Discussion
This is the first pediatric case series to describe the outcome of
switching triazole antifungal agents in the setting of AIH, highlighting
this as a potential approach to managing drug-related hepatotoxicity.
Given oral antifungal options in children are limited to triazole
antifungals and AIH is the most common adverse event resulting in
cessation of therapy 8, identifying an approach to
managing AIH and preserving the use of this drug class is critical.
Published data on this approach to AIH are limited. Three case reports
and one audit in adults demonstrated improvement after switching between
triazole antifungals. Spellberg et al. described an adult with
coccidioidal meningitis and fluconazole-related hepatotoxicity that
improved with switching to voriconazole 2. Further, a
retrospective audit of 23 adults with acute myeloid leukemia who had
switched from posaconazole to isavuconazole, demonstrated improvement in
all 20 patients with CTCAE Grade 1 hepatotoxicity or more1. Of these, six patients had grade 3-4 abnormalities
in liver transaminases with all patients showing improvement and in 2/6
patients, the LFTs normalised 4 weeks after the change in therapy1. A further case report described a patient with
intracerebral aspergillosis who developed voriconazole-related
hepatotoxicity which resolved after changing to posaconazole3. Similarly switching from voriconazole to
posaconazole in combination with caspofungin was found to result in
resolution of hepatotoxicity in an immunocompetent adult with invasive
aspergillosis 4. These data suggest a lack of
cross-hepatotoxicity between triazole antifungals that requires further
study.
The mechanism of liver injury from triazole antifungals is poorly
understood but thought to be due to triazole alteration of inhibition of
cytochrome P450 enzymes, acute inflammatory response, and mitochondrial
dysfunction. An in vivo study in rats demonstrated worsening
toxicity when fluconazole or itraconazole were administered a CYP450
inhibitor compared with azole therapy alone, suggesting CYP450
inhibition may have an important role in the mechanism of hepatotoxicity9. However, for posaconazole-induced hepatotoxicity,
an in vitro study suggested a different mechanism, through
mitochondrial dysfunction 10. Data are limited on the
relationship between azole dose and AIH for itraconazole and
posaconazole, however, no clear relationship has been identified in
pediatric studies of fluconazole and voriconazole 8,
11.
This case series adds to the growing body of evidence suggesting that
there is a lack of cross-hepatotoxicity between azole antifungals and
switching within the class is a potential approach to management of AIH.
Further large clinical studies are needed to determine whether this
approach could be routinely considered.