Role of fluconazole in a case of rapid onset ritonavir and inhaled fluticasone-associated secondary adrenal insufficiency

CASE REPORT

A 52-year-old man taking ritonavir, atazanavir and efavirenz for HIV infection had chronic bronchitis that was managed long-term with inhaled fluticasone propionate (250 µg twice daily). After presenting with worsening dyspnoea, wheezing and nasal congestion, his inhaled dose of fluticasone was increased to 500 µg twice daily in addition to nasal fluticasone (0.05%). After two months on this new regimen, he presented with a one-month history of fatigue, muscle weakness and cramping, mouth sores, odynophagia and hoarseness. Physical examination revealed a blood pressure (BP) of 147/84, consistent with his baseline BP on diltiazem for an established history of essential hypertension, and oropharyngeal candidiasis. Routine laboratory studies were normal except for an elevated serum blood glucose of 7.4 mmol/L. His fasting serum blood glucose levels had been normal for several years previously and was 4.8 mmol/L just prior to increasing his dose of fluticasone. His CD4 count and viral load were 323 cells/mL (36%) and undetectable, respectively, compared with 817 cells/mL (40%) and undetectable two months previously. He was treated with a seven-day course of oral fluconazole (400 mg daily) and advised to discontinue the fluticasone. His oral candidiasis improved, but two days after initiating fluconazole therapy, he experienced acute onset of severe fatigue, malaise and lower extremity oedema. On presentation to the clinic a few days later, the patient was hypotensive without changes in his antihypertensive regimen (BP 98/55 supine) with a pulse of 82, which changed to 86/52 and 102, respectively, one minute after standing. Physical examination revealed a fatigued but alert man with 4+ pitting oedema of the lower extremities, which was not present at the prior visit, and no signs of heart failure or portal hypertension. Laboratory testing revealed a morning cortisol level of 1.7 µg/dL, and a follow-up cosyntropin (250 µg) stimulation test demonstrated a blunted response of 9.6 and 12.8 µg/dL at 30 and 60 minutes after injection, respectively. The patient's adrenocorticotrophic hormone level was also low at 5 pg/mL. The patient was diagnosed with exogenous Cushing's syndrome and secondary adrenal insufficiency and his symptoms resolved over the next several weeks with hydrocortisone replacement and subsequent taper. His candidiasis resolved and subsequent CD4 counts were 418 cells/mL (38%) and 1574 cells/mL (40%) one and two months later, respectively.

DISCUSSION

Concomitant use of ritonavir with inhaled glucocorticoids has recently been described in association with exogenous Cushing's syndrome and secondary adrenal insufficiency, resulting in significant morbidity. ¹ Protease inhibitors and fluconazole interact with numerous drugs through inhibition of the CYP3A4 isoenzyme, the mechanism by which fluticasone is metabolized. ² It is well documented that systemic, exogenous glucocorticoids suppress the hypothalamic–pituitary–adrenal axis, either directly through supraphysiological doses or, less commonly, by metabolic inhibition of smaller doses. ³ Our patient took ritonavir and low-dose fluticasone concomitantly for 12 uneventful months, but soon after increasing his dose of fluticasone his CD4 count markedly declined and he developed oral candidiasis. We believe that chronic use of ritonavir and increasing doses of inhaled and nasal fluticasone resulted in exogenous Cushing's syndrome and subclinical adrenal insufficiency with subsequent cell-mediated immunosuppression and development of oral candidiasis, as glucocorticoids are well known to selectively suppress the cellular immune axis and susceptibility to mucocutaneous candidiasis. ⁴

Although sudden discontinuation of fluticasone certainly contributed to the development of symptomatic adrenal insufficiency in our patient, we believe fluconazole exacerbated that presentation over a brief period of time. However, that effect does not appear to be related to its effect on the CYP3A4 isoenzyme. Significant fluconazole–ritonavir interactions have not been described, even though co-administration increases ritonavir concentrations by 15%. ⁵ Although ketoconazole and itraconazole increase fluticasone levels, clinically significant fluconazole–fluticasone interactions have not been reported previously. ⁶ As fluticasone was discontinued at the same time fluconazole was initiated and the half-life of fluticasone is less than eight hours, it is unlikely that fluconazole contributed to further adrenal axis suppression by driving up ritonavir and fluticasone levels. However, several reports suggest that fluconazole inhibits adrenal steroidogenesis, observations which have been validated using an in vitro adrenal adenoma cell line assay. ^7–9 Prior reports of ritonavir–fluticasone-associated adrenal insufficiency describe onset of clinically apparent adrenal insufficiency within one week of discontinuing fluticasone. ¹⁰ We believe fluconazole may have contributed to the rapidity of onset and severity of symptoms in our patient through this adrenal inhibitory effect. This case raises further awareness of this potential adverse interaction and emphasizes the importance of weighing the risks and benefits of non-systemic fluticasone use in HIV patients taking ritonavir. Co-administration should be avoided but, when medically necessary, patients should be monitored closely to ensure early recognition and intervention of medication-induced Cushing's syndrome, and evaluation for adrenal insufficiency and replacement hydrocortisone should be considered before withdrawal of fluticasone or fluconazole treatment of candidiasis to avert development of symptomatic secondary adrenal insufficiency.