Adrenal Insufficiency Following Withdrawal of Inhaled Fluticasone in a Patient on HIV Antiretroviral Regimen with Cobicistat

Introduction:
It is under recognized that inhaled steroids can be absorbed systemically, particularly when combined with medications that decrease the metabolism of the corticosteroids. This can lead to Cushingoid features and, upon sudden withdrawal of the inhaled steroid, may result in secondary adrenal insufficiency. We report a case of adrenal insufficiency in a patient on long-term cobicistat and inhaled fluticasone following sudden discontinuation of the inhaled fluticasone. 

Case Description:
A 73-year-old male with HIV on long term antiretroviral therapy and asthma managed with fluticasone presented with fatigue and progressive dyspnea on exertion for 3 weeks. History revealed that the patient had discontinued the inhaled fluticasone for 3 weeks prior due to lack of refills. The patient remained adherent to HIV antiretroviral therapy with Symtuza®, a combination pill containing darunavir, emtricitabine, tenofovir, and cobicistat, a CYP3A4 inhibitor. Physical exam revealed stable vital signs, central adiposity, maroon abdominal striae, and diffuse muscle weakness. On 2 separate days, morning serum cortisol measured <1.0 mcg/dL (6.7 - 22.6 mcg/dL). Cosyntropin 250 mcg stimulation test performed revealed cortisol <1.0 mcg/dL (6.7 - 22.6 mcg/dL) and ACTH 4.6 pg/ml (7.2 - 63 pg/ml) at time 0, cortisol 9.0 mcg/dL at time 30 minutes, cortisol 10.6 mcg/dL at time 60 minutes, consistent with secondary adrenal insufficiency. Full pituitary panel, MRI pituitary, and CT abdomen and pelvis were unremarkable. Clinical presentation attributed to adrenal insufficiency in setting of withdrawal of inhaled fluticasone, which had a potentiated effect due to decreased corticosteroid metabolism in setting of concurrent use with the CYP3A4 inhibitor, cobicistat. Patient’s antiretroviral medications were changed to dolutegravir, emtricitabine, and tenofovir to eliminate CYP3A4 inhibiting effect of cobicistat and maintenance hydrocortisone was initiated to prevent adrenal crisis with improvement in fatigue and muscle weakness. Repeat testing was not completed as patient was lost to follow up. 

Discussion:
In patients on inhaled steroids it is important to recognize that there may be significant systemic absorption especially when combined with CYP3A4 inhibitors that decrease glucocorticoid metabolism, resulting in Cushingoid features. Abrupt withdrawal of inhaled steroids in this setting may result in clinically significant secondary adrenal insufficiency.