- Email: [email protected]
O168 THE FIRST PRIMARY BILIARY CIRRHOSIS (PBC) PHASE 3 TRIAL IN TWO DECADES – AN INTERNATIONAL STUDY OF THE FXR AGONIST OBETICHOLIC ACID IN PBC PATIENTS
LATE BREAKING ABSTRACTS prior null/partial response to peginterferon/ribavirin (null/partial; N = 205), and those medically ineligible for, or previously intolerant of, peginterferon/ribavirin (ineligible/intolerant; N = 235) received DCV+ASV for 24 weeks. Primary endpoint was sustained virologic response at posttreatment Week 12 (SVR12 ). Results: Overall, patients were 49% male, 68% white, and 71% IL28B non-CC; 30% had cirrhosis. SVR12 rates among DCV+ASV-treated patients were 90%, 82%, and 82% in the naive, null/partial, and ineligible/intolerant groups (table). No differences in SVR12 rates were observed based on age, gender, race, or IL28B genotype; SVR12 rates were similar across all groups in noncirrhotic (85%; n = 437) and cirrhotic (84%; n = 206) patients. Serious AEs occurred in 6% and AEs leading to discontinuation (reversible elevated ALT/AST most common) in 2%, with no deaths. Grade 3/4 laboratory abnormalities were uncommon, including low incidences of ALT elevations (first 12 weeks) with DCV+ASV or placebo in naive patients (2% for both). Conclusions: DCV+ASV provided high SVR12 rates of 90% (treatmentnaive) and >80% (null/partial and ineligible/intolerant), including in cirrhotics, and was generally well tolerated in patients with HCV genotype 1b infection.
Results: 158 patients were randomized (83 placebo, 75 simvastatin). Eleven were excluded from the full analysis set. The primary endpoint was met by 30/78 patients in the placebo group and 22/69 in the simvastatin group (NS). Rebleeding rates were 28% in placebo and 25% in simvastatin group (NS). Seventeen (22%) patients died in the placebo group as compared to 6 (9%) in the simvastatin group (p = 0.030). In Child A/B patients (n = 124) mortality decreased from 21% in placebo to 5% in simvastatin (p = 0.003), whereas there was no difference in Child C patients (25% vs 27%; ns). Serious adverse events occurred in 53% and 49% in placebo and simvastatin groups (related to medication in 13% vs 10%, ns). Conclusions: Addition of simvastatin to standard therapy did not improve rebleeding but there was a marked survival benefit with simvastatin, restricted to Child A/B patients.
Table 1. HCV RNA response, n (%) a
SVR12 (mITT; primary endpoint) Cirrhotics Non-cirrhotics Week 4 (RVR) End of treatment Virologic failures Virologic breakthrough Posttreatment relapse d
Treatment naive (N = 203)
Null/partial responders (N = 205) b
Ineligible/intolerant (N = 235) c
182 (90) 29/32 (91) 153/171 (89) 168 (83) 189 (93)
168 (82) 55/63 (87) 113/142 (80) 150 (73) 174 (85)
192 (82) 88/111 (79) 104/124 (84) 159 (68) 204 (87)
9 (4)
26 (13)
20 (9)
5/189 (3)
7/174 (4)
12/204 (6)
a HCV RNA < assay lower limit of quantitation (LLOQ), TD or TND for SVR ;
O167 ADDITION OF SIMVASTATIN TO STANDARD TREATMENT IMPROVES SURVIVAL AFTER VARICEAL BLEEDING IN PATIENTS WITH CIRRHOSIS. A DOUBLE-BLIND RANDOMIZED TRIAL (NCT01095185) J.G. Abraldes1 , C. Villanueva2 , C. Aracil3 , J. Turnes4 , M. HernandezGuerra5 , J. Genesca6 , C.A. Navascues7 , J. Castellote8 , J.L. Calleja9 , A. Albillos10 , J. Bosch1 , BLEPS Study Group. 1 Hospital Clinic. Ciberehd, 2 Hospital de Sant Pau., Barcelona, 3 Hospital Arnau de Vilanova, Lleida, 4 Complejo Hospitalario de Pontevedra, Pontevedra, 5 Hospital Universitario de Canarias, Tenerife, 6 Hospital Vall D’Hebron, Barcelona, 7 Hospital Central de Asturias, Oviedo, 8 Hospital de Bellvitge, Hospitalet de Llobregat, 9 Hospital Puerta de Hierro, 10 Hospital Ramon y Cajal, Madrid, Spain E-mail: [email protected] Background and Aims: Standard therapy to prevent variceal rebleeding is the combination of beta-blockers and banding ligation, but rebleeding and mortality are still high. Simvastatin decreases portal pressure, improves hepatocellular function and may reduce fibrosis. We aimed to assess whether adding simvastatin to standard therapy could improve rebleeding and death. Methods: In this double-blind RCT, patients with cirrhosis (from 14 centers) initiating standard prophylaxis to prevent rebleeding were randomly assigned (stratified by Child: A/B vs C) within 10 days of bleeding to simvastatin (20 mg 15 days, 40 mg thereafter) or placebo. Patients were followed for up to 24 months. Primary endpoint was a composite of rebleeding and death. Key secondary endpoints were death and rebleeding.
O168 THE FIRST PRIMARY BILIARY CIRRHOSIS (PBC) PHASE 3 TRIAL IN TWO DECADES – AN INTERNATIONAL STUDY OF THE FXR AGONIST OBETICHOLIC ACID IN PBC PATIENTS F. Nevens1 , P. Andreone2 , G. Mazzella3 , S. Strasser4 , C. Bowlus5 , P. Invernizzi6 , J. Drenth7 , P. Pockros8 , J. Regula9 , B. Hansen10 , R. Hooshmand-Rad11 , S. Sheeron11 , D. Shapiro11 . 1 UZ Leuven, Leuven, Belgium; 2 Medicina Interna, Dipartimento di Scienze Mediche e Chirurgiche, 3 Dipartimento Scienze Mediche e Chirurgiche, Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; 4 Royal Prince Alfred Hospital, Sydney, NSW, Australia; 5 Univ of CA Davis Medical Center, Sacramento, CA, United States; 6 Liver Unit and Center for Autoimmune Diseases, Humanitas Clinical and Research Center, Rozzano, Italy; 7 Dept. of Gastroenterology & Hepatology (huispost 455), UMC St. Radboud, Nijmegen, Nijmegen, The Netherlands; 8 Scripps Clinic, La Jolla, CA, United States; 9 Cancer Centre, Warsaw, Poland; 10 Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; 11 Intercept Pharmaceuticals, San Diego, CA, United States E-mail: [email protected] Background and Aims: Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid) is a highly potent, selective FXR agonist. In Ph2 PBC studies, 10–50 mg OCA (±UDCA) produced significant biochemical improvement in cholestasis markers. The Global PBC Study Group (GPBCSG) confirms that patients with alkaline phosphatase (ALP) >1.67×ULN or bilirubin >ULN have a greatly increased risk of transplantation or death [HR (95% CI): 2.83 (2.4–3.4); p < 1×10−34 ]. Methods: This was an international, double-blind, placebocontrolled (PBO) trial. PBC patients ± UDCA (if taking UDCA, on a stable dose) with ALP >1.67×ULN or bilirubin <2×ULN were
Journal of Hepatology 2014 vol. 60 | S523–S537
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LATE BREAKING ABSTRACTS randomized to PBO, OCA 5 or 10 mg for 12 months. Patients titrated from 5 mg to 10 mg after 6 mo, if necessary; Pre-study UDCA continued. The primary endpoint was attaining the GPBCSG ALP/Bilirubin goal and ALP reduction ≥15%. Results: All groups were well matched. Mean age: 55.8 yrs, female: 91%, Caucasian: 94%. The median UDCA dose was 15.3 mg/kg; 7% were UDCA-intolerant. Overall, 91% of patients completed the study. OCA was superior to PBO: A statistically greater proportion of OCA-treated patients achieved the ALP/Bili response criteria. Further data will be presented at the conference. Conclusions: OCA given to patients with an inadequate response to or unable to tolerate UDCA produced clinically and statistically meaningful biochemical improvements which have been shown to be strongly correlated with clinical benefit. O169 RIFAXIMIN VERSUS LACTULOSE IN THE TREATMENT OF MINIMAL HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS: A PROSPECTIVE, RANDOMIZED, ACTIVE-COMPARATOR, NON-INFERIORITY TRIAL O. Goyal1 , S.S. Sidhu1 , R.A. Parker2 , J. Prasad3 , H. Kishore1 , A. Sood1 , V. Mehta1 , R.S. Chhina1 . 1 Gastroenterology, D.M.C. and Hospital, Ludhiana, India; 2 University of Edinburgh, Edinburgh, United Kingdom; 3 Community Medicine Department, Christian Medical College, Vellore, India E-mail: [email protected] Background and Aims: Minimal hepatic encephalopathy (MHE) in cirrhotics has a significant impact on health related quality of life (HRQOL). Treatment of MHE is under evolution. We aimed to compare the efficacy of rifaximin versus lactulose in improving neuropsychometric (NP) test performance (primary outcome measure) and HRQOL in patients with MHE. Methods: In this prospective, randomized, single-blinded, noninferiority trial (registration no. CTRI/2009/091/000979), MHE was diagnosed if any two NP tests (number/figure connection tests, picture completion, digit symbol, and block design) were deranged beyond 2 standard deviations of normal. HRQOL was assessed using sickness impact profile (SIP) questionnaire (Johns Hopkins University, USA). Total sample size of 112 patients was required for 80% power, a = 0.05 and non-inferiority margin of −5% for MHE reversal (Rifaximin–Lactulose). Statistical analysis using SAS software version 9.3. Results: Out of 527 cirrhotics screened, 351 were found eligible and tested for MHE. Out of these, 112 (31.9%) had MHE, and were randomized to receive lactulose (n = 55; 30–120 ml/day) or rifaximin (n = 57; 1200 mg/day) for 3 months. By intention-to-treat analysis, proportion of patients with MHE reversal at 3 months was similar in lactulose and rifaximin groups [67.2% (37/55) vs. 64.9% (37/57); −2.3% difference, 90% CI: −16.2% to 11.6%]. Both groups showed significant improvement in HRQOL; rifaximin being non-inferior to lactulose. Also, rifaximin has greater costeffectiveness as compared to lactulose. Both groups had similar frequency of adverse effects. Conclusions: Although rifaximin and lactulose had similar rates of MHE reversal, the non-inferiority of rifaximin over lactulose for MHE reversal could not be established. However, rifaximin was non-inferior to lactulose in improvement of HRQOL, and also more cost-effective than lactulose.
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O170 DYSREGULATED UNFOLDED PROTEIN RESPONSE CONTROL IN THE ABSENCE OF CANONICAL IKK/NF-úB SIGNALLING LEADS TO SEVERE LIVER DAMAGE AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA 1 Y. Sunami1,2 , M. Ringelhan3,4 , M. Lu1 , N. Huser ¨ , E. Kakai2 , 5 F. Leithauser ¨ , J. Kleeff1 , D. Hartmann1 , S. Gul2 , S. Wissel2 , 3,4 C. Brunner2 , P. Riedl6 , R. Schirmbeck6 , P. Strnad7 , M. Heikenwalder ¨ , T. Wirth2 . 1 General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, 2 Institute of Physiological Chemistry, University of Ulm, Ulm, 3 Institute of Virology, Technical University Munich, 4 Helmholtz Zentrum Munich, Munich, 5 Institute of Pathology, 6 Department of Internal Medicine I, University Medical Center Ulm, Ulm, 7 Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany E-mail: [email protected] Background and Aims: The NF-úB transcription factors are constitutively activated in many tumours, where they are thought to provide a critical survival signal for cancer cells. Accordingly, an inhibition of NF-úB is considered a potential approach in antitumour therapy. Here we investigate the role of NF-úB signalling in hepatocytes and immune cells using animals overexpressing hepatitis B virus surface antigen (HBsAg), an established model of virus-induced hepatocarcinogenesis. Methods: HBsAg-overexpressing mice were crossed with animals overexpressing a dominant negative mutant of IKK2 (upstream kinase in canonical NF-úB signalling) under the control of tetracycline-inducible LAP-promoter (hepatocellular canonical NF-úB inactivation) or with constitutive MyD88 knockouts. Results: When the hepatic canonical NF-úB pathway is inhibited, the animals developed a more pronounced hepatocellular carcinoma than the single HBsAg transgenes. Furthermore, the HBsAg with NF-úB inhibition displayed significantly higher extent of liver damage as indicated by transaminase levels, as well as higher proliferation rates. Similarly, double-transgenic MyD88 knockout/HBsAg mice displayed both higher extent of liver damage and accelerated tumour development compared to the single HBsAg transgenes. HBsAg transgene expression in combination with inhibition of canonical NF-úB signalling, but not with MyD88-deficiency, leads to dysregulation of unfolded protein response control, including upregulation of ER-stress marker CHOP. Conclusions: In HBsAg-overexpressing mice, NF-úB signalling in both hepatocytes and immune cells protects from hepatocarcinogenesis, yet due to different mechanisms. Inhibition of canonical NF-úB leads to activation of ER stress, an increased cellular damage and cellular turnover, and compensatory hyperproliferation, which in turn accelerates the carcinogenesis.
Journal of Hepatology 2014 vol. 60 | S523–S537
Results: 158 patients were randomized (83 placebo, 75 simvastatin). Eleven were excluded from the full analysis set. The primary endpoint was met by 30/78 patients in the placebo group and 22/69 in the simvastatin group (NS). Rebleeding rates were 28% in placebo and 25% in simvastatin group (NS). Seventeen (22%) patients died in the placebo group as compared to 6 (9%) in the simvastatin group (p = 0.030). In Child A/B patients (n = 124) mortality decreased from 21% in placebo to 5% in simvastatin (p = 0.003), whereas there was no difference in Child C patients (25% vs 27%; ns). Serious adverse events occurred in 53% and 49% in placebo and simvastatin groups (related to medication in 13% vs 10%, ns). Conclusions: Addition of simvastatin to standard therapy did not improve rebleeding but there was a marked survival benefit with simvastatin, restricted to Child A/B patients.
Table 1. HCV RNA response, n (%) a
SVR12 (mITT; primary endpoint) Cirrhotics Non-cirrhotics Week 4 (RVR) End of treatment Virologic failures Virologic breakthrough Posttreatment relapse d
Treatment naive (N = 203)
Null/partial responders (N = 205) b
Ineligible/intolerant (N = 235) c
182 (90) 29/32 (91) 153/171 (89) 168 (83) 189 (93)
168 (82) 55/63 (87) 113/142 (80) 150 (73) 174 (85)
192 (82) 88/111 (79) 104/124 (84) 159 (68) 204 (87)
9 (4)
26 (13)
20 (9)
5/189 (3)
7/174 (4)
12/204 (6)
a HCV RNA < assay lower limit of quantitation (LLOQ), TD or TND for SVR ;
O167 ADDITION OF SIMVASTATIN TO STANDARD TREATMENT IMPROVES SURVIVAL AFTER VARICEAL BLEEDING IN PATIENTS WITH CIRRHOSIS. A DOUBLE-BLIND RANDOMIZED TRIAL (NCT01095185) J.G. Abraldes1 , C. Villanueva2 , C. Aracil3 , J. Turnes4 , M. HernandezGuerra5 , J. Genesca6 , C.A. Navascues7 , J. Castellote8 , J.L. Calleja9 , A. Albillos10 , J. Bosch1 , BLEPS Study Group. 1 Hospital Clinic. Ciberehd, 2 Hospital de Sant Pau., Barcelona, 3 Hospital Arnau de Vilanova, Lleida, 4 Complejo Hospitalario de Pontevedra, Pontevedra, 5 Hospital Universitario de Canarias, Tenerife, 6 Hospital Vall D’Hebron, Barcelona, 7 Hospital Central de Asturias, Oviedo, 8 Hospital de Bellvitge, Hospitalet de Llobregat, 9 Hospital Puerta de Hierro, 10 Hospital Ramon y Cajal, Madrid, Spain E-mail: [email protected] Background and Aims: Standard therapy to prevent variceal rebleeding is the combination of beta-blockers and banding ligation, but rebleeding and mortality are still high. Simvastatin decreases portal pressure, improves hepatocellular function and may reduce fibrosis. We aimed to assess whether adding simvastatin to standard therapy could improve rebleeding and death. Methods: In this double-blind RCT, patients with cirrhosis (from 14 centers) initiating standard prophylaxis to prevent rebleeding were randomly assigned (stratified by Child: A/B vs C) within 10 days of bleeding to simvastatin (20 mg 15 days, 40 mg thereafter) or placebo. Patients were followed for up to 24 months. Primary endpoint was a composite of rebleeding and death. Key secondary endpoints were death and rebleeding.
O168 THE FIRST PRIMARY BILIARY CIRRHOSIS (PBC) PHASE 3 TRIAL IN TWO DECADES – AN INTERNATIONAL STUDY OF THE FXR AGONIST OBETICHOLIC ACID IN PBC PATIENTS F. Nevens1 , P. Andreone2 , G. Mazzella3 , S. Strasser4 , C. Bowlus5 , P. Invernizzi6 , J. Drenth7 , P. Pockros8 , J. Regula9 , B. Hansen10 , R. Hooshmand-Rad11 , S. Sheeron11 , D. Shapiro11 . 1 UZ Leuven, Leuven, Belgium; 2 Medicina Interna, Dipartimento di Scienze Mediche e Chirurgiche, 3 Dipartimento Scienze Mediche e Chirurgiche, Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; 4 Royal Prince Alfred Hospital, Sydney, NSW, Australia; 5 Univ of CA Davis Medical Center, Sacramento, CA, United States; 6 Liver Unit and Center for Autoimmune Diseases, Humanitas Clinical and Research Center, Rozzano, Italy; 7 Dept. of Gastroenterology & Hepatology (huispost 455), UMC St. Radboud, Nijmegen, Nijmegen, The Netherlands; 8 Scripps Clinic, La Jolla, CA, United States; 9 Cancer Centre, Warsaw, Poland; 10 Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; 11 Intercept Pharmaceuticals, San Diego, CA, United States E-mail: [email protected] Background and Aims: Obeticholic acid (OCA, 6-ethyl chenodeoxycholic acid) is a highly potent, selective FXR agonist. In Ph2 PBC studies, 10–50 mg OCA (±UDCA) produced significant biochemical improvement in cholestasis markers. The Global PBC Study Group (GPBCSG) confirms that patients with alkaline phosphatase (ALP) >1.67×ULN or bilirubin >ULN have a greatly increased risk of transplantation or death [HR (95% CI): 2.83 (2.4–3.4); p < 1×10−34 ]. Methods: This was an international, double-blind, placebocontrolled (PBO) trial. PBC patients ± UDCA (if taking UDCA, on a stable dose) with ALP >1.67×ULN or bilirubin <2×ULN were
Journal of Hepatology 2014 vol. 60 | S523–S537
S525
LATE BREAKING ABSTRACTS randomized to PBO, OCA 5 or 10 mg for 12 months. Patients titrated from 5 mg to 10 mg after 6 mo, if necessary; Pre-study UDCA continued. The primary endpoint was attaining the GPBCSG ALP/Bilirubin goal and ALP reduction ≥15%. Results: All groups were well matched. Mean age: 55.8 yrs, female: 91%, Caucasian: 94%. The median UDCA dose was 15.3 mg/kg; 7% were UDCA-intolerant. Overall, 91% of patients completed the study. OCA was superior to PBO: A statistically greater proportion of OCA-treated patients achieved the ALP/Bili response criteria. Further data will be presented at the conference. Conclusions: OCA given to patients with an inadequate response to or unable to tolerate UDCA produced clinically and statistically meaningful biochemical improvements which have been shown to be strongly correlated with clinical benefit. O169 RIFAXIMIN VERSUS LACTULOSE IN THE TREATMENT OF MINIMAL HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS: A PROSPECTIVE, RANDOMIZED, ACTIVE-COMPARATOR, NON-INFERIORITY TRIAL O. Goyal1 , S.S. Sidhu1 , R.A. Parker2 , J. Prasad3 , H. Kishore1 , A. Sood1 , V. Mehta1 , R.S. Chhina1 . 1 Gastroenterology, D.M.C. and Hospital, Ludhiana, India; 2 University of Edinburgh, Edinburgh, United Kingdom; 3 Community Medicine Department, Christian Medical College, Vellore, India E-mail: [email protected] Background and Aims: Minimal hepatic encephalopathy (MHE) in cirrhotics has a significant impact on health related quality of life (HRQOL). Treatment of MHE is under evolution. We aimed to compare the efficacy of rifaximin versus lactulose in improving neuropsychometric (NP) test performance (primary outcome measure) and HRQOL in patients with MHE. Methods: In this prospective, randomized, single-blinded, noninferiority trial (registration no. CTRI/2009/091/000979), MHE was diagnosed if any two NP tests (number/figure connection tests, picture completion, digit symbol, and block design) were deranged beyond 2 standard deviations of normal. HRQOL was assessed using sickness impact profile (SIP) questionnaire (Johns Hopkins University, USA). Total sample size of 112 patients was required for 80% power, a = 0.05 and non-inferiority margin of −5% for MHE reversal (Rifaximin–Lactulose). Statistical analysis using SAS software version 9.3. Results: Out of 527 cirrhotics screened, 351 were found eligible and tested for MHE. Out of these, 112 (31.9%) had MHE, and were randomized to receive lactulose (n = 55; 30–120 ml/day) or rifaximin (n = 57; 1200 mg/day) for 3 months. By intention-to-treat analysis, proportion of patients with MHE reversal at 3 months was similar in lactulose and rifaximin groups [67.2% (37/55) vs. 64.9% (37/57); −2.3% difference, 90% CI: −16.2% to 11.6%]. Both groups showed significant improvement in HRQOL; rifaximin being non-inferior to lactulose. Also, rifaximin has greater costeffectiveness as compared to lactulose. Both groups had similar frequency of adverse effects. Conclusions: Although rifaximin and lactulose had similar rates of MHE reversal, the non-inferiority of rifaximin over lactulose for MHE reversal could not be established. However, rifaximin was non-inferior to lactulose in improvement of HRQOL, and also more cost-effective than lactulose.
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O170 DYSREGULATED UNFOLDED PROTEIN RESPONSE CONTROL IN THE ABSENCE OF CANONICAL IKK/NF-úB SIGNALLING LEADS TO SEVERE LIVER DAMAGE AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA 1 Y. Sunami1,2 , M. Ringelhan3,4 , M. Lu1 , N. Huser ¨ , E. Kakai2 , 5 F. Leithauser ¨ , J. Kleeff1 , D. Hartmann1 , S. Gul2 , S. Wissel2 , 3,4 C. Brunner2 , P. Riedl6 , R. Schirmbeck6 , P. Strnad7 , M. Heikenwalder ¨ , T. Wirth2 . 1 General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, 2 Institute of Physiological Chemistry, University of Ulm, Ulm, 3 Institute of Virology, Technical University Munich, 4 Helmholtz Zentrum Munich, Munich, 5 Institute of Pathology, 6 Department of Internal Medicine I, University Medical Center Ulm, Ulm, 7 Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany E-mail: [email protected] Background and Aims: The NF-úB transcription factors are constitutively activated in many tumours, where they are thought to provide a critical survival signal for cancer cells. Accordingly, an inhibition of NF-úB is considered a potential approach in antitumour therapy. Here we investigate the role of NF-úB signalling in hepatocytes and immune cells using animals overexpressing hepatitis B virus surface antigen (HBsAg), an established model of virus-induced hepatocarcinogenesis. Methods: HBsAg-overexpressing mice were crossed with animals overexpressing a dominant negative mutant of IKK2 (upstream kinase in canonical NF-úB signalling) under the control of tetracycline-inducible LAP-promoter (hepatocellular canonical NF-úB inactivation) or with constitutive MyD88 knockouts. Results: When the hepatic canonical NF-úB pathway is inhibited, the animals developed a more pronounced hepatocellular carcinoma than the single HBsAg transgenes. Furthermore, the HBsAg with NF-úB inhibition displayed significantly higher extent of liver damage as indicated by transaminase levels, as well as higher proliferation rates. Similarly, double-transgenic MyD88 knockout/HBsAg mice displayed both higher extent of liver damage and accelerated tumour development compared to the single HBsAg transgenes. HBsAg transgene expression in combination with inhibition of canonical NF-úB signalling, but not with MyD88-deficiency, leads to dysregulation of unfolded protein response control, including upregulation of ER-stress marker CHOP. Conclusions: In HBsAg-overexpressing mice, NF-úB signalling in both hepatocytes and immune cells protects from hepatocarcinogenesis, yet due to different mechanisms. Inhibition of canonical NF-úB leads to activation of ER stress, an increased cellular damage and cellular turnover, and compensatory hyperproliferation, which in turn accelerates the carcinogenesis.
Journal of Hepatology 2014 vol. 60 | S523–S537