ORAL PRESENTATIONS
in-vitro BT-mimicking experiments, using the CaCo2 (human
enterocyte-like)-cell line were performed in TranswellsTM.
Results: Vehicle-treated BDL-rats showed reduced ileal FXR
pathway expression (P = 0.02 vs. healthy control) which was
associated with increased BT, ileal permeability (through
increased claudin-2-expession), recruitment of macrophages,
natural killer and dendritic cells and interferon-g (IFN-g)-expression (P < 0.05 vs. control). Following INT-747-treatment,
immune cell recruitment and IFN-g expression were markedly
reduced which was associated with normalized permeability (by
up-regulated claudin-1, occludin and zonula-occludens-protein-1)
(P < 0.05 vs. BDL+vehicle). Following INT-747-treatment plasma
bilirubin decreased from 12.4±0.4 to 8.4±0.7mg/dl in BDL-rats
(P < 0.01). In vitro, IFN-g induced increased permeability and
E. coli translocation which remained unaffected with INT-747-
preincubation.
Conclusions: In experimental cholestasis, FXR-agonism restores
ileal permeability and decreases BT by attenuating intestinal
inflammation, demonstrating a crucial protective role for FXR in
the gut-liver axis.
O3
ADDING PEGINTERFERON TO ENTECAVIR INCREASES RESPONSE
RATES IN HBeAg-POSITIVE CHRONIC HEPATITIS B PATIENTS:
WEEK 96 RESULTS OF A GLOBAL MULTICENTER RANDOMISED
TRIAL (ARES STUDY)
W.P. Brouwer1, Q. Xie2, M.J. Sonneveld1, N.P. Zhang3, Q. Zhang4,
F. Tabak5, A. Streinu6, J.-Y. Wang3, R. Idilman7, H.W. Reesink8,
M. Diculescu9, K. Simon10, M. Voiculescu11, M. Akdogan12,
W. Mazur13, J.G.P. Reijnders1, E. Verhey1, B.E. Hansen1,14,
H.L.A. Janssen1,15. 1Gastroenterology & Hepatology, Erasmus MC
University Medical Center, Rotterdam, Netherlands; 2Infectious
Diseases, Ruijin Hospital, Shanghai Jiaotong University School of
Medicine, 3Gastroenterology & Hepatology, Zhong Shan Hospital, Fu
Dan University, 4Gastroenterology and Hepatology, Shanghai Public
Health Center, Fu Dan University, Shanghai, China; 5Cerrahpasa
Medical Faculty, Istanbul, Turkey; 6National Institute of Infectious
Diseases, Bucharest, Romania; 7University of Ankara, Medical
School, Ankara, Turkey; 8Gastroenterology & Hepatology, Academic
Medical Centre, Amsterdam, Netherlands; 9Gastroenterology &
Hepatology, Fundeni Cinical Institute, Bucharest, Romania; 10Infectious
Diseases and Hepatology, Wroclaw Medical University, Wroclaw,
Poland; 11Internal Medicine, Fundeni Cinical Institute, Bucharest,
Romania; 12Gastroenterology & Hepatology, Yuksek Ihsitas Hospital,
Ankara, Turkey; 13Specialistic Medical Practice, Zawiercie, Poland;14Public Health, Erasmus MC University Medical Center, Rotterdam,
Netherlands; 15Center for Liver Disease, Toronto Western and General
Hospital, University Health Network, Toronto, ON, Canada
E-mail: [email protected]
Background and Aims: It is unknown whether adding
peginterferon (PEG-IFN) to entecavir (ETV) is safe and enhances
response rates.
Methods: In this global, multicentre, investigator-initiated
randomised-controlled trial, HBeAg-positive chronic hepati-
tis B (CHB) patients with compensated liver-disease started on
ETV-monotherapy (0.5mg/day) and were randomized to either
PEG-IFN alpha-2a add-on (180mg/week) from week 24–48, or to
continue ETV-monotherapy. Response was defined as HBeAg-loss
with HBVDNA <200 IU/ml. Responders at week 48 stopped ETV at
week 72. Here we report on the results at week 96.
Results: Of the 175 patients in the modified intention-to-
treat analysis, 85 were allocated to ETV+PEG-IFN add-on
therapy and 90 to ETV-monotherapy. HBV-genotype A/B/C/D was
present in 7%/19%/42%/32%, respectively. At week 96, 26 (31%)
patients in the add-on versus 18 (20%) in the monotherapy-
arm achieved the response (p = 0.107). Twenty (24%) patients in
the add-on versus 10 (11%) in the monotherapy-arm achieved
HBeAg-seroconversion with HBVDNA <200 IU/ml (p = 0.029). After
adjustment for the difference in HBVDNA at week 24 add-
on therapy was independently associated with higher response
rates (Odds-ratio = 3.1, 95%confidence-interval = 1.4–6.9, p = 0.007).
Adding-on PEG-IFN to ETV led to more decline in HBsAg (0.27
versus 0.04 log10IU/ml, figure), HBeAg (1.10 versus 0.74 log10IU/ml),
HBVDNA (1.24 versus 0.85 log10IU/ml) (all p <0.05), and to more
sustained response after ETV-discontinuation [9/14 (64%) versus
2/8 (25%), p = 0.076]. One patient with add-on therapy lost HBsAg
(p =0.302). Combination of PEG-IFN and ETV was well-tolerated.
Conclusions: Twenty-four weeks PEG-IFN add-on was safe
and resulted in more viral decline and higher response rates
compared to ETV-monotherapy. PEG-IFN add-on therapy appeared
to prevent relapse after stopping ETV and may therefore facilitate
discontinuation of nucleos(t)ide analogues.
Figure: HBsAg decline from randomization at wk 24.
O4
PROLONGED THERAPY OF HEPATITIS DELTA FOR 96 WEEKS
WITH PEGYLATED-INTERFERON-a-2a PLUS TENOFOVIR OR
PLACEBO DOES NOT PREVENT HDVRNA RELAPSE AFTER
TREATMENT: THE HIDIT-2 STUDY
H. Wedemeyer1,2, C. Yurdaydin3, S. Ernst4, F.A. Caruntu5,
M.G. Curescu6, K. Yalcin7, U.S. Akarca8, S. Gurel9, S. Zeuzem10,
A. Erhardt11, S. Luth12, G.V. Papatheodoridis13, O. Keskin3, K. Port1,
M. Radu5, M.K. Celen7, R. Ildeman3, J. Stift14, B. Heidrich1,2,
I. Mederacke2, S. Hardtke1,2, A. Koch4, H.P. Dienes2,14, M.P. Manns1,2,
HIDIT-2 Study Group. 1Gastroenterology, Hepatology and
Endocrinology, Hannover Medical School, 2German Liver Foundation,
HepNet Study-House, Hannover, Germany; 3Ankara University
Medical Faculty, Ankara, Turkey; 4Biometry, Hannover Medical
School, Hannover, Germany; 5institutul de Boli Infectioase, Bucharest,6University of Medicine and Pharmacy, Timisoara, Romania; 7Medical
Faculty, Dicle University, Diyarbarkir, 8Medical Faculty, Ege University,
Izmir, 9Medical Faculty, Uludag University, Bursa, Turkey; 10Johann
Wolfgang Goethe University Medical Center, Frankfurt am Main,11Gastroenterology, Hepatology and Infectiology, Heinrich Heine
University, Dusseldorf, 12Dept. of Medicine 1, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany; 13Academic
Gastroenterology Dept., Laiko General Hospital, Athens, Greece;14University of Vienna, Vienna, Austria
E-mail: [email protected]
Background and Aims: Hepatitis delta is the most severe form of
chronic viral hepatitis. Pegylated interferon alfa for 1.0–1.5 years
is effective in 25–30% of patients. The aim of the investigator-
initiated HIDIT-2 trial was to investigate the efficacy of 96 weeks
of PEG-IFNa-2a therapy plus tenofovir or placebo in patients with
hepatitis delta. We here report the efficacy analysis after 24 weeks
after the end of treatment.
Methods: 120 HDV-RNA-positive patients were recruited in 4
countries (Turkey n=50, Germany n=46, Romania n =19, Greece
n =5). Patients were randomized to receive either 180mg PEG-IFNa-
S2 Journal of Hepatology 2014 vol. 60 | S1–S22
ORAL PRESENTATIONS
2a weekly plus tenofovir disoproxil fumarate (300mg once daily;
TFVarm A, n =59) or plus placebo (PBOarm B; n =61).
Results: The mean age was 40±11 years and 54 patients (45%) had
liver cirrhosis. At the end of treatment HDVRNA was negative
in 28 patients (48%) receiving combination therapy and in 20
patients (33%) receiving PEG-IFNa-2a and placebo (ITT analysis).
Post-treatment, 36% and 39% of patients experienced an HDVRNA
relapse while 1 and 6 patients became HDVRNA undetectable after
treatment was stopped. The post-treatment week 24 HDV responses
were 29% in tenofovir-treated patients and 21% in the placebo arm.
Lower baseline HDVRNA and HBsAg levels were associated with
the week 120 HDVRNA response. HBsAg was negative in 7 patients
(3 TFVarm; 4 PBO).
Conclusions: Prolonged administration of PEG-IFNa-2a and
tenofovir for 96 weeks does not prevent post-treatment relapse
in HDV-infected patients. 48 weeks of PEG-IFNa-2a remains the
standard therapy of hepatitis delta. Alternative treatment strategies
are urgently needed.
O5
PRIMARY SCLEROSING CHOLANGITIS FROM A GLOBAL
PERSPECTIVE – A MULTICENTER, RETROSPECTIVE,
OBSERVATIONAL STUDY OF THE INTERNATIONAL
PSC STUDY GROUPT.J. Weismuller1,2, J.A. Talwalkar3, C.Y. Ponsioen4, D.N. Gotthardt5,
H.-U. Marschall6, S. Naess7, K. Holm7, R.K. Weersma8, K.N. Lazaridis3,
J. Fevery9, P.J. Trivedi10, C. Schramm11, O. Chazouilleres12, T. Muller13,
M. Farkkila14, S. Almer15,16, S. Pereira17, A.L. Mason18, A. Floreani19,
P. Milkiewicz20, H. Harley21, A. Pares22, L. de Vries4, C. Manser23,
N. Gatselis24, C. Berg25, H. Lenzen2, M. Benito de Valle6, M. Imam3,
G. Kirchner26, P. de Leuw27, V. Zimmer28, L. Fabris19, F. Braun29,
G.M. Hirschfield10, M. Marzioni30, B.D. Juran3, C.P. Strassburg1,2,
U. Beuers4, M.P. Manns2, E. Schrumpf7, T.H. Karlsen7, A. Bergquist16,
K.M. Boberg7, International PSC Study Group. 1Department of
Internal Medicine 1, University of Bonn, Bonn, 2Department of
Gastroenterology, Hepatology and Endocrinology, Hannover Medical
School, Hannover, Germany; 3Division of Gastroenterology and
Hepatology, Mayo Clinic, Rochester, MN, United States; 4Department
of Gastroenterology and Hepatology, Academic Medical Center,
Amsterdam, Netherlands; 5Department of Internal Medicine,
University Hospital of Heidelberg, Heidelberg, Germany; 6Department
of Internal Medicine, Sahlgrenska Academy and University Hospital,
Gothenburg, Sweden; 7Norwegian PSC Research Center, Oslo
University Hospital Rikshospitalet, Oslo, Norway; 8Department
of Gastroenterology and Hepatology, University Medical Center
Groningen and University of Groningen, Groningen, Netherlands;9Department of Hepatology, University Hospital Gasthuisberg, Leuven,
Belgium; 10NIHR Biomedical Research Unit and Centre for Liver
Research, University of Birmingham, Birmingham, United Kingdom;111st Department of Medicine, University Medical Center Hamburg-
Eppendorf, Hamburg, Germany; 12Service d’Hepatologie, Hopital Saint
Antoine, Assistance Publique-Hopitaux de Paris, Faculte de Medecine
Pierre et Marie Curie, Paris, France; 13Department of Internal Medicine,
Hepatology and Gastroenterology, Charite Universitatsmedizin Berlin,
Berlin, Germany; 14Division of Gastroenterology, Department of
Medicine, Helsinki University Central Hospital, Helsinki, Finland;15Gastroenterology & Hepatology, Linkoping University, Linkoping,16Division of Gastroenterology and Hepatology, Karolinska University
Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; 17UCL
Institute for Liver and Digestive Health, London, United Kingdom;18Division of Gastroenterology and Hepatology, University of Alberta,
Edmonton, AB, Canada; 19Department of Surgical, Oncological and
Gastroenterological Sciences, University of Padova, Padova, Italy;20Liver Unit and Liver Research Laboratories, Pomeranian Medical
University, Szczecin, Poland; 21Department of Gastroenterology
and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia;22Liver Unit, Hospital Clınic, University of Barcelona, Barcelona,
Spain; 23Division for Gastroenterology and Hepatology, University
Hospital Zurich (USZ), Zurich, Switzerland; 24Department of Medicine
and Research Laboratory of Internal Medicine, University Hospital
of Larissa, University of Thessaly, Larissa, Greece; 25Department
of Gastroenterology, Hepatology, and Infectiology, Medical Clinic,
University of Tubingen, Tubingen, 26Department of Internal Medicine I,
University Hospital of Regensburg, Regensburg, 27Department of
Internal Medicine 1, Johann Wolfgang Goethe-University Hospital,
Frankfurt, 28Saarland University Medical Center, Homburg, 29UKSH,
Campus Kiel, Kiel, Germany; 30Department of Gastroenterology,
Universita Politecnica delle Marche, Ancona, Italy
E-mail: [email protected]
Background and Aims: Existing studies on the clinical presentation
and the course of Primary Sclerosing Cholangitis (PSC) are based
on observations in single centres or certain geographical regions
and the different institutions report variable results regarding
risk of malignancy, transplant-free survival and association with
inflammatory bowel disease (IBD).
Methods: All patients diagnosed with PSC between 1/1/1980 and
12/31/2010 from 33 institutions in 16 countries were included in the
study. Data on clinical presentation, survival, liver transplantation
(LT), IBD and malignancy were retrospectively analyzed.
Results: The participants submitted data on 7312 PSC-patients and
after exclusion of patients with insufficient follow-up information
5948 patients (65.2% male, mean age at diagnosis 40.5 years)
remained for analysis. 89% had a large-duct, 4.3% a small-duct
PSC and 6.4% had a PSC with features of autoimmune hepatitis
(AIH). IBD was present in 69% (79.5% Ulcerative Colitis (UC)).
The 5-, 10-, 20- and overall transplant-free survival rates were
80.7%, 72%, 66.3% and 65.6% (median transplant-free survival time
14.5 years). Hepatobiliary malignancies were diagnosed in 10.9%
and colorectal carcinoma in 11.2%. Women had a slightly better
transplant-free survival (69% vs. 63.9%, p = 0.045) and a lower
incidence of hepatobiliary malignancies (7.9% vs. 12.5%, p < 0.001).
Patients with small-duct disease and with features of AIH had a
significantly (p < 0.001) better transplant-free survival and a lower
rate of hepatobiliary malignancies. The influence of IBD on survival
and malignancy-rate was slight and statistically not significant.
Conclusions: This multicentric study-approach avoids center-
specific and regional characteristics and identifies risk parameters
that influence the clinical course of PSC.
O6
SOFOSBUVIR/LEDIPASVIR FIXED DOSE COMBINATION IS
SAFE AND EFFECTIVE IN DIFFICULT-TO-TREAT POPULATIONS
INCLUDING GENOTYPE-3 PATIENTS, DECOMPENSATED
GENOTYPE-1 PATIENTS, AND GENOTYPE-1 PATIENTS WITH
PRIOR SOFOSBUVIR TREATMENT EXPERIENCE
E.J. Gane1, R.H. Hyland2, D. An2, P.S. Pang2, W.T. Symonds2,
J.G. Mchutchison2, C.A. Stedman3. 1Auckland Clinical Studies,
Auckland, New Zealand; 2Gilead Sciences, Inc., Foster City, CA, United
States; 3Christchurch Clinical Studies Trust, Christchurch, New Zealand
E-mail: [email protected]
Background and Aims: In the era of all oral direct-acting antiviral
(DAA) combinations, there remain groups of patients who are
considered more difficult to treat due to advanced liver disease,
HCV genotype 3, or failure on earlier DAA regimens. This study
aimed to explore the efficacy and safety of sofosbuvir/ledipasvir
(SOF/LDV) fixed dose combination in these populations.
Methods: 50 treatment-naïve patients with HCV genotype 3 were
randomized equally to receive SOF/LDV with or without RBV for
12 weeks. 20 patients with HCV genotype 1 and Child–Turcotte–
Pugh Class B were assigned to receive SOF/LDV for 12 weeks. In
addition, 19 patients with HCV genotype 1 who had relapsed after
receiving SOF + RBV +/− GS-9669 for 12 weeks or SOF/LDV + RBV
for 6 weeks were assigned to receive SOF/LDV+RBV for 12 weeks.
Journal of Hepatology 2014 vol. 60 | S1–S22 S3
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