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. 2016 Mar;129(3):283-91.e5.
doi: 10.1016/j.amjmed.2015.10.029. Epub 2015 Nov 17.

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

Vincent Lo Re 3rd  1 , Dean M Carbonari  2 , James D Lewis  3 , Kimberly A Forde  3 , David S Goldberg  2 , K Rajender Reddy  4 , Kevin Haynes  2 , Jason A Roy  2 , Daohang Sha  5 , Amy R Marks  6 , Jennifer L Schneider  6 , Brian L Strom  7 , Douglas A Corley  6
Affiliations

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

Vincent Lo Re 3rd et al. Am J Med. 2016 Mar.

Abstract

Background: 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.

Methods: 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.

Results: 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]).

Conclusions: 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.

Keywords: Acute liver failure; Azole; Drug-induced liver injury; Hepatotoxicity.

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Conflict of interest statement

Conflict of Interest: VLR, DMC, and KH have received research grant support (to the University of Pennsylvania) from AstraZeneca and Gilead Sciences. JDL has received research grant support (to the University of Pennsylvania) from Bayer, Nestle Health Science, and Takeda and has served as a consultant to AstraZeneca, Amgen, MedImmune, Merck, Nestle Health Science, Gilead, Pfizer, Rebiotix, and Takeda. DSG has received research grant support (to the University of Pennsylvania) from Bayer HealthCare and Intercept Pharmaceuticals. KRR has received research grant support (to the University of Pennsylvania) from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck and has served as an advisor to Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck. JAR has received research grant support (to the University of Pennsylvania) from AstraZeneca. BLS has received research grant support (to Rutgers University) from AstraZeneca and Bristol-Myers Squibb.

Figures

Figure
Figure
Selection of patients for the study. *Azole antifungal agents of interest include ketoconazole, itraconazole, fluconazole, voriconazole, and posaconazole. †Index date defined as earliest qualifying date an oral antifungal drug was dispensed in an outpatient setting on or after January 1, 2004. ‡Severe acute liver injury defined by inpatient or outpatient international normalized ratio ≥1.5 (in the absence of anticoagulation therapy) and serum total bilirubin >2 times upper limit of normal, with both abnormalities recorded within 30 days of each other. KPNC = Kaiser Permanente Northern California.
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Comment in

  • Effects of Treatment with Azoles Are Overstated.
    Vendetti N, Salas M, Waskin H, Mast TC. Vendetti N, et al. Am J Med. 2017 Aug;130(8):e367. doi: 10.1016/j.amjmed.2017.02.044. Am J Med. 2017. PMID: 28734383 No abstract available.
  • The Reply.
    Lo Re V 3rd, Carbonari DM, Lewis JD, Roy JA, Corley DA. Lo Re V 3rd, et al. Am J Med. 2017 Aug;130(8):e369. doi: 10.1016/j.amjmed.2017.03.062. Am J Med. 2017. PMID: 28734384 No abstract available.

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