title: Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status.
abstract: Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals.
  
  
  
  We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes.
  
  
  
  Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0-60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35]).
  
  
  
  Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Electronic address: vincentl@mail.med.upenn.edu.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lo Re
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Carbonari
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: James D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Forde
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldberg
authors.affiliation: Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Haynes
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roy
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Daohang
authors.initials: D
authors.lastname: Sha
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Marks
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Schneider
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Rutgers Biomedical and Health Sciences, Rutgers, the State University of New Jersey, Newark.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Strom
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002140:California / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002908:Chronic Disease / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000453:epidemiology; D017114:Liver Failure, Acute / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000637:Transaminases / Q000032:analysis*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D000637:Transaminases
keywords: Acute liver failure; Azole; Drug-induced liver injury; Hepatotoxicity