Ritonavir and cobicistat are potent inhibitors of the hepatic cytochrome P450 3A4 (CYP3A4) isoenzyme [1,2]. They are used in clinical practice to boost the levels of antiretrovirals in the treatment of HIV infection; ritonavir is commonly used to boost protease inhibitors, and cobicistat is currently available as part of a fixed-dose combination containing elvitegravir, cobicistat, tenofovir and emtricatibine [Stribild (STB)], where it is used to boost elvitegravir [1,3]. This powerful enzyme inhibition has the potential for serious drug–drug interactions (DDIs).
There are, however, important differences in the action of ritonavir and cobicistat on the hepatic enzymes; for example, ritonavir is also a potent inhibitor of p-glycoprotein 1 (PgP), and induces UDP-glucuronosyltransferase 1A (UGT-1A), whereas cobicistat does not . Despite these differences, where data are lacking, the magnitude of interaction between cobicistat and many co-medications which are CYP P450 substrates is assumed to be similar to that of ritonavir. It is clinically important to provide clinical evidence which confirms or refutes these assumptions.
The interaction between the inhaled and intranasal corticosteroids and ritonavir is well recognized. Most corticosteroid medications are substrates of CYP3A4 and concomitant administration can result in extremely high systemic levels of exogenous corticosteroid; adrenal suppression and Cushing's syndrome have been described in case reports . Data for evidence of an interaction between cobicistat and corticosteroid are sparse, and the manufacturer advises caution in their use . Here, we present a case of adrenal suppression caused by co-administration of cobicistat and fluticasone nasal spray.
In June 2014, a 39-year-old man attended a routine HIV clinic appointment and complained of reduced libido and erectile dysfunction. He was diagnosed with HIV in 2009 after being treated for latent syphilis. He had a past history of hiatus hernia, gastro-oesophageal reflux, polycythaemia secondary to cigarette smoking, migraine, depression and intermittent cocaine use. He also had mild chronic obstructive pulmonary disease (COPD) and nasal congestion for which he was under the care of the ear, nose and throat (ENT) department.
He was started on antiretrovirals in September 2011 and had a fully suppressed HIV viral load since October 2012. His antiretrovirals were changed from co-formulated rilpivirine, tenofovir and emtricatibine (Eviplera) to co-formulated elvitegravir, cobicistat, emtricatibine and tenofovir (Stribild), in March 2014, because of concerns about reduced absorption of rilpivirine with the use of proton pump inhibitors. His most recent CD4+ cell count in February 2014 was 796 cells/μl.
His other medications were gabapentin, co-dydramol, citalopram, zopiclone, omeprazole, folic acid and beclomethasone inhaler 100 mcg twice daily and salbutamol inhaler as required. He had been started on fluticasone nasal drops 800 mcg twice daily in February 2013 for nasal congestion.
Blood tests to investigate the cause of his low libido showed a 9 a.m. cortisol of less than 50 nmol/l (normal range 140–500 nmol/l) with low adrenocorticotropic hormone (ACTH) and abnormal short synacthen test (SST) with inadequate cortisol response to tetracosactide (see Fig. 1). A diagnosis of iatrogenic adrenal suppression was made. The fluticasone nasal drops were changed to beclomethasone nasal spray, and physiological steroid replacement with hydrocortisone 10 mg twice daily was commenced and weaned over 2 weeks. On repeat testing, SST and ACTH had normalized (see Fig. 1).
To the best of our knowledge, this is the first reported case of cobicistat–fluticasone interaction causing iatrogenic adrenal suppression.
Fluticasone is metabolized through CYP3A4, and adrenal suppression and Cushing's syndrome have been described with co-administration of inhaled and nasal fluticasone and protease inhibitors . Indeed, a recent review of the literature found that of all inhaled and nasal corticosteroids, fluticasone was most commonly implicated in problematic interactions with protease inhibitors . Beclomethasone is not a substrate of CYP3A4, and inhaled or nasal beclomethasome is therefore considered safer than other corticosteroids [5,6]. The recovery of our patient's adrenal axis function after a switch to beclomethasone supports this hypothesis.
The case serves as a reminder to clinicians to always consider DDIs in the context of powerful hepatic enzyme inhibitors, and in particular when they are co-administered with inhaled or nasal steroids. More research is needed to study the effect of cobicistat on metabolism of various steroids. Until more data are available, use of cobicistat with fluticasone should be avoided. Clinicians are encouraged to use online resources such as the Liverpool University HIV drug interaction website (http://www.hiv-druginteractions.org) prior to concurrently prescribing drugs and antiretrovirals.
Conflicts of interest
There are no conflicts of interest.
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