- Email: [email protected]
Treatment and prognosis of acute severe autoimmune hepatitis
ORAL PRESENTATIONS 12 Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 13Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, United States E-mail: [email protected]
Background and Aims: Combinations of first-generation antiviral agents (DAAs) have been effective in treating HCV infection. However, these regimens are not equally potent across all HCV genotypes and patient populations, and may require the use of ribavirin (RBV) to increase efficacy or shorten treatment duration. The once-daily, oral, RBV-free, pangenotypic DAA regimen consisting of the NS3/4A protease inhibitor glecaprevir (GLE, formerly ABT-493, identified by AbbVie and Enanta) and the NS5A inhibitor pibrentasvir (PIB, formerly ABT-530), collectively G/P, demonstrated high rates of sustained virologic response (SVR) in phase 2 studies. The objective of the phase 3 EXPEDITION-1 study is to evaluate the efficacy and safety of 12 weeks of G/P in patients with HCV GT 1, 2, 4, 5 or 6 infection and compensated cirrhosis. Methods: EXPEDITION-1 is a phase 3, single arm, multicenter, openlabel study evaluating the efficacy and safety of G/P in adults with chronic HCV GT1, 2, 4, 5 or 6 infection and compensated cirrhosis who are either HCV treatment-naïve or treatment-experienced (with IFN/pegIFN ± RBV, or sofosbuvir + RBV±pegIFN). Patients received G/P (300 mg/120 mg) once daily for 12 weeks. The primary efficacy variable was SVR at 12 weeks post treatment (SVR12). Safety was assessed in all patients who received at least 1 dose of study drug. Results: A total of 146 patients were enrolled in the study; 25% had prior treatment experience. Patients had either HCV GT1 (59.6%), GT2 (23.3%), GT4 (11.0%), GT5 (1.4%) or GT6 (4.8%) infection. SVR12 was achieved by 145/146 (99.3%) patients, with one GT1a-infected patient experiencing relapse at post-treatment week 8. The majority of AEs were mild (65%). The most common AEs (≥10%) were fatigue and headache. Of the 11 patients (7.5%) who experienced serious AEs, none were deemed related to study drugs. One patient died post-treatment due to an AE not related to study drug (cerebral hemorrhage). One patient with a previous history of esophageal varices experienced esophageal variceal bleeding on Day 22 without worsening of hepatic function. No discontinuations of study drug due to adverse events occurred and no subject had ≥Grade 3 ALT elevations. Conclusions: SVR12 was achieved by 99.3% of patients with GT1, 2, 4, 5 or 6 HCV infection and compensated cirrhosis treated with G/P for 12 weeks, supporting the pangenotypic efficacy of the regimen. The regimen was well tolerated, with mostly mild AEs reported, and no serious AEs were considered study-drug related.
Autoimmune and cholestatic liver disease I PS-001 Treatment and prognosis of acute severe autoimmune hepatitis E. De Martin1, A. Coilly2, P. Houssel-Debry3, I. Ollivier-Hourmand4, A. Heurgue-Berlot5, F. Artru6, S. Barge7, O. Chazouilleres8, C. Silvain9, C. Duvoux10, G.-P. Pageaux11, C. Besch12, M. Bourlière13, H. Fontaine14, V. de Ledinghen15, J. Dumortier16, F. Conti17, S. Radenne18, M. Debette-Gratien19, O. Goria20, J. Boursier21, J.-M. Peron22, F. Durand23, P. Borrentain24, P. Potier25, A. Minello26, A. Abergel27, J.-M. Perarnau28, J.-B. Nousbaum29, M. Rudler30, L. Alric31, R. Anty32, N. Sturm33, M. Sebagh34, H. Agostini35, D. Samuel1, J.-C. Duclos-Vallée1 and FILFOIE consortium. 1Centre Hépato-Biliaire and APHP hôpital Paul Brousse, Villejuif; 2Centre Hépato-Biliaire, APHP Hopital Paul Brousse, Paris; 3CHU Rennes, Rennes; 4CHU Caen, Caen; 5 CHU Reims, Reims; 6CHU Lille, Lille; 7CHU Jean Verdier, Bondy; 8CHU St Antoine, Paris; 9CHU Poitiers, Poitiers; 10CHU Mondor, Creteil; 11CHU
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Montpellier, Montpellier; 12CHU Strasbourg, Strasbourg; 13Hôpital St Joseph, Marseille; 14CHU Cochin, Paris; 15CHU Bordeaux, Bordeaux; 16 Hôpital Edouard Herriot, Lyon; 17Service de transplantation hépatique, Pitié Salpetriere, Paris; 18Hôpital de la Croix Rousse, Lyon; 19 CHU Limoges, Limoges; 20CHU Rouen, Rouen; 21CHU Angers, Angers; 22 Hepatogastroenterologie, Hôpital Purpan, Toulouse; 23CHU Beaujon, Paris; 24Hôpital de la Timone, Marseille; 25CHU Orleans, Orleans; 26 CHU Dijon, Dijon; 27CHU Clermand-Ferrant, Clermand-Ferrant; 28CHU Tours, Tours; 29CHU Brest, Brest; 30Pitié Salpetriere, Paris; 31Médecine interne et Hepatogastroenterologie, CHU Toulouse, Toulouse; 32CHU Nice, Nice; 33Anatomie et cytologie pathologique, CHU Grenoble, Grenoble; 34Anatomie et cytologie pathologiques, APHP hôpital Paul Brousse, Villejuif; 35Unité de Recherche Clinique des Hôpitaux universitaires Paris Sud, Paris, France E-mail: [email protected] Background and Aims: Acute severe autoimmune hepatitis (AS-AIH) is a heterogeneous disease leading to a challenging management. Main issue is the steroids benefit. The aim wasto describe AS-AIH establishing predictive factors of steroids response. Methods: Multicenter retrospective study conducted in 18 French centers from 2010 to 2015. Inclusion criteria were 1. No previous medical history of AIH 2. Biopsy-proven or native liver-proven AIH 3. IAIHG (International AutoImmune Hepatitis Group) score definite or probable 4. PT < 50% or INR > 1.5 5. In the absence of 4th criteria bilirubin >200 µmol/L. Fibrosis stage was evaluated according to METAVIR score. The response to steroids therapy was defined by survival without liver transplantation (LT). Results: One hundred and four pts were included, 75 (72%) female, median age: 53 [18–89] years. At admission: 9 (9%) pts had hepatic encephalopathy and 15 (14%) clinical ascites. Biology was: total bilirubin 250 [16–748] µmol/L, ALT 996 [41–3581] IU/L, INR 2.3 [1.3–9] and creatinine 62 µmol/dL (50–369). Median MELD score was 27 [15–40]. Ninety-four (90%) pts underwent liver biopsy before therapy decision. Cirrhosis was detected in 19% of pts. Median IgG level was 22.5 g/L [1.2–60.5], ANA > 1:80 n = 48 (46%), ASMA > 1:80 n = 43 (41%). Nine (9%) pts underwent LT and 1 died. Ninety-four (90%) pts underwent steroids therapy with a median time since admission of 6 [0–29] days. Among them, 25 (27%) underwent LT (median time of 12 [2–319] days since steroids therapy) and 7 (7%) died. Sixty-two (66%) pts responded with a median decline of MELD score of 4 [1–6], between day 0 and 7 of therapy (delta). Factors significantly associated with steroids response were INR at admission ( p = 0.0001) and improvement of delta-INR ( p = <0.0001), deltabilirubin ( p = 0.0166) and delta-MELD ( p = 0.0152). Infection occurred in 25 (24%) pts with median time of 5 [−9 to 33] days, among them 3 died within the first month. Overall survival was 90% with a median follow-up of 2.3 [1–6.9] years. LT-free survival at 7, 15 and 30 days was 90%, 78% and 60% respectively. Late LT (11 months) was performed in 1 patient. Conclusions: This study is the largest cohort of AS-AIH including 104 pts. Despite their serious condition, overall survival was 90%. However, early LT was required for one third of our pts. Steroids therapy was effective in 66% of pts. Their beneficial effect was mainly observed in pts with low INR at admission and with the improvement of hepatic function during the first 7 days of therapy. PS-002 Common variation near glial-derived neurotrophic factor is associated with progression of hepatic collagen content in a genome-wide association study of liver fibrosis phenotypes in patients with primary sclerosing cholangitis P. Shea1, G. Hirschfield2, M. Shiffman3, B. McColgan4, Z. Goodman5, R. Myers4, M. Subramanian4, B. Eksteen6, H. Janssen7, C. Bowlus8, A. Muir9, A. Montano-Loza10, J. McHutchison4, M. Manns11, R. Chapman12, S. Kleinstein1, C. Levy13, D. Goldstein1. 1Institute for Genomic Medicine, Columbia University, New York, United States; 2 Center for Liver Research, NIHR Biomedical Research Unit, Birmingham,
Journal of Hepatology 2017 vol. 66 | S1–S32
Background and Aims: Combinations of first-generation antiviral agents (DAAs) have been effective in treating HCV infection. However, these regimens are not equally potent across all HCV genotypes and patient populations, and may require the use of ribavirin (RBV) to increase efficacy or shorten treatment duration. The once-daily, oral, RBV-free, pangenotypic DAA regimen consisting of the NS3/4A protease inhibitor glecaprevir (GLE, formerly ABT-493, identified by AbbVie and Enanta) and the NS5A inhibitor pibrentasvir (PIB, formerly ABT-530), collectively G/P, demonstrated high rates of sustained virologic response (SVR) in phase 2 studies. The objective of the phase 3 EXPEDITION-1 study is to evaluate the efficacy and safety of 12 weeks of G/P in patients with HCV GT 1, 2, 4, 5 or 6 infection and compensated cirrhosis. Methods: EXPEDITION-1 is a phase 3, single arm, multicenter, openlabel study evaluating the efficacy and safety of G/P in adults with chronic HCV GT1, 2, 4, 5 or 6 infection and compensated cirrhosis who are either HCV treatment-naïve or treatment-experienced (with IFN/pegIFN ± RBV, or sofosbuvir + RBV±pegIFN). Patients received G/P (300 mg/120 mg) once daily for 12 weeks. The primary efficacy variable was SVR at 12 weeks post treatment (SVR12). Safety was assessed in all patients who received at least 1 dose of study drug. Results: A total of 146 patients were enrolled in the study; 25% had prior treatment experience. Patients had either HCV GT1 (59.6%), GT2 (23.3%), GT4 (11.0%), GT5 (1.4%) or GT6 (4.8%) infection. SVR12 was achieved by 145/146 (99.3%) patients, with one GT1a-infected patient experiencing relapse at post-treatment week 8. The majority of AEs were mild (65%). The most common AEs (≥10%) were fatigue and headache. Of the 11 patients (7.5%) who experienced serious AEs, none were deemed related to study drugs. One patient died post-treatment due to an AE not related to study drug (cerebral hemorrhage). One patient with a previous history of esophageal varices experienced esophageal variceal bleeding on Day 22 without worsening of hepatic function. No discontinuations of study drug due to adverse events occurred and no subject had ≥Grade 3 ALT elevations. Conclusions: SVR12 was achieved by 99.3% of patients with GT1, 2, 4, 5 or 6 HCV infection and compensated cirrhosis treated with G/P for 12 weeks, supporting the pangenotypic efficacy of the regimen. The regimen was well tolerated, with mostly mild AEs reported, and no serious AEs were considered study-drug related.
Autoimmune and cholestatic liver disease I PS-001 Treatment and prognosis of acute severe autoimmune hepatitis E. De Martin1, A. Coilly2, P. Houssel-Debry3, I. Ollivier-Hourmand4, A. Heurgue-Berlot5, F. Artru6, S. Barge7, O. Chazouilleres8, C. Silvain9, C. Duvoux10, G.-P. Pageaux11, C. Besch12, M. Bourlière13, H. Fontaine14, V. de Ledinghen15, J. Dumortier16, F. Conti17, S. Radenne18, M. Debette-Gratien19, O. Goria20, J. Boursier21, J.-M. Peron22, F. Durand23, P. Borrentain24, P. Potier25, A. Minello26, A. Abergel27, J.-M. Perarnau28, J.-B. Nousbaum29, M. Rudler30, L. Alric31, R. Anty32, N. Sturm33, M. Sebagh34, H. Agostini35, D. Samuel1, J.-C. Duclos-Vallée1 and FILFOIE consortium. 1Centre Hépato-Biliaire and APHP hôpital Paul Brousse, Villejuif; 2Centre Hépato-Biliaire, APHP Hopital Paul Brousse, Paris; 3CHU Rennes, Rennes; 4CHU Caen, Caen; 5 CHU Reims, Reims; 6CHU Lille, Lille; 7CHU Jean Verdier, Bondy; 8CHU St Antoine, Paris; 9CHU Poitiers, Poitiers; 10CHU Mondor, Creteil; 11CHU
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Montpellier, Montpellier; 12CHU Strasbourg, Strasbourg; 13Hôpital St Joseph, Marseille; 14CHU Cochin, Paris; 15CHU Bordeaux, Bordeaux; 16 Hôpital Edouard Herriot, Lyon; 17Service de transplantation hépatique, Pitié Salpetriere, Paris; 18Hôpital de la Croix Rousse, Lyon; 19 CHU Limoges, Limoges; 20CHU Rouen, Rouen; 21CHU Angers, Angers; 22 Hepatogastroenterologie, Hôpital Purpan, Toulouse; 23CHU Beaujon, Paris; 24Hôpital de la Timone, Marseille; 25CHU Orleans, Orleans; 26 CHU Dijon, Dijon; 27CHU Clermand-Ferrant, Clermand-Ferrant; 28CHU Tours, Tours; 29CHU Brest, Brest; 30Pitié Salpetriere, Paris; 31Médecine interne et Hepatogastroenterologie, CHU Toulouse, Toulouse; 32CHU Nice, Nice; 33Anatomie et cytologie pathologique, CHU Grenoble, Grenoble; 34Anatomie et cytologie pathologiques, APHP hôpital Paul Brousse, Villejuif; 35Unité de Recherche Clinique des Hôpitaux universitaires Paris Sud, Paris, France E-mail: [email protected] Background and Aims: Acute severe autoimmune hepatitis (AS-AIH) is a heterogeneous disease leading to a challenging management. Main issue is the steroids benefit. The aim wasto describe AS-AIH establishing predictive factors of steroids response. Methods: Multicenter retrospective study conducted in 18 French centers from 2010 to 2015. Inclusion criteria were 1. No previous medical history of AIH 2. Biopsy-proven or native liver-proven AIH 3. IAIHG (International AutoImmune Hepatitis Group) score definite or probable 4. PT < 50% or INR > 1.5 5. In the absence of 4th criteria bilirubin >200 µmol/L. Fibrosis stage was evaluated according to METAVIR score. The response to steroids therapy was defined by survival without liver transplantation (LT). Results: One hundred and four pts were included, 75 (72%) female, median age: 53 [18–89] years. At admission: 9 (9%) pts had hepatic encephalopathy and 15 (14%) clinical ascites. Biology was: total bilirubin 250 [16–748] µmol/L, ALT 996 [41–3581] IU/L, INR 2.3 [1.3–9] and creatinine 62 µmol/dL (50–369). Median MELD score was 27 [15–40]. Ninety-four (90%) pts underwent liver biopsy before therapy decision. Cirrhosis was detected in 19% of pts. Median IgG level was 22.5 g/L [1.2–60.5], ANA > 1:80 n = 48 (46%), ASMA > 1:80 n = 43 (41%). Nine (9%) pts underwent LT and 1 died. Ninety-four (90%) pts underwent steroids therapy with a median time since admission of 6 [0–29] days. Among them, 25 (27%) underwent LT (median time of 12 [2–319] days since steroids therapy) and 7 (7%) died. Sixty-two (66%) pts responded with a median decline of MELD score of 4 [1–6], between day 0 and 7 of therapy (delta). Factors significantly associated with steroids response were INR at admission ( p = 0.0001) and improvement of delta-INR ( p = <0.0001), deltabilirubin ( p = 0.0166) and delta-MELD ( p = 0.0152). Infection occurred in 25 (24%) pts with median time of 5 [−9 to 33] days, among them 3 died within the first month. Overall survival was 90% with a median follow-up of 2.3 [1–6.9] years. LT-free survival at 7, 15 and 30 days was 90%, 78% and 60% respectively. Late LT (11 months) was performed in 1 patient. Conclusions: This study is the largest cohort of AS-AIH including 104 pts. Despite their serious condition, overall survival was 90%. However, early LT was required for one third of our pts. Steroids therapy was effective in 66% of pts. Their beneficial effect was mainly observed in pts with low INR at admission and with the improvement of hepatic function during the first 7 days of therapy. PS-002 Common variation near glial-derived neurotrophic factor is associated with progression of hepatic collagen content in a genome-wide association study of liver fibrosis phenotypes in patients with primary sclerosing cholangitis P. Shea1, G. Hirschfield2, M. Shiffman3, B. McColgan4, Z. Goodman5, R. Myers4, M. Subramanian4, B. Eksteen6, H. Janssen7, C. Bowlus8, A. Muir9, A. Montano-Loza10, J. McHutchison4, M. Manns11, R. Chapman12, S. Kleinstein1, C. Levy13, D. Goldstein1. 1Institute for Genomic Medicine, Columbia University, New York, United States; 2 Center for Liver Research, NIHR Biomedical Research Unit, Birmingham,
Journal of Hepatology 2017 vol. 66 | S1–S32