studies

1064A AASLD ABSTRACTS HEPATOLOGY, October, 2015
Obaid S. Shaikh - Grant/Research Support: Gilead Sciences, Shinongi Pharmaceuticals;
Speaking and Teaching: Simply Speaking
The following authors have nothing to disclose: Arun Mannem, Vivek Sharma,
Fadi Francis, Thomas V. Cacciarelli
1754
Effect of simeprevir administration on dose-normalized
concentration of calcineurin inhibitors in solid organ
transplant recipients with hepatitis C infection
Heather Johnson 1,2 , Maxwell A. Brown 2 , Alicia B. Lichvar 2 ,
Michael A. Dunn 1 , Kapil B. Chopra 1 ; 1 University of Pittsburgh,
PIttsburgh, PA; 2 UPMC Presbyterian, Pittsburgh, PA
Background Simeprevir (SMV) is a second generation NS3/4A
protease inhibitor that lacks the immunomodulatory and other
adverse effects of interferon, representing an attractive therapeutic
alternative for the treatment of hepatitis C virus infection
in solid organ transplant recipients. The effect of P-glycoprotein
(P-gp) inhibition by SMV on serum concentrations of the calcineurin
inhibitors (CNI) cyclosporine (CsA) and tacrolimus (TAC)
is not well described in the literature. The purpose of this analysis
was to determine the magnitude of effect of P-gp inhibition
with SMV on CNI blood levels. Methods Liver transplant recipients
(LTRs) on maintenance immunosuppression with a CNI
who initiated antiviral treatment with SMV between 1/2014
and 4/ 2015 were included in this analysis. SMV was administered
along with the NS5B polymerase inhibitor sofosbuvir for
recurrent Genotype 1 allograft HCV. Dose-normalized levels
were calculated by dividing CNI trough levels by the CNI total
daily dose in order to account for CNI dose changes related
to changes in CNI trough levels over time. Dose-normalized
CNI levels in patients receiving 12 weeks of SMV were compared
using Friedman’s ANOVA. Median percent change in
dose-normalized levels were compared between LTRs with low
(0–2) and high (3–6) Metavir scores using the Mann-Whitney
U test. Results Nineteen patients were identified for inclusion in
this analysis, of whom 15 (78.9%) received 12 weeks of SMV
and 4 (21.1%) received 24 weeks of SMV. The majority of
patients were Caucasian (100.0%), male (63.2%), liver transplant
recipients (100.0%) on maintenance immunosuppression
with TAC (n=17) with an average age of 59.2 years (SD±6.7).
There was no significant difference between dose-normalized
levels of TAC at baseline and during HCV treatment. Three
patients (15.8%) had an increase in CNI dose and 4 patients
(21.1%) had a decrease in CNI dose following initiation of
SMV. There was no significant difference in median percent
change in dose-normalized TAC levels between groups with
low and high Metavir scores. Conclusions Patients on maintenance
immunosuppression with TAC who were treated with 12
weeks of SMV did not experience significant changes in their
dose-normalized TAC trough levels. More frequent monitoring
of TAC trough levels does not appear to be warranted in transplant
recipients initiating SMV therapy.
Disclosures:
The following authors have nothing to disclose: Heather Johnson, Maxwell A.
Brown, Alicia B. Lichvar, Michael A. Dunn, Kapil B. Chopra
1755
Bioluminescence imaging of mesenchymal stem cells by
over expression hepatocyte nuclear factor4α: tracking
survival and biodistribution
Pei-yi Xie, Xiaojun Hu, Xiaochun Meng, Hong Shan; Department of
Radiology, The Third Affiliated Hospital of Sun Yat-sen University,
Guangzhou, China
Hepatocytes from human bone marrow-derived mesenchymal
stem cells (hBM-MSCs) are expected to be a useful source
for cell transplantation. However, relatively low efficiency of
hepatic differentiation of hBM-MSCs remains unsolvable in clinical
application. Hepatocyte nuclear factor 4alpha (HNF4α),
a critical transcription factor, is essential for the entire process
of liver development. The purpose of this study was to construct
MSCs with over expression HNF4α and investigate their
hepatic differentiation and therapeutic potential for treating
Fulminant hepatic failure (FHF) rats, and track their survival
and biodistribution after transplantation by bioluminescence
imaging (BLI). HNF4α gene was transduced into hBM-MSCs by
lentiviral vector (pLV/Final-puro-hHNF4α-hrGFP). HNF4α-transduced
MSCs (E7-hHNF4α) and GFP-transduced MSCs cells
(E7-hrGFP ) were labeled with pLENTi-CMV-luc2-mKate2 and
analyzed for their hepatic functions such as measurements
of albumin, urea, glucose, cytochrome P450 activity,Indocyanine
green (ICG) uptake and release, and drug metabolization
in vitro. FHF modals of Sprague-Dawley (SD) rats were
established and divided into three groups: PBS, E7-hrGFP and
E7-hHNF4α cells’ transplantation. After 2.0×10 6 cells transplantation,
BLI was used to dynamically track the survival and
biodistribution of implanted E7-hrGFP cells and E7-hHNF4α
cells. The restoration of biological functions of the livers receiving
transplantation was assessed via a variety of approaches
such as mortality rate determination, serum biochemical analysis,
and histological, immunohistochemical, and genetic analysis.
In vitro, E7-hHNF4α cells showed mature hepatic functions
including albumin secretion, urea production, glycogen storage,
cytochrome P450 activity, ICG uptake and release and
drug metabolization. They improved liver functions in vivo after
transplantation into the D-galactosamine-injured rats’ liver as
evidenced by the fact that AST, ALT, TBIL returned to normal
levels in recipient FHF rats. The result of 30-day survival rates
suggested that E7-hHNF4α cells’ transplantation via superior
mesenteric vein (SMV) was able to significantly prolong the
survival of FHF rats compared with the other two groups. BLI,
histochemisty, and RT-PCR results confirmed the presence of
transplanted E7-hrGFP cells and E7-hHNF4α cells in recipient
rat livers. CONCLUSION: Our data revealed that E7-hHNF4α
cells could not only differentiate into functional hepatocyte-like
cells in vitro, but could also improve liver functions and prolong
the survival time of FHF rats. And BLI is a useful tool to track the
transplanted cells survival and biodistribution.
Disclosures:
The following authors have nothing to disclose: Pei-yi Xie, Xiaojun Hu, Xiaochun
Meng, Hong Shan