studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 563A
713
Resistance Analysis of Treatment-Naïve and DAA-Experienced
Genotype 1 Patients with and without Cirrhosis
Who Received Short-Duration Treatment with Sofosbuvir/GS-5816+
GS-9857
Edward J. Gane 2 , Evguenia S. Svarovskaia 1 , Robert H. Hyland 1 ,
Luisa M. Stamm 1 , Anu Osinusi 1 , Diana M. Brainard 1 , Krishna
Chodavarapu 1 , Michael D. Miller 1 , Hongmei Mo 1 , Christian
Schwabe 3 ; 1 Gilead Sciences Inc, Foster City, CA; 2 New Zealand
Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand;
3 Auckland Clinical Studies Ltd, Auckland, New Zealand
Introduction: Pretreatment resistance associated variants (RAVs)
have been associated with relapse following short treatment
durations with regimens containing three or more directly
acting antivirals (DAAs). GS-9857, a potent pan-genotypic
HCV NS3 protease inhibitor (PI) administered with SOF/
GS-5816, a fixed dose combination of pan-genotypic NS5B
and NS5A inhibitors, for 6 weeks was highly effective in treatment-naïve
genotype (GT) 1 HCV patients without cirrhosis.
Each compound in this three-drug combination demonstrated
a high barrier to resistance, in vitro. The aim of this study
was to characterize the effect of pretreatment RAVs on the
treatment outcome and the viral resistance in patients who
relapsed following treatment with SOF/GS-5816+GS-9857
for 4 or 6 weeks. Methods: Treatment-naïve GT1 HCV-infected
patients with or without cirrhosis were treated for 4 or
6 weeks with SOF/GS-5816+GS-9857 (n=30). Treatment-experienced
patients with or without cirrhosis who failed a
prior multi-DAA regimen were treated for 6 weeks with SOF/
GS-5816+GS-9857 (n=45). NS3, NS5A and NS5B were
amplified and deep sequenced (1% detection assay cut-off).
All patients were sequenced pretreatment and at the time
of virologic failure (all relapse). Results: Pretreatment deep
sequencing analysis of NS3, NS5A and NS5B was successful
for all 75 patients enrolled. Pretreatment NS3 and/or NS5A
RAVs were detected in 51% (23/45) of treatment naïve and
46% (14/30) in DAA-experienced patients. NS5B RAVs were
detected in 1/75 (1%) of patients. Among the different treatment
groups, SVR12 rates in patients with and without pretreatment
RAVs were similar (Table). In the 4 week treatment arm,
76% (11/15) of patients relapsed; no RAVs emerged in any
of these 11 patients. In combined 6 week treatment arms, 22%
(13/60) of patients relapsed; of these 13 patients, one treatment
naïve patient with cirrhosis had low levels of a NS3 RAV
emerge (V55A, 1.9%). No other NS3, NS5A, or NS5B RAVs
emerged. Conclusions: In contrast to DAA regimens with SOF
and other NS5A and NS3 inhibitors, pretreatment RAVs did
not affect response to short durations of treatment with SOF/
GS-5816+GS-9857.Virologic failure was not associated with
emergence of resistance. These clinical results suggest a high
barrier to resistance with co-administration with SOF, GS-5816
and GS-9857 as was seen in vitro with the individual agents.
Disclosures:
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie, Janssen,
Gilead Sciences, Janssen Cilag, Achillion, Merck, Tekmira; Speaking and
Teaching: AbbVie, Gilead Sciences, Merck
Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc; Stock Shareholder:
Gilead Sciences Inc
Robert H. Hyland - Employment: Gilead Sciences, Inc; Stock Shareholder: Gilead
Sciences, Inc
Luisa M. Stamm - Employment: Gilead Sciences
Anu Osinusi - Employment: gilead sciences
Diana M. Brainard - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Michael D. Miller - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Hongmei Mo - Employment: Gilead Science Inc
The following authors have nothing to disclose: Krishna Chodavarapu, Christian
Schwabe
714
Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir
Co-Administered with Ribavirin in Adults with
Genotype 4 Chronic Hepatitis C Infection and Cirrhosis
(AGATE-I)
Tarik Asselah 2 , Tarek I. Hassanein 3 , Roula B. Qaqish 1 , Jordan J.
Feld 4 , Christophe Hezode 5 , Stefan Zeuzem 6 , Peter Ferenci 7 , Tami
Pilot-Matias 1 , Yao Yu 1 , Rebecca Redman 1 , Niloufar Mobashery 1 ;
1 AbbVie, Inc, North Chicago, IL; 2 Centre de Recherche sur l’Inflammation,
Inserm UMR 1149, Université Paris Diderot, AP-HP
Hôpital Beaujon, Clichy, France; 3 Southern California Liver Centers
and Southern California Research Center, Coronado, CA;
4 Toronto Centre for Liver Disease, University of Toronto, Toronto,
ON, Canada; 5 Henri Mondor University Hospital, AP-HP, Université
Paris-Est, Creteil, France; 6 J.W. Goethe University, Frankfurt,
Germany; 7 Medical University Vienna, Vienna, Austria
Purpose: HCV genotype 4 (GT4) represents approximately
20% of global HCV infection. Although GT4 infection is
more common in the Middle East and sub-Saharan Africa,
with globalization, GT4 is now seen increasingly in Europe
and many other countries. In the Phase 2b PEARL-I study, the
efficacy and safety of the two direct acting antiviral agents
(2DAA) ombitasvir (OBV), a NS5A inhibitor and paritaprevir,
a NS3/4A protease inhibitor identified by AbbVie and
Enanta, co-dosed with ritonavir (PTV/r) with or without ribavirin
(RBV) were assessed in 135 subjects with HCV GT4 infection
without cirrhosis. SVR12 was 100% in both treatment naïve
(TN) and prior interferon (IFN) and RBV treatment experienced
(TE) subjects receiving 2DAA+RBV for 12 weeks. This study
extends those observations by evaluating OBV/PTV/r with
RBV in HCV GT4-infected subjects with compensated cirrhosis.
Methods: This ongoing Phase 3, randomized, open-label, multinational
study (NCT 02265237) enrolled HCV GT4-infected
TN subjects or IFN/RBV or pegIFN/RBV TE subjects with compensated
cirrhosis. Subjects were randomized 1:1 to receive
co-formulated OBV/PTV/r once daily (25 mg/150 mg/100
mg) co-administered with weight based RBV for 12 (Arm A) or
16 weeks (Arm B) with an approximately equal number of TN
and TE subjects in each arm. A 24 week treatment arm (C) and
an exploratory assessment in subjects who have experienced
virologic failure with either sofosbuvir/pegIFN/RBV or sofosbuvir/RBV
will follow. The primary objectives are to assess safety
and SVR12 rates of these 2 DAA regimens as compared to a
historical SVR12 rate for HCV GT4-infected subjects treated
with pegIFN/RBV. Results: At the time of the abstract, 55 and
56 cirrhotic subjects were randomized into Arms A and B,
respectively. Of the 111 subjects, 48% were TN and 52%
were TE with IFN/RBV or pegIFN/RBV (30% prior nulls, 12%
prior relapsers and 10% partial responders). At baseline, 91%
of subjects had a Child-Pugh score of 5, 6% of 6 and 3% of
7. Overall, 72% are male, 78% White and 17% Black or
African American. The mean age is 57 years and mean BMI