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: w.p.brouwer@erasmusmc.nl

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: wedemeyer.heiner@mh-hannover.de

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: tobias.weismueller@gmx.de

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: edgane@adbh.govt.nz

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