis
Robert J. Fontana 1 , Fred Poordad 2 , Eugene R. Schiff 3 , John M.
Vierling 4 , Charles S. Landis 5 , Rafia Bhore 6 , Philip Yin 7 , Stephanie
Noviello 6 , Eugene S. Swenson 7 ; 1 University of Michigan Medical
Center, Ann Arbor, MI; 2 University of Texas Health Science Center,
Texas Liver Institute, San Antonio, TX; 3 University of Miami
Milller School of Medicine, Schiff Center for Liver Diseases, Miami,
FL; 4 Baylor College of Medicine, Houston, TX; 5 University of Washington
School of Medicine, Seattle, WA; 6 Bristol-Myers Squibb,
Princeton, NJ; 7 Bristol-Myers Squibb, Wallingford, CT
Background: The pangenotypic combination of daclatasvir
(DCV) and sofosbuvir (SOF), with or without ribavirin (RBV) has
achieved SVR12 rates of 82-98% in multiple high-need patient
populations with chronic HCV infection. In the phase 3 ALLY-1
study, DCV+SOF+RBV achieved SVR12 in 83% of patients
with advanced cirrhosis and in 94% of those with post-liver
transplant recurrence. We evaluated changes over time in liver
disease parameters among patients from the advanced cirrhosis
cohort of ALLY-1. Methods: This open-label study enrolled
treatment-naive or -experienced adults with HCV infection of
any genotype (GT). Patients in the advanced cirrhosis cohort
(N=60) received 12 weeks of treatment with DCV 60 mg
+ SOF 400 mg once-daily and RBV (initially 600 mg/day,
adjusted for hemoglobin and creatinine clearance). The primary
endpoint was HCV RNA