studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 777A
1150
Combination therapies with daclatasvir and asunaprevir
on NS3-D168 mutated hepatitis C virus in human
hepatocyte chimeric mice
Hiromi Kan 1 , Michio Imamura 1 , Nobuhiko Hiraga 1 , Eisuke
Miyaki 1 , Takuro Uchida 1 , Masataka Tsuge 1 , Hiromi Abe 1 , Nelson
Hayes 1 , Hiroshi Aikata 1 , Chise Tateno 2 , Kazuaki Chayama 1 ;
1 Department of Gastroenterology and Metabolism, Applied Life
Sciences, Institute of Biomedical & Health Sciences, Hiroshima
University, Hiroshima, Japan; 2 PhoenixBio Co., Ltd., Higashihiroshima,
Japan
Background and Aim: The frequency of emergent drug-resistant
strains of hepatitis C virus (HCV) in patients who failed to
respond to simeprevir plus peginterferon (PEG-IFN) and ribavirin
(RBV) combination therapy decreased after cessation of
the treatment. However, it is not clear whether or not the HCV
NS3-D168 mutation affects the outcome of an IFN-free combination
therapy including NS5A inhibitor, daclatasvir and NS3
protease inhibitor, asunaprevir. In this study, we investigated
the relationship between the effect of daclatasvir plus asunaprevir
treatment and the frequencies of drug-resistant NS3-D168
variants using HCV-infected mice. Methods: Injection with wildtype
and NS3 D168 mutated genotype 1b HCV mixed serum
to human hepatocyte chimeric uPA-SCID mice enabled us to
develop mice with various frequencies of NS3-D168 mutation.
These mice were treated with 40 mg/kg of asunaprevir alone or
in combination with 10 mg/kg daclatasvir for four weeks (provided
by Bristol-Meyers Squibb Research and Development).
Frequencies of NS3-D168 mutation at baseline were analyzed
by ultra-deep sequencing. Some mice infected with NS3-D168
substitutions were administered with either intramuscular injection
of 30 μg/kg of PEG-IFN-alfa twice a week or 200 mg/kg
of telaprevir (provided from Mitsubishi Tanabe Pharma) orally
twice per day for four weeks. Results: Mice with high NS3-
D168 variant frequencies showed a low susceptibility to asunaprevir
mono-therapy and failed to respond to daclatasvir plus
asunaprevir therapy. In contrast, mice with a low frequency
(less than approximately 14%) of NS3-D168 variants showed
a similar susceptibility to asunaprevir mono-therapy with wildtype
HCV-infected mice and achieved viral eradication with
four weeks of daclatasvir plus asunaprevir therapy. Although
telaprevir or PEG-IFN treatment resulted in a reduction of serum
HCV RNA levels, no significant decrease in the frequency of
NS3-D168 substitutions was achieved. Conclusion: Daclatasvir
and asunaprevir treatment could eliminate NS3-D168-mutated
HCV if the frequency at baseline was low. Using either telaprevir
or IFN might cause no significant reductions in NS3-
D168 mutation. It is necessary to confirm that the frequency of
NS3-D168 variants has decreased sufficiently before adopting
daclatasvir plus asunaprevir therapy in patients with simeprevir
plus PEG-IFN/RBV treatment failure.
Disclosures:
Kazuaki Chayama - Consulting: AbbVie; Grant/Research Support: Ajinomoto,
Astellas, Asuka, Bayer, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen,
Kowa, Mitsubishi Tanabe, MSD, Eli Lily, Nippon Kayaku, Nippon Shinyaku,
Otsuka, Roche, Takeda, Toray, Torii, Tsumura, Zeria; Speaking and Teaching:
Eisai, Ajinomoto, AbbVie, Abott, Astellas, AstraZeneca, Asuka, Bayer, BMS,
Chugai, Daiichi Sankyo, Dainippon Sumitomo, J&J, Jimro, Miyarisan, MSD,
Nihon Kayaku, Olympus
The following authors have nothing to disclose: Hiromi Kan, Michio Imamura,
Nobuhiko Hiraga, Eisuke Miyaki, Takuro Uchida, Masataka Tsuge, Hiromi Abe,
Nelson Hayes, Hiroshi Aikata, Chise Tateno
1151
HepCure: An Innovative web-based toolkit to train a
new cohort of hepatitis C providers and increase patient
engagement
Ponni V. Perumalswami 1 , Korin Parrella 2 , Jason Rogers 3 , Rahul
Patel 4 , Brooke Wyatt 1 , Kian Bichoupan 1 , Andrea D. Branch 1 , Brian
Kim 1 , Anna Patel 1 , Joseph Lawler 1 , Alicia Stivala 2 , Alyson Harty 1 ,
Donald Gardenier 2 , Michel Ng 1 , Catherine Amory 2 , Aaron M.
Vanderhoff 1 , Douglas Dieterich 1 , Ashish Atreja 3 , Jeffrey J. Weiss 2 ;
1 Liver Diseases, Icahn School of Medicine at Mount Sinai, New
York, NY; 2 Medicine, Icahn School of Medicine at Mount Sinai,
New York, NY; 3 Medicine- Division of Gastroenterology, Icahn
School of Medicine at Mount Sinai, New York, NY; 4 Parsus Solutions,
LLC, Scottsdale, AZ
Background and Aims: There is a great need to expand the
number of health care professionals treating hepatitis C and
to optimize patient engagement. The aim of this study is to
develop and operationalize HepCure (http://hepcure.org),
a web-based application (app) with three components: An
open access toolkit (a dashboard) that enhances providers’
ability to deliver guideline-based HCV care; a patient app that
provides education, medication reminders, and a platform
for tracking adherence and symptoms; and a tele-education
platform for medical providers. Methods: The HepCure app
is a collaboration among an academic, tertiary care medical
center, the New York State (NYS) Department of Health,
and NYS community health centers. A working group of multidisciplinary
HCV experts (Hepatology, Internal Medicine,
Psychology, Social Work, and Public Health) was created to
develop content for the HepCure dashboard. Input from this
group was used to develop wireframes. Focus groups were
held with providers and patients to refine wireframes. National
guidelines (AASLD/IDSA) were used to identify key patient
characteristics to determine treatment recommendations to
build decision support algorithms. The app has the capability
to de-identify patient data to directly discuss cases selected
by providers at weekly tele-education sessions with experts.
Results: The HepCure platform captures United States Centers
for Medicaid and Medicare and NYS HCV quality indicators
for population health management, provides decision support
algorithms for providers that can be updated in real time with
newly approved HCV treatment regimens and incorporates
a tele-education platform with access to experts. The Hep-
Cure Provider Dashboard (http://providers.hepcure.org) was
launched in November 2014. Weekly tele-education sessions
have been conducted since February 2015 (n=17) and each
session has been archived with open access. These sessions
have been attended by an average of 13 ± 7 attendees a
week and archived sessions have been viewed an average of
8 ± 3 times. A patient mobile app which can be linked to the
provider dashboard was launched in June 2015 to increase
patient engagement. Conclusions: Providers are interested in
web-based tools to help them master HCV treatment and stay
current with ongoing changes in treatment paradigms. Patients
with HCV desire web-based tools to help them learn more
about and navigate HCV treatment. The HepCure platform is
an innovative model that can be adapted globally in line with
local HCV treatment guidelines to train a new generation of
HCV providers, collect real world data, and foster comparative
effectiveness research.
Disclosures:
Kian Bichoupan - Consulting: Janssen Pharmaceuticals, Gilead Sciences
Andrea D. Branch - Grant/Research Support: Gilead, Janssen
Alyson Harty - Advisory Committees or Review Panels: Gilead; Consulting: Gilead,
Jannsen, Acaria Pharmacy, Abbvie