Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome:Results from The GALA Study

BACKGROUND: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (&gt;6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and &lt;10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those &lt;5.0 mg/dL. Median TB levels between ≥5.0 and &lt;10.0 mg/dL and &gt;10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to &lt;5.0 mg/dL. Median TB &lt;5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p&lt;0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB &lt;5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.</p

SURGICAL BILIARY DIVERSION IS ASSOCIATED WITH AN INCREASED RISK OF LIVER TRANSPLANTATION OR DEATH IN ALAGILLE SYNDROME

SURGICAL BILIARY DIVERSION IS ASSOCIATED WITH AN INCREASED RISK OF LIVER TRANSPLANTATION OR DEATH INALAGILLE SYNDROME★ Shannon M. Vandriel1, Kathleen M. Loomes2, David A.Piccoli3, Elizabeth Rand3, Li-Ting Li4, Huiyu She4, JianShe Wang4, Rima L. Fawaz5, Silvia Nastasio6, Henkjan J.Verkade7, M. Kyle Jensen8, Catalina Jaramillo8, Nathalie Rock9, Irena Jankowska10, Piotr Czubkowski10, Dorota Gliwicz-Miedzińska10, Henry C. Lin11, Deirdre A. Kelly12, Catherine Larson-Nath13, Florence Lacaille14, Dominique Debray15, Saul Karpen16, Rene Romero17, Cristina Molera Busoms18, Étienne M. Sokal19, Tanguy Demaret19, Nehal M. El-Koofy20, Mohamed A. Elmonem20, Shikha S. Sundaram21, Alexander Chaidez21, Palaniswamy Karthikeyan22, Wikrom Karnsakul23, Winita Hardikar24, Sahana Shankar25, Ruben E. Quiros-Tejeira26, Seema Alam27, Pinar Bulut28, Christina Hajinicolaou29, Victorien M. Wolters30, Zerrin Önal31, Emmanuel M. Gonzales32, Emmanuel Jacquemin32, Jérôme Bouligand33, Lorenzo D'Antiga34,Emanuele Nicastro35, Noelle H. Ebel36, Jeffrey A. Feinstein37, Björn Fischler38, Henrik Arnell38, Susan Siew39, Michael O. Stormon39, Kyung Mo Kim40, Seak Hee Oh40, Amin J. Roberts41, Helen M. Evans41, Maria Camila Sanchez42, Maria Lorena Cavalieri42, Way Seah Lee43, Chatmanee Lertudomphonwanit44, Ryan T. Fischer45, Orith Waisbourd-Zinman46, James E.Squires47, Cigdem Arikan48, Jesus Quintero Bernabeu49,50, Mureo Kasahara51, Elisa Carvalho52, Cristina Targa Ferreira53, Pamela L. Valentino54,Giuseppe Indolfi55, John Eshun56, Pier Luigi Calvo57, Dev M. Desai58, Aglaia Zellos59, Antal Dezsőfi60, Sabina Wiecek61, Gabriella Nebbia62, Raquel Borges Pinto63, Maria Rogalidou64, María Legarda Tamara65, Andreanne N. Zizzo66, Jennifer Garcia67, Kathleen B. Schwarz68,Niviann Blondet69, Marisa Beretta70, Thomas Damgaard Sandahl71, Jernej Brecelj72, Cristina Gonçalves73,74,Eberhard Lurz75, Ermelinda Santos-Silva76, Nanda Kerkar77, Quais Mujawar78, Christos Tzivinikos79, Uzma Shah80, Carolina Jimenez-Rivera81, Jesus M. Banales82, Richard J. Thompson83, Bettina E. E. Hansen84,85, Binita M. Kamath86 and The Global ALagille Alliance (GALA) Study Group, (1)The Hospital for Sick Children and the University of Toronto, (2)The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, (3)The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, (4)Children's Hospital of Fudan University, the Center for Pediatric Liver Diseases, (5)Yale University School of Medicine, New Haven, CT, (6)Boston Children's Hospital and Harvard Medical School, Boston, MA, (7)University Medical Center Groningen, (8)University of Utah, Primary Children’s Hospital, (9)Swiss Pediatric Liver Center, University Hospitals Geneva and University of Geneva,(10)The Children's Memorial Health Institute, (11)Oregon Health and Science University, (12)Birmingham Women’s & Children's Hospital NHS Trust and University of Birmingham, (13)University of Minnesota, (14)Necker‐ Enfants Malades Hospital, University of Paris, (15)National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis),Filfoie, ERN RARE LIVER, Necker‐Enfants Malades Hospital, University of Paris, (16)Children’s Healthcare ofAtlanta, (17)Children’s Healthcare of Atlanta & Emory University School of Medicine, Atlanta, GA, (18)Hospital Sant Joan De Déu, (19)Cliniques Universitaires SaintLuc, (20)Cairo University, (21)Children’s Hospital of Colorado and University of Colorado School of Medicine, (22)Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, (23)Johns Hopkins University School of Medicine, (24)Royal Children’s Hospital, (25) Mazumdar Shaw Medical Center, Narayana Health, (26) Children's Hospital & Medical Center and University of Nebraska Medical Center, (27)Institute of Liver and Biliary Sciences, (28)Phoenix Children’s Hospital, (29)Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, (30)University Medical Center Utrecht, (31)Istanbul University Istanbul Medical Faculty, (32)Centre De Référence De l’Atrésie Des Voies Biliaires Et Des Cholestases Génétiques (AVB-CG), Fsmr Filfoie, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Faculté De Médecine Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hépatinov Université Paris-Saclay, (33)Hôpitaux Universitaires Paris-Saclay, Assistance PubliqueHôpitaux De Paris, Centre Hospitalier Universitaire De Bicêtre, (34)Ospedale Papa Giovanni XXIII, Bergamo, Italy, (35)Ospedale Papa Giovanni XXIII, (36)Stanford University School of Medicine, (37)Stanford University School of Medicine, Lucile Packard Children’s Hospital, (38)Astrid Lindgren Children's Hospital, Karolinska University Hospital and Department of Women's and Children's Health, (39)The Children’s Hospital at Westmead, (40)University of Ulsan College of Medicine, Asan Medical Center Children’s Hospital, (41)Starship Child Health, (42)Hospital Italiano Buenos Aires, (43) University of Malaya, (44)Ramathibodi Hospital Mahidol University, (45)Children's Mercy Kansas City, (46) Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, (47)UPMC Children's Hospital of Pittsburgh, (48)Koc University School of Medicine, (49)Biodonostia Health Research Institute – Donostia University Hospital –, University of the Basque Country (UPV/EHU), (50) Hospital Universiatri Vall D'hebron, (51)Organ Transplantation Center, National Center for Child Health and Development, (52)Hospital De Base Do Distrito Federal, Hospital Da Criança De Brasília, Centro Universitário De Brasília, (53)Hospital Da Criança Santo Antônio, Universidade Federal De Ciências Da Saúde De Porto Alegre, Complexo Hospitalar Santa Casa, (54) Seattle Children’s Hospital, (55)University of Florence and Meyer Children's University Hospital, (56)Le Bonheur Children's Hospital and the University of Tennessee Health Science Center, (57)Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Citta' Della Salute e Della Scienza, (58)Children's Health – Children's Medical Center, (59)Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece, (60)Semmelweis University, (61)Medical University of Silesia in Katowice, (62)Fondazione Irccs Ca’ Granda Ospedale Maggiore Policlinico, (63)Hospital Da Criança Conceição Do Grupo Hospitalar Conceição, (64)Agia Sofia Children's Hospital, University of Athens, (65)Cruces University Hospital, (66)Children's Hospital, London Health Sciences Centre, Western University, (67)Miami Transplant Institute, University of Miami, (68) University of California San Diego, Rady Children’s Hospital San Diego, (69)Seattle Children’s Hospital, Seattle, (70)Wits Donald Gordon Medical Centre, University of the Witwatersrand, (71)Aarhus University, (72)University Medical Center Ljubljana, (73)European Reference Network on Hepatological Diseases (ERN RARE-LIVER), (74)Pediatric Gastroenterology/ Hepatology Center Lisbon, (75)Von Hauner Children's Hospital, University Hospital, Lmu Munich, (76)Centro Hospitalar Universitário De Santo António, (77)University of Rochester Medical Center, (78)University of Manitoba, (79)Al Jalila Children’s Specialty Hospital, Mohammed Bin Rashid University of Medicine and Health Sciences, (80)Harvard Medical School, Massachusetts General Hospital for Children, Royal Oak, MI, (81)Children's Hospital of Eastern Ontario, (82)Biodonostia Health Research Institute - Donostia University Hospital, Universidad Del País Vasco (UPV/EHU), Centro De Investigación Biomédica En Red De Enfermedades Hepáticas y Digestivas (CIBERehd), (83)Institute of Liver Studies, King's College London, London, United Kingdom, (84)Toronto General Hospital University Health Network, (85)Institute of Health Policy, Management and Evaluation, (86)Division of Gastroenterology, Hepatology and Nutrition, the Hospital for Sick Children, Toronto, ON, Canada Background: Alagille syndrome (ALGS) is an inherited liver disorder dominated by high γ-glutamyltransferase (GGT) cholestasis. Previous studies have demonstrated limited efficacy of surgical interruption of the enterohepatic circulation in ALGS, with varying degrees of improvement in pruritus and xanthomas. Utilizing theGALA database, we sought to evaluate whether surgicalbiliary diversion (SBD) alters the natural history of liver disease. Methods: Multicenter retrospective analysis of children with clinically and/or genetically confirmed ALGS. Laboratory data were collected preoperatively (−6 to 0 mo) and postoperatively (3 to 12 mo). Paired sample t-tests were used to compare continuous variables, and McNemar’s tests were used to compare binominal variables pre-and postoperatively. Receiver operating characteristic (ROC) curves were used to determine the optimal laboratory threshold for predicting native liver survival (NLS) following SBD. Cox proportional hazards models were constructed to determine NLS in ALGS-SBD patients. Results: Of 1673 ALGS patients, 3.7% (n=62; 54.8% male) underwent SBD from 26 centers. The median age of SBD was 2.5 years (IQR 1.8 – 4.4). Most ALGS patients underwent a partial external biliary diversion (54.8%, n =34), followed by a partial internal biliary diversion in 19.4% (n =12) and ileal exclusion in 12.9% (n=8). 100% (n=62) of patients reported pruritus at the time of SBD, and 51.4% (n =18/35) reported xanthomas. ALGS-SBD patients had a 2.5-fold greater risk of liver transplantation (LT) or death (95%CI 1.6 – 3.9; p<0.01). Following SBD, there were no significant differences in total bilirubin (TB) (8.8 vs. 9.1 mg/dL, p=0.51), ALT (159.5 vs. 189.7 U/L, p=0.38),GGT (495.0 vs. 459.5 U/L, p=0.21) or cholesterol (493.0 vs. 414.6 mg/dL, p=0.21). Availability of serum bile acids (SBA) was limited; however, in 10 patients with SBAs preand postoperatively, there was a significant reduction following SBD (257.2 vs. 97.7 μmol, p=0.05). Among these patients, 80% achieved NLS. TB levels <4.0 mg/dL following SBD were significantly associated with longer NLS (p=0.05; AUC TB, 0.784; sensitivity, 94%; specificity, 52%). There were no significant improvements in pruritus (100% vs. 91.7%, p=0.25) or xanthomas (51.4% vs. 45.1%, p=0.67) after SBD. Conclusion: SBD in ALGS was associated with an increased risk of LT or death. SBD may be a marker for severe hepatic phenotype in ALGS. In contrast to PFIC, SBD does not appear to improve NLS in ALGS. However, in a subset of ALGS-SBD patients with SBA, higher rates of NLS were noted in those who experienced a substantial decrease in post-operative SBA levels. These findings also indicate that post-SBD TB levels can be used as a biomarker for NLS. In an era of ileal bile acid transporter (IBAT) inhibitors, SBD may become obsolete in ALGS.Disclosures: Shannon M. Vandriel – Mirum Pharmaceuticals: Consultant, No, No; Kathleen M. Loomes – Albireo: Grant/Research Support(research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Albireo: Consultant, No, No; Mirum: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Mirum: Consultant, No,No; Travere Therapeutics: Consultant, No, No; Henkjan J. Verkade – Ausnutria BV, lbireo, Danone Nutricia Research, Intercept, Mirum, Orphalan, and Vivet: Consultant, No, No; Saul Karpen – Albireo/Ipsen: Consultant, No, No; Mirum: Consultant, No, No; HemoShear: Consultant, No, No; Intercept: Consultant, No, No; Wikrom Karnsakul – Albireo: Consultant, No, No; Mirum:Consultant, No, No; Travere Therapeutics: Grant/Research Support (research funding from ineligiblecompanies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Emmanuel M. Gonzales – Laboratoires C.T.R.S.,Mirum, Vivet Therapeutics, and Albireo: Consultant, No, No; Lorenzo D'Antiga – Albireo, Alexion, Mirum, Selecta, Vivet, Spark, Tome, and Genespire: Consultant, No, No;Ryan T. Fischer – Albireo and Mirum: Consultant, No, No; Giuseppe Indolfi – Albireo and Mirum: Consultant,No, No; Kathleen B. Schwarz – Gilead Sciences, Inc.: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institutionreceives the research grant and manages the funds),Yes, No; Sarepta: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; UpToDate: Consultant, No, No; Albireo: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Thomas Damgaard Sandahl – Arbomed: Consultant,No, No; Prime: Consultant, No, No; Alexion: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Univar: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Orphalan: Speaking and Teaching, Yes, No; Vivet Therapeutics: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives the research grant and manages the funds), No, No; Richard J. Thompson – Generation Bio: Stock –privately held company (individual stocks and stock options), No, No; Generation Bio: Consultant, No, No;Mirum Pharma: Consultant, Yes, No; Albireo Phamra: Consultant, Yes, No; Rectify Pharma: Consultant, No, No; Rectify Pharma: Stock – privately held company (individual stocks and stock options), No, No; Alnylam:Consultant, No, No;Binita M. Kamath – Albireo, Mirum, and Audentes:Consultant, No, No; Albireo and Mirum: Grant/Research Support (research funding from ineligible companies should be disclosed by the principal or named investigator even if that individual’s institution receives theresearch grant and manages the funds), No, No; The following people have nothing to disclose: Silvia Nastasio, Deirdre A. Kelly, Étienne M. Sokal, Shikha S. Sundaram, Palaniswamy Karthikeyan, Winita Hardikar,Seema Alam, Emanuele Nicastro, Way Seah Lee,James E. Squires Disclosure information not available at the time of publication: David A. Piccoli, Elizabeth Rand, Li-Ting Li, Huiyu She, Jian-She Wang, Rima L. Fawaz, M. Kyle Jensen, Catalina Jaramillo, Nathalie Rock, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzińska, Henry C. Lin, Catherine Larson-Nath, Florence Lacaille, Dominique Debray, Rene Romero, Cristina Molera Busoms, Tanguy Demaret, Nehal M. El-Koofy, Mohamed A. Elmonem, Alexander Chaidez, Sahana Shankar, Ruben E. Quiros-Tejeira, Pinar Bulut, Christina Hajinicolaou, Victorien M. Wolters, Zerrin Önal, EmmanuelJacquemin, Jérôme Bouligand, Noelle H. Ebel, Jeffrey A. Feinstein, Björn Fischler, Henrik Arnell, Susan Siew, Michael O. Stormon, Kyung Mo Kim, Seak Hee Oh, Amin J. Roberts, Helen M. Evans, Maria Camila Sanchez, Maria Lorena Cavalieri, Chatmanee Lertudomphonwanit, Orith Waisbourd-Zinman, Cigdem Arikan, Jesus Quintero Bernabeu, Mureo Kasahara, Elisa Carvalho, Cristina Targa Ferreira, Pamela L. Valentino, John Eshun, Pier Luigi Calvo, Dev M. Desai, Aglaia Zellos, Antal Dezsőfi, Sabina Wiecek, Gabriella Nebbia, Raquel Borges Pinto, Maria Rogalidou, María Legarda Tamara, Andreanne N. Zizzo, Jennifer Garcia, Niviann Blondet, Marisa Beretta, Jernej Brecelj, Cristina Gonçalves, Eberhard Lurz, Ermelinda Santos-Silva, Nanda Kerkar, Quais Mujawar,Christos Tzivinikos, Uzma Shah, Carolina JimenezRivera, Jesus M. Banales, Bettina E. E. Hanse

SERUM BILE ACIDS ARE ASSOCIATED WITH NATIVE LIVER SURVIVAL IN PATIENTS WITH ALAGILLE SYNDROME: RESULTS FROM THE GALA STUDY GROUP

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Differential prevalence of extrahepatic clinical manifestations in patients with Jagged1 and NOTCH2-associated Alagille syndrome

Background: Alagille syndrome (ALGS) is a phenotypically heterogeneous, autosomal dominant disorder, resulting from pathogenic variants in Jagged1 (JAG1) or NOTCH2. The natural history of liver disease in ALGS is highly variable and there are no known genotypic predictors of hepatic outcomes. The Global ALagille Alliance (GALA) Study Group has ascertained the largest genetically confirmed ALGS cohort to date, permitting exploration of JAG1 and NOTCH2 genotype-phenotype correlations. Method: International multicentre retrospective study of children with ALGS, born between Jan-1997 and Aug-2019 with a pathogenic or likely pathogenic (LP) variant in JAG1 or NOTCH2. Variants were classified according to the American College of Medical Genetics and Genomics criteria. Phenotypic differences were compared between JAG1-and-NOTCH2- ALGS patients and between those with a truncating, non-truncating or structural JAG1 variant, using Chi-square test or Fisher’s exact test. Transplant-free survival (TFS) and overall survival (OS) rates were analyzed using the Kaplan-Meier method. Results: Among 845 genotyped ALGS patients, a pathogenic or LP variant in JAG1 was identified in 97.5% (n=824) and a pathogenic or LP NOTCH2 variant in 2.5% (n=21). Of JAG1 variants, truncating were identified in 73% (n=604), non-truncating in 17% (n=137), and structural variants in 10% (n=83). The phenotypes of JAG1-ALGS patients were clinically indistinguishable with respect to liver involvement, including a history of neonatal cholestasis (NC) (82% vs. 81% vs. 82%, p=0.95) and presence of bile duct paucity (66% vs. 55% vs. 61%, p=0.27). Similarly, no significant differences in the prevalence of extrahepatic manifestations were identified (Table). Ten- and 18-year TFS in ALGS patients with a history of NC and either a truncating (n=473), non-truncating (n=110), or structural JAG1 variant (n=62) were comparable (log-rank, P=0.24). OS rates at 10- and 18-years were ≥88% (log-rank, P=0.08). JAG1-and-NOTCH2 ALGS patients were similar in terms of history of NC (90% vs. 82%, P=0.55), bile duct paucity (54% (n=7/13) vs. 64% (n=202/317, P=0.56), renal anomalies (28% vs. 36%, P=0.50) and vascular anomalies (27% vs. 32%, P=0.79). Those with a NOTCH2 variant were significantly less likely to have characteristic facies (52% vs. 89%, P<0.001), an ECHO-confirmed cardiac anomaly (38% vs. 92%, P<0.001), posterior embryotoxon (13% vs. 52%, P=0.002), or butterfly vertebrae (0% vs. 43%, P<0.001). Ten- and 18-year TFS in patients presenting with NC were comparable between groups (59% and 74%; 49% and 61%, respectively; log-rank P =0.33). OS rates at 10- and 18-years were ≥88% in both groups (log-rank P =0.73). Conclusion: We present the largest, comprehensive genetic analysis in ALGS. No phenotypic differences were observed between ALGS patients with a truncating, non-truncating or structural JAG1 variant. The clinical heterogeneity in ALGS patients harbouring the same pathogenic variant further implicates genetic modifiers in defining the ALGS phenotype. NOTCH2-ALGS patients exhibit significantly reduced penetrance of extrahepatic features in comparison to JAG1-ALGS patients, however the natural history with respect to TFS and OS did not differ between groups

Clinical features and outcomes in an international cohort of 731 Alagille syndrome patients from 19 countries

Abstract : Background: Alagille syndrome (ALGS) is a multisystem disorder, typically presenting with neonatal cholestasis. Prior cohort studies in ALGS largely come from tertiary center liver centers and therefore select for the most severely affected cholestatic patients. As a result, the full spectrum of ALGS liver involvement remains unclear. Furthermore, a comprehensive assessment of extrahepatic manifestations in a large cohort of patients is missing. In 2017, the Global ALagille Alliance (GALA) Study Group was established to overcome these limitations. Methods: This is a retrospective multicentre study in children and young adults with a clinically and/or genetically confirmed diagnosis of ALGS, born between January 1997-May 2019. Histopathological findings before and after 6 months were compared using chi-square test. Native liver survival (NLS) in patients presenting with neonatal cholestasis and overall survival were estimated using cox regression analysis. Results: 731 ALGS (41% female) subjects from 32 centres were included (median follow-up 4.75 yrs, IQR 2.0-10.2). Among the 76% (n=554/731) genetically-confirmed patients, 95% had a JAG1 mutation and 4% a NOTCH2mutation (70% de novo). Presence of any cardiac anomaly and characteristic facies were the most common clinical manifestations, 87% (each), followed by posterior embryotoxon, 45%, butterfly vertebrae, 43% and renal anomalies, 38%. Available MRI and CT reports (mostly performed for screening) revealed cerebral and intra-abdominal vascular anomalies in 36% (n=57/159) and 26% (n=27/105) of subjects, respectively. 79% of ALGS subjects presented with neonatal cholestasis. 299 initial liver biopsy reports were reviewed (Table 1) and revealed an increasing frequency of bile duct paucity with age and of note, bile duct plugs in 6% of biopsies <6 months. 9% of subjects presenting with neonatal cholestasis had a Kasai, and 2% had a biliary diversion (median age 1 5yrs) 23% underwent liver transplantation at a median age of 2.6 yrs 10- and 18-year NLS were 69.7% and 56.5%, respectively. Overall survival rates were 92.9% and 90.7%, respectively. Conclusion: Here we describe the largest global cohort of ALGS to date representing a broad range of institutions. Only 56 5% of ALGS patients presenting with neonatal cholestasis reached adulthood with their native livers. The burden of asymptomatic vasculopathies exceeds previous reports and highlights the need for increased surveillance in ALGS. The GALA study database provides a platform for detailed analysis of the natural history of ALGS

HIV Viral Suppression Results in Higher Antibody Responses in HIV-Positive Women Vaccinated with the Quadrivalent Human Papillomavirus Vaccine

Objective: To evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24 months. Design: Between November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5 mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 18, and 24 months. Adverse events were recorded throughout. Results: Of 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38 years (IQR 32-45, range 15-66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had suppressed HIV viral load (VL<40c/ml) at baseline, with a median CD4 count of 510 cells/mm³ (376-695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74-3.05 fold higher peak antibody response compared to those without (p from 0.006-<0.0001). Conclusions: This study is the first to examine the qHPV vaccine in HIV-positive women out to 24 months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination.Medicine, Faculty ofNon UBCFamily Practice, Department ofInfectious Diseases, Division ofObstetrics and Gynaecology, Department ofPathology and Laboratory Medicine, Department ofPediatrics, Department ofPopulation and Public Health (SPPH), School ofMedicine, Department ofReviewedFacultyUnknow

Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Background and Aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the Global ALagille Alliance (GALA) study. Approach and Results: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189–0.491; p &lt; 0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.</p