- Email: [email protected]
93 RIFAXIMIN IS EFFECTIVE IN MAINTAINING REMISSION IN HEPATIC ENCEPHALOPATHY: RESULTS OF A LARGE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL
S39
Saturday, April 25
GENERAL SESSION 3 & AWARDS CEREMONY 2
93 RIFAXIMIN IS EFFECTIVE IN MAINTAINING REMISSION IN HEPATIC ENCEPHALOPATHY: RESULTS OF A LARGE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL N. Bass1 , K. Mullen2 , S. Sigal3 , A. Sanyal4 , F. Poordad5 , K. Merchant6 , S. Huang6 , A. Shaw6 , E. Bortey6 , W. Forbes6 . 1 University of California San Francisco, San Francisco, CA, 2 Case Western Reserve University, Cleveland, OH, 3 Weill Medical College of Cornell University, New York, New York, 4 Medical College of Virginia, Richmond, VA, 5 CedarsSinai Medical Center, Los Angeles, CA, 6 Salix Pharmaceuticals, Inc, Morrisville, NC, USA E-mail: [email protected] Background and Aims: Previous studies have indicated that the minimally absorbed, gut-selective antibiotic rifaximin is effective in the treatment of hepatic encephalopathy (HE). This multinational trial was designed to assess the efficacy and safety of rifaximin in maintaining remission in patients with a history of HE. Methods: Rifaximin 550 mg twice daily was evaluated in a randomized, double-blind, placebo-controlled trial for 6 months in patients with a history of HE. Patients with cirrhosis who had 2 episodes of HE (Conn score 2) within 6 months prior to screening and were currently in remission (defined as a Conn score = 0 or 1) were enrolled. Continued therapy with lactulose was permitted. The primary endpoint was time to first breakthrough HE episode (increase of Conn score to 2; or a Conn score and asterixis grade increase of 1 each, if baseline Conn score = 0). During the 6-month treatment period, patients were assessed in the clinic and via telephone. Results: A total of 299 patients were randomized to either rifaximin (n = 140) or placebo (n = 159). Demographics and baseline characteristics were similar between the groups. Rifaximin significantly reduced the risk of an HE breakthrough episode by 58% compared to placebo (hazard ratio [HR]=0.421; 95% confidence interval [CI], 0.276−0.641; p < 0.0001). At 6 months, breakthrough HE episodes were experienced by 22% of patients in the rifaximin group and 46% in the placebo group (p < 0.0001), thus, the number needed to treat is 4. Rifaximin treatment also reduced the risk of worsening HE symptoms, as measured by increase from baseline in Conn score (HR = 0.463; 95% CI, 0.312−0.685; p < 0.0001) and asterixis grade (HR = 0.646; 95% CI, 0.414−1.008; p = 0.0523). Additional secondary endpoints and subgroup analyses supported the primary efficacy results. The safety profile of rifaximin was comparable to placebo over the 6-month treatment period. Conclusion: In this large, randomized, controlled trial, rifaximin at a dose of 1100 mg/d provided significant protection against clinical HE breakthrough (58% risk reduction) during the 6-month treatment period. This outcome indicated that treatment of only four patients is required to prevent one case of breakthrough HE.
94 FUNCTIONAL ANALYSIS OF HEPATIC GENE EXPRESSION PROFILING FROM PATIENTS WITH ALCOHOLIC HEPATITIS REVEALS NEW TARGETS FOR THERAPY M. Dom´ınguez1 , J.J. Lozano2 , A. Loaeza1 , R. Miquel3 , J. Colmenero1 , M. Moreno1 , J.-C. Garc´ıa-Pag´an1 , J. Bosch1 , V. Arroyo1 , P. Gin`es1 , R. Bataller1 . 1 Liver Unit, Hospital Cl´ınic, 2 Liver Unit, Centro de Estudos de Investigaci´on Biom´edica en Red de Enfemedades Hep´aticas y Digestivas (CIBERehd), 3 Pathology Unit, Hospital Cl´ınic, Barcelona, Spain E-mail: [email protected] Background and Aims: Alcoholic hepatitis (AH) occurs in subjects with heavy alcohol intake and carries a high short-term mortality. The pathogenesis of AH is poorly understood and current treatments are not fully effective. Therefore, there is a clear need to uncover new pathogenic pathways in order to identify new targets for therapy. We investigated the potential pathways implicated in the pathogenesis AH through a functional analysis of hepatic gene expression profile by the microarray technique in patients with AH. Methods: Patients with biopsy-proven AH were prospectively included. Hepatic expression of 20,000 genes was evaluated by DNA microarrays (chip Affymetrix Hgu133plus2) in RNA isolated from livers of patients with AH (n = 17) and normal livers (n = 7). Functional analysis was assessed by Gene Set Enrichment Analysis (GSEA) program. KEGG (Kyoto Enciclopedia of Gene and Genomics) database was use to identify pathways implicated in AH. LIMMA software was used for identification of groups of genes differentially expressed (FDR < 5%). Quantitative PCR was used to confirm the expression of selected genes. Results: The median age of patients with AH was 49 years and 72% have severe AH (ABIC score 6.71). Unsupervised clustering analysis allowed the differentiation of livers with AH from normal livers (p < 0.001). Gene expression profile analysis revealed 1,262 genes differentially expressed in patients with AH compared to controls. Functional analysis revealed 6 pathways that were differentially expressed in patients with AH: cell communication (24 genes), extracellular matrix (ECM)-receptor interaction (24 genes), focal adhesion (58 genes), cell cycle (49 genes), cytokine-cytokine receptor interaction (33 genes) and GAP junction (15 genes). A detailed analysis of genes belonging to these pathways identified new targets for therapy: osteopontin (fold-expression compared to control: 67.17), IL-8 (11.91), thrombospondin (16.70), HGF (7.83) and TNFRSF12A (10.32); p < 0.0001 compared to control for all. Conclusions: Functional analysis of hepatic gene expression profiling in patients with AH allows the identification of pathways that contain potential targets for therapy. Further studies in experimental models should investigate the functional role of these genes in AH.
Saturday, April 25
GENERAL SESSION 3 & AWARDS CEREMONY 2
93 RIFAXIMIN IS EFFECTIVE IN MAINTAINING REMISSION IN HEPATIC ENCEPHALOPATHY: RESULTS OF A LARGE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL N. Bass1 , K. Mullen2 , S. Sigal3 , A. Sanyal4 , F. Poordad5 , K. Merchant6 , S. Huang6 , A. Shaw6 , E. Bortey6 , W. Forbes6 . 1 University of California San Francisco, San Francisco, CA, 2 Case Western Reserve University, Cleveland, OH, 3 Weill Medical College of Cornell University, New York, New York, 4 Medical College of Virginia, Richmond, VA, 5 CedarsSinai Medical Center, Los Angeles, CA, 6 Salix Pharmaceuticals, Inc, Morrisville, NC, USA E-mail: [email protected] Background and Aims: Previous studies have indicated that the minimally absorbed, gut-selective antibiotic rifaximin is effective in the treatment of hepatic encephalopathy (HE). This multinational trial was designed to assess the efficacy and safety of rifaximin in maintaining remission in patients with a history of HE. Methods: Rifaximin 550 mg twice daily was evaluated in a randomized, double-blind, placebo-controlled trial for 6 months in patients with a history of HE. Patients with cirrhosis who had 2 episodes of HE (Conn score 2) within 6 months prior to screening and were currently in remission (defined as a Conn score = 0 or 1) were enrolled. Continued therapy with lactulose was permitted. The primary endpoint was time to first breakthrough HE episode (increase of Conn score to 2; or a Conn score and asterixis grade increase of 1 each, if baseline Conn score = 0). During the 6-month treatment period, patients were assessed in the clinic and via telephone. Results: A total of 299 patients were randomized to either rifaximin (n = 140) or placebo (n = 159). Demographics and baseline characteristics were similar between the groups. Rifaximin significantly reduced the risk of an HE breakthrough episode by 58% compared to placebo (hazard ratio [HR]=0.421; 95% confidence interval [CI], 0.276−0.641; p < 0.0001). At 6 months, breakthrough HE episodes were experienced by 22% of patients in the rifaximin group and 46% in the placebo group (p < 0.0001), thus, the number needed to treat is 4. Rifaximin treatment also reduced the risk of worsening HE symptoms, as measured by increase from baseline in Conn score (HR = 0.463; 95% CI, 0.312−0.685; p < 0.0001) and asterixis grade (HR = 0.646; 95% CI, 0.414−1.008; p = 0.0523). Additional secondary endpoints and subgroup analyses supported the primary efficacy results. The safety profile of rifaximin was comparable to placebo over the 6-month treatment period. Conclusion: In this large, randomized, controlled trial, rifaximin at a dose of 1100 mg/d provided significant protection against clinical HE breakthrough (58% risk reduction) during the 6-month treatment period. This outcome indicated that treatment of only four patients is required to prevent one case of breakthrough HE.
94 FUNCTIONAL ANALYSIS OF HEPATIC GENE EXPRESSION PROFILING FROM PATIENTS WITH ALCOHOLIC HEPATITIS REVEALS NEW TARGETS FOR THERAPY M. Dom´ınguez1 , J.J. Lozano2 , A. Loaeza1 , R. Miquel3 , J. Colmenero1 , M. Moreno1 , J.-C. Garc´ıa-Pag´an1 , J. Bosch1 , V. Arroyo1 , P. Gin`es1 , R. Bataller1 . 1 Liver Unit, Hospital Cl´ınic, 2 Liver Unit, Centro de Estudos de Investigaci´on Biom´edica en Red de Enfemedades Hep´aticas y Digestivas (CIBERehd), 3 Pathology Unit, Hospital Cl´ınic, Barcelona, Spain E-mail: [email protected] Background and Aims: Alcoholic hepatitis (AH) occurs in subjects with heavy alcohol intake and carries a high short-term mortality. The pathogenesis of AH is poorly understood and current treatments are not fully effective. Therefore, there is a clear need to uncover new pathogenic pathways in order to identify new targets for therapy. We investigated the potential pathways implicated in the pathogenesis AH through a functional analysis of hepatic gene expression profile by the microarray technique in patients with AH. Methods: Patients with biopsy-proven AH were prospectively included. Hepatic expression of 20,000 genes was evaluated by DNA microarrays (chip Affymetrix Hgu133plus2) in RNA isolated from livers of patients with AH (n = 17) and normal livers (n = 7). Functional analysis was assessed by Gene Set Enrichment Analysis (GSEA) program. KEGG (Kyoto Enciclopedia of Gene and Genomics) database was use to identify pathways implicated in AH. LIMMA software was used for identification of groups of genes differentially expressed (FDR < 5%). Quantitative PCR was used to confirm the expression of selected genes. Results: The median age of patients with AH was 49 years and 72% have severe AH (ABIC score 6.71). Unsupervised clustering analysis allowed the differentiation of livers with AH from normal livers (p < 0.001). Gene expression profile analysis revealed 1,262 genes differentially expressed in patients with AH compared to controls. Functional analysis revealed 6 pathways that were differentially expressed in patients with AH: cell communication (24 genes), extracellular matrix (ECM)-receptor interaction (24 genes), focal adhesion (58 genes), cell cycle (49 genes), cytokine-cytokine receptor interaction (33 genes) and GAP junction (15 genes). A detailed analysis of genes belonging to these pathways identified new targets for therapy: osteopontin (fold-expression compared to control: 67.17), IL-8 (11.91), thrombospondin (16.70), HGF (7.83) and TNFRSF12A (10.32); p < 0.0001 compared to control for all. Conclusions: Functional analysis of hepatic gene expression profiling in patients with AH allows the identification of pathways that contain potential targets for therapy. Further studies in experimental models should investigate the functional role of these genes in AH.