studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 765A
Disclosures:
Emmanouil Sinakos - Advisory Committees or Review Panels: AbbVie; Speaking
and Teaching: AbbVie, Bristol-Myers Squibb, Gilead, Janssen
Ioannis Goulis - Consulting: Gilead Sciences, Abbvie, Janssen-Cilag, Janssen-Cilag,
BMS; Grant/Research Support: BMS; Speaking and Teaching: BMS, Gilead
Sciences, Janssen-Cilag
George V. Papatheodoridis - Advisory Committees or Review Panels: Merck
Sharp & Dohme, Novartis, Abbvie, Boerhinger Ingelheim, Bristol-Meyer Squibb,
Gilead, Roche, Janssen, GlaxoSmith Kleine; Grant/Research Support: Roche,
Gilead, Bristol-Meyer Squibb, Abbvie, Janssen; Speaking and Teaching: Merck
Sharp & Dohme, Bristol-Meyer Squibb, Gilead, Roche, Janssen, Abbvie
The following authors have nothing to disclose: Dimitrios Kountouras, Ioannis
Koskinas, Stylianos Karatapanis, Alexandra Kourakli, Efthimia Vlachaki, Antonios
Kattamis, Konstantinos Maragkos, Fotini Petropoulou, Barbara Toli, Evangelos
Akriviadis
1127
NS3 Q80K Polymorphism in Viral Isolates from Liver
Tissues and Serum Samples of Naïve HCV Genotype 1a
Patients.
Deborah D’Aliberti 2 , Irene Cacciola 2 , Salvatore Benfatto 1 , Federica
Mannino 1 , Roberto Filomia 2 , Concetta Beninati 1 , Giovanni
Raimondo 2 , Teresa Pollicino 1 ; 1 Pediatric, Gynecological, Microbiological
and Biomedical Sciences, University Hospital of Messina,
Messina, Italy; 2 Clinical and Experimental Medicine, University
Hospital of Messina, Messina, Italy
Background and Aim – NS3 Q80K is a polymorphism commonly
detected in genotype (G) 1a HCV strains. It is associated
with a reduced antiviral activity of HCV proteinase inhibitors
(PIs) in vitro and its emergence is generally considered a cause
of response failure to Simeprevir as well as to other PIs in
HCV-G1a patients. Several studies have evaluated the prevalence
of Q80K polymorphism in HCV isolates from treatment
naïve patients of different geographic areas. However, the
data available concern only circulating viral isolates, whereas
there is no information about the variability of HCV strains in
the liver where the viral replication occurs and the HCV quasispecies
diversity reaches the highest level of complexity. Aim of
our study was to investigate the presence of Q80K substitution
in HCV-G1a isolates from liver tissues and serum samples of
patients from south of Italy, naïve to any antiviral treatment.
Patients and Methods – HCV NS3 protease sequences of HCV
isolates from paired serum and liver biopsy samples of 11 naïve
patients with HCV-G1a chronic infection, and from serum samples
of additional 20 naïve HCV-G1a infected patients were
analysed by population sequencing and ultra-deep pyrosequencing
(UDPS) (mutant detection sensitivity 1%; >3000
sequences/patient). Results – The Q80K substitution was found
in 8/11 liver tissues (72.7%; in 7 present at levels between 1%
and 10%, and in 1 at level ≈97% of the virus quasispecies) and
in 5/11 corresponding serum samples (45.4%; in 4 present at
level ≈1%, and in 1 at level ≈97% of the virus quasispecies) by
UDPS. Of the additional 20 sera examined, 13 (65%) showed
the Q80K substitution by UDPS (in 11 present at level ≈1%,
in 1 present at level ≈20%, and in 1 present at level ≈99% of
the virus quasispecies). On the whole, the Q80K substitution
was detected in 18/31 sera (58%) analysed. By population
sequencing, the Q80K substitution was detected only in samples
from 2 of the 31 patients (6.4%) analyzed. In particular,
the Q80K substitution was found in the paired liver and serum
samples from 1 patient and in the serum sample from another
patient with no liver specimen available (in all these 3 samples
the Q80K was present in 97-99% of the entire viral populations
by UDPS). Conclusions – HCV-G1a strains carrying
Q80K polymorphism are commonly present both in liver and
in serum of infected patients. However, they are present as
minor populations in almost all the cases, suggesting that the
Q80K substitution does not confer fitness advantage at least to
the HCV-G1a viral strains circulating in our geographic area.
Disclosures:
Giovanni Raimondo - Speaking and Teaching: BMS, Gilead, Roche, Merck,
Janssen, Bayer, MSD
Teresa Pollicino - Speaking and Teaching: Gilead, Roche, Janssen, BMS, MSD,
Bayer, Abbvie
The following authors have nothing to disclose: Deborah D’Aliberti, Irene Cacciola,
Salvatore Benfatto, Federica Mannino, Roberto Filomia, Concetta Beninati
1128
Safety and Efficacy of Treatment with Daily Sofosbuvir
400 mg + Ribavirin 200 mg for 24 Weeks in Genotype
1 or 3 HCV-Infected Patients with Severe Renal Impairment
Paul Martin 2 , Edward J. Gane 3 , Grisell Ortiz-Lasanta 4 , Lin Liu 1 ,
Karim Sajwani 1 , Brian Kirby 1 , Jill M. Denning 1 , Luisa M. Stamm 1 ,
Diana M. Brainard 1 , John G. McHutchison 1 , Eric Lawitz 5 , Stuart
C. Gordon 6 , Richard A. Robson 7 ; 1 Gilead Sciences, Raleigh, NC;
2 University of Miami, FL, USA, Miami, FL; 3 University of Auckland,
Auckland, New Zealand; 4 Fundcion de Investigacion, San Juan,
PR; 5 Texas Liver Institute, San Antonio, TX; 6 Henry Ford Health
System, Detroit, MI; 7 Christchurch Clinical Studies Trust, Ltd, Christchurch,
New Zealand
Background: HCV-infected patients with severe renal impairment
have had limited treatment options with suboptimal
response rates and poor tolerability of IFN-based regimens.
SOF 200 mg+RBV studied previously was safe and relatively
well tolerated in patients with severe renal impairment, but SVR
rates were low. The current study evaluated the safety, pharmacokinetics
(PK) and efficacy of SOF 400mg+RBV for 24 weeks
in genotype 1 or 3 HCV-infected patients with severe renal
impairment. Methods: Treatment-naïve or experienced patients
± cirrhosis and a creatinine clearance (CLcr) less than 30mL/
min (by Cockcroft-Gault equation), not on dialysis, received
open-label treatment with SOF 400mg+RBV 200mg once daily
for 24 wks. We examined on-treatment virologic response, PK
and safety including echocardiograms read by a central reader
pre-treatment and at Week 12 of therapy. Results: 10 patients (6
GT1a, 2 GT1b, 2 GT3a) were enrolled and have been treated
for 12-24 wks (median 16 wks): 8 male, 5 white, 4 black, 1
Pacific Islander, mean age 58; 4 with cirrhosis, 7 treatment-experienced,
5 IL28B genotype non-CC, mean baseline CLcr
26.2 mL/min, and mean baseline hemoglobin (Hb)11.3 g/dL.
All patients had a rapid virologic decline similar to those with
normal renal function. Exposure of GS-331007, the primary
circulating SOF metabolite which is renally eliminated, was
~6-fold higher and SOF was ~1.4 fold higher than observed
in subjects in the Phase 2/3 population. Adverse events (AEs)
reported in more than one patient were anemia (n=3) and
dizziness (n=2). Two patients had treatment-emergent SAEs,
1 patient discontinued treatment just before week 12 due to
an SAE of acute respiratory failure, and 1 patient experienced
hematemesis. No patients had RBV dose-reduction, interruption
or discontinuation with the exception of the one patient who
discontinued study treatment due to an SAE. Three patients
on epoetin at baseline continued throughout treatment. No
patients started epoetin or had a blood transfusion during the
treatment period. Changes in renal function, hemoglobin, and
cardiac parameters are shown in Table 1. Conclusions: SOF
400mg daily + RBV 200mg in GT1 or 3 HCV-infected patients
with severe renal impairment was well-tolerated and resulted in
rapid virologic suppression through Wk 12 of treatment. Final
safety, PK and efficacy (SVR12) will be presented.