studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 321A
217
Daclatasvir and Sofosbuvir in Patients with Recurrent
HCV Following Liver Transplantation and Advanced
Fibrosis or Cirrhosis: United States Multicenter Treatment
Protocol
Paul Y. Kwo 1 , Michael W. Fried 2 , K. Rajender Reddy 3 , Consuelo
Soldevila-Pico 4 , Saro Khemichian 5 , Jama M. Darling 2 , Andrew
A. Napoli 6 , Beatrice Anduze-Faris 6 , Robert S. Brown 7 ; 1 Indiana
University, Indianapolis, IN; 2 University of North Carolina, Chapel
Hill, NC; 3 Department of Medicine, University of Pennsyslvania,
Philadelphia, PA; 4 Department of Medicine, University of Florida,
Gainesville, GA; 5 Keck School of Medicine, University of Southern
California, Los Angeles, CA; 6 Bristol-Meyers Squibb, Plainsboro,
NJ; 7 Department of Medicine, Columbia University College of Physicians
& Surgeons, New York, NY
Background: In the United States, there are limited treatment
options for liver transplant recipients with recurrent HCV and
advanced fibrosis/cirrhosis. In a Phase 3 study, the pangenotypic
combination of daclatasvir (DCV) and sofosbuvir (SOF)
with ribavirin demonstrated SVR rates of 94% in liver transplant
recipients with HCV recurrence. This analysis reports interim
findings from a U.S. Treatment Use protocol in patients with
recurrent HCV following liver transplantation and advanced
fibrosis or cirrhosis. Methods: In this multicenter, open-label,
expanded access study, DCV was provided for use in combination
with SOF, with or without RBV at the investigator’s
discretion, for up to 24 weeks in genotype 1-6 patients with
F3 fibrosis, cirrhosis, or fibrosing cholestatic hepatitis (FCH)
following liver transplantation. The HCV TARGET consortium of
academic and community medical centers and data collection
methodology were utilized. This interim analysis includes 51
patients who have enrolled and initiated treatment at 20 sites.
Results: Of the 51 patients treated, 49 received DCV+SOF
and 2 received DCV+SOF+RBV. Patients were predominantly
male (77%), white (82%) and infected with HCV genotype 1
(73%) or genotype 3 (24%). Fifty-seven percent had failed
prior treatment with IFN-based regimens (12% included a
protease inhibitor). Cirrhosis was present in 82% of patients,
including 57% with evidence of post transplant hepatic decompensation,
8% had a kidney transplant, and 8% had FCH. At
baseline, median HCV RNA was 2.9 x 10 6 IU/ml, the mean
(range) for platelets was 129 (41-239) x10 3 cells/uL, albumin
3.4 (1.7-6.3) g/dL, total bilirubin 1.5 (0.3-13) mg/dL, INR 1.1
(1.0-1.5), and creatinine clearance was 83 (40-190) ml/min.
MELD was ≥10 in 48% of patients with available scores. Of
21 patients with available data, the end of treatment virologic
response was 100%. All four patients who reached post-treatment
week 12 achieved SVR. Adverse events occurring in
≥10% of patients were fatigue, headache, nausea, and arthralgia.
Serious adverse events of interest included transplant rejection
(n=1) and renal failure (n=4). Two patients discontinued
treatment for adverse events; 1 due to renal failure leading to
death (unrelated to treatment) and 1 due to death of unknown
cause. SVR results for 31 patients will be available for presentation.
Conclusion: DCV+SOF for 24 weeks was well-tolerated
in this population with severe recurrent post-transplant hepatitis
C. Interim data indicate effective end of treatment antiviral
response and SVR in the patients receiving this regimen
through compassionate use.
Disclosures:
Paul Y. Kwo - Advisory Committees or Review Panels: Abbvie, Abbott, Novartis,
Merck, Gilead, BMS, Janssen; Consulting: BMS; Grant/Research Support:
Roche, Abbvie, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead, Vertex,
Merck, Idenix; Speaking and Teaching: Merck, Merck
Michael W. Fried - Consulting: Merck, Abbvie, Janssen, Bristol Myers Squibb,
Gilead; Grant/Research Support: Merck, AbbVie, Janssen, Bristol Myers Squibb,
Gilead; Patent Held/Filed: HCCPlex
K. Rajender Reddy - Advisory Committees or Review Panels: Merck, Janssen,
Vertex, Gilead, BMS, Abbvie; Grant/Research Support: Merck, BMS, Ikaria,
Gilead, Janssen, AbbVie
Saro Khemichian - Advisory Committees or Review Panels: Gilead, AbbVie, BMS;
Speaking and Teaching: Gilead, AbbVie, Salix
Jama M. Darling - Consulting: BristolMyers Squibb; Grant/Research Support:
BristolMyers Squibb
Andrew A. Napoli - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers
Squibb
Beatrice Anduze-Faris - Employment: Bristol-Myers Squibb
Robert S. Brown - Consulting: Gilead, Janssen, Abbvie, Merck, BMS
The following authors have nothing to disclose: Consuelo Soldevila-Pico
218
Rapid Decline In Interferon Stimulated Genes In Prior
HCV Non-Responders Re-Treated With Direct Acting
Antivirals
Hawwa Alao 1 , Yun Ju Kim 1 , Elizabeth C. Wright 4 , Margaret
Cam 2 , Elenita M. Rivera 1 , Nancy Fryzek 1 , David E. Kleiner 3 , Fang
Zhang 1 , Edward Doo 1 , Yaron Rotman 1 , Christopher Koh 1 , Theo
Heller 1 , Jay H. Hoofnagle 1 , T. Jake Liang 1 , Marc G. Ghany 1 ;
1 Liver Diseases Branch, National Institutes of Health, Bethesda,
MD; 2 NCI, NIH, Bethesda, MD; 3 LP, NCI, NIH, Bethesda, MD;
4 Office of the Director, NIDDK, NIH, Bethesda, MD
BACKGROUND: The development of direct acting antiviral
(DAA) agents has revolutionized therapy of chronic hepatitis
C. Prior non-responders are known to have high baseline
hepatic expression of interferon stimulated genes (ISGs). The
effect of potent DAAs on ISG expression is unknown. AIM: To
investigate the effect of an oral DAA regimen on ISG expression
in prior failures to interferon-based regimens with chronic
hepatitis C (CHC). METHODS: Subjects with HCV genotype
1b infection who had failed to respond to peginterferon and
ribavirin were re-treated with asunaprevir anddaclatasvir for
24 weeks. Subjects were monitored after therapy for 12 weeks
to determine SVR12. Patients underwent paired liver biopsies,
the first within 12 weeks before therapy and the second at
either week 2 or 4 on therapy. Microarray analysis (Affymetrix
Human Gene 2.0 ST array, Santa Clara, CA) was performed
on liver biopsy tissue and on-therapy gene expression was
compared to baseline. All subjects provided informed consent
to participate. RESULTS: 11 patients with chronic HCV genotype
1b infection had paired biopsies available for microarray
analysis. The 11 patients included 6 women, mean age
62 years, mean HCV RNA 6.8 log 10
IU/mL, 4 with cirrhosis.
The SVR rate was 64%. All 4 failures experienced virological
breakthrough between weeks 4-12. At the week 2 biopsy, 5 of
5 subjects had detectable virus (