studies

566A AASLD ABSTRACTS HEPATOLOGY, October, 2015
naire-HCV(CLDQ-HCV) and Work Productivity and Activity
Impairment.421 patients were randomized and received ≥1
dose of study drug(GZR/EBR:n=316,Placebo:n=105).Mean
change from baseline in PRO scores (95% CIs) by treatment
group and treatment group differences in mean change scores
(95%CIs) were estimated.Results:At TW12, in general, GZR/
EBR had more favorable changes than placebo [Figure].GZR/
EBR group had mean improvement (95% CIs exclude 0) in
general and HCV-specific HRQOL. Placebo group had mean
improvement in HCV-specific HRQOL, but a mean decline in
Social Functioning (SF).Treatment group differences favored
GZR/EBR over placebo in MCS (2.33 (95%CI:0.28,4.37))
and SF (7.25 (95%CI:2.47,12.04)). At FW4, for GZR/EBR
(data not shown),mean improvements in general and HCV-specific
HRQOL,fatigue levels,and activity impairment were
observed.Treatment group differences favored GZR/EBR over
placebo in Role Limitations-Physical(4.97(95%CI:0.17,9.77)),-
General Health(4.94(95%CI:1.30,8.59)),S-
F(6.97(95%CI:2.38,11.57)) and overall health(EQ-VAS
5.42(95% CI:1.87,8.97)).Conclusion:Treatment with GZR/
EBR had a positive impact on PROs compared to placebo.In
addition, changes in PROs were substantially more favorable
than the large declines in PROs historically associated with
interferon and ribavirin-containing regimens.
Disclosures:
Jean Marie Arduino - Employment: Merck & Co., Inc
Yang Wang - Employment: Merck
Deborah D. Brown - Employment: Merck & Co., Inc.; Stock Shareholder: Merck
& Co., Inc
Shazia Khawaja - Employment: Merck
Joan R. Butterton - Employment: Merck Sharp & Dohme Corp.; Stock Shareholder:
Merck Sharp & Dohme Corp.
Michael Robertson - Employment: Merck; Stock Shareholder: Merck
Chizoba Nwankwo - Employment: Merck
T. Christopher Mast - Employment: Merck Research Laboratories
The following authors have nothing to disclose: Elisa Martinez
718
Characterization of HCV Resistance from a 3-Day
Monotherapy Study of GS-9857, a Novel Pangenotypic
NS3/4A Protease Inhibitor
Eric Lawitz 2 , Hadas Dvory-Sobol 1 , Jenny C. Yang 1 , Luisa M.
Stamm 1 , James Taylor 1 , Diana M. Brainard 1 , Michael D. Miller 1 ,
Hongmei Mo 1 , Maribel Rodriguez-Torres 3 ; 1 Gilead Sciences, Foster
City, CA; 2 The Texas Liver Institute, University of Texas Health
Science Center, San Antonio, TX; 3 Fundacion de Investigacion,
Rio Pedras, PR
Background: GS-9857 is a pangenotypic hepatitis C virus
(HCV) NS3/4A protease inhibitor (PI) with potent antiviral
activity against HCV genotypes (GT) 1-6 and improved
coverage of GT1 NS3 resistance associated variants (RAVs)
associated with other HCV PIs, in preclinical replicon studies.
In a 3-day monotherapy study in patients infected with HCV
GT 1, 2, 3 or 4, GS-9857 was well tolerated and resulted
in maximal mean viral load reduction >3 log 10
IU/mL at the
100mg dose across all genotypes. This analysis characterizes
the HCV NS3 sequence data from this phase 1b study. Methods:
The full-length NS3 gene was amplified and successfully
deep sequenced using MiSeq for 58 patients at baseline and
53 patients post-baseline using a 1% cutoff for reporting. NS3
RAVs were defined as amino acid substitutions historically
associated with resistance to HCV PIs, including positions 36,
41, 43, 54, 55, 80, 122, 155, 156, 168 and 170 of the NS3
protease gene of HCV GT1. Results: Baseline HCV NS3 RAVs
were present in the HCV of 37% (9/24) of patients with GT1a,
17% (1/6) of patients with GT1b and 16% (3/19) of patients
with GT3; there were no baseline NS3 RAVs present in patients
with GT2 (n=5) or GT4 (n=4). Mean maximal viral load reductions
over 3 days of GS-9857 administration were similar in
patients with and without baseline NS3 RAVs. The table summarizes
the number of patients with treatment-emergent (TE)
NS3 RAVs by genotype. Overall, by deep sequencing analysis,
the majority of patients (74%, 39/53) did not have TE NS3
RAVs, and there were no TE NS3 RAVs in patients with GT2
or 4. A156T or A156V were the most prevalent substitutions
in patients with GT1a or 1b infection and were not observed
in patients with GT3 infection. One GT3 patient had low levels
of A156P (2.3%). Conclusions: The presence of NS3 RAVs at
baseline had no impact on treatment response to 3 days of
monotherapy with GS-9857 in this phase 1b study. The lack of
selection of NS3 RAVs in the majority of patients demonstrates
an improved resistance profile of GS-9857.
Number of Patients with Treatment Emergent (TE) NS3 RAVs Following
3 Days Monotherapy with GS-9857 by Deep Sequencing
Analysis
Disclosures:
Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals,
Regulus, Theravance, Enanta, Idenix Pharmaceuticals, Janssen, Merck
& Co, Novartis, Gilead; Grant/Research Support: AbbVie, Achillion Pharmaceuticals,
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith-
Kline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co,
Novartis, Nitto Denko, Theravance, Salix, Enanta; Speaking and Teaching: Gilead,
Janssen, AbbVie, Bristol Meyers Squibb