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.