In this paper we report a case of iatrogenic Cushing syndrome due to a pharmacological interaction between fluticasone and cobicistat. Inhaled corticosteroids were previously thought to be safe, but increasing numbers of cases of iatrogenic Cushing syndrome are being reported, especially in patients taking cytochrome P450 inhibitors, including cobicistat. Although the drug interaction between cobicistat and fluticasone has been described elsewhere, to our knowledge we present one of the first descriptions of iatrogenic Cushing syndrome due to this pharmacological interaction

A. Giacomelli

E. Monge

V. Colombo

English

AIR Universita degli studi di Milano

CASE REPORTS 445
Le Infezioni in Medicina, n. 4, 445-448, 2019
Corresponding author
Elisa Monge
E-mail: elisa.monge@unimi.it
Iatrogenic Cushing syndrome due  
to drug interaction between inhaled 
fluticasone and cobicistat 
Elisa Monge, Valeria Colombo, Andrea Giacomelli
III Division of Infectious Diseases, L. Sacco University Hospital, Milan, Italy
In this paper we report a case of iatrogenic Cushing syn-
drome due to a pharmacological interaction between 
fluticasone and cobicistat. Inhaled corticosteroids were 
previously thought to be safe, but increasing numbers 
of cases of iatrogenic Cushing syndrome are being re-
ported, especially in patients taking cytochrome P450 
inhibitors, including cobicistat. Although the drug in-
SUMMARY
teraction between cobicistat and fluticasone has been 
described elsewhere, to our knowledge we present 
one of the first descriptions of iatrogenic Cushing syn-
drome due to this pharmacological interaction.
Keywords: HIV, drug interactions, cobicistat, corticos-
teroid, pharmacokinetics.
n INTRODUCTION
Pharmacological interactions are a well-known challenge in the management of HIV infection 
[1]. Current antiretroviral treatment (ART) has im-
proved life-expectancy and turned HIV infection 
into a chronic illness. As the HIV population ages, 
comorbidities have become more and more com-
mon and made drug interactions a major concern 
[2]. Besides Infectious Diseases Physicians, this 
problem may involve other specialists to whom 
HIV-infected patients are increasingly referred to 
for concurrent disorders.
n CASE REPORT
A 49-year-old man with a long-standing HIV-1 
infection presented for a scheduled visit to our In-
fectious Disease Clinic reporting a history of pro-
gressive muscle weakness leading to walking dif-
ficulties, abdominal distension, weight gain, an-
kle edema and dysthymia. He also complained of 
worsening back pain that had appeared 2 weeks 
earlier. His antiretroviral therapy was darunavir/
cobicistat and emtricitabine/tenofovir (started 
one year before), CD4-T lymphocytes were 601/
μL and HIV-1 RNA replication was suppressed 
in plasma. His past medical history was notable 
for a diagnosis of Hodgkin lymphoma (2013); hy-
pertension (under treatment with perindopril); 
alcoholic fatty liver disease; dyslipidemia; ciga-
rette smoking; obstructive sleep apnea with con-
tinuous-positive-airway-pressure treatment and 
chronic obstructive pulmonary disease (COPD). 
Five months earlier, during hospitalization for an 
exacerbation of COPD, a Pulmonary Specialist 
prescribed treatment with fluticasone/formoterol 
combination inhaler. 
Clinical examination revealed: abdominal disten-
sion with red striae (Figure 1), moon facies (Fig-
ure 2), dorso-cervical fat accumulation, proximal 
muscle weakness, bilateral ankle edema and skin 
telangiectasias. Blood test showed: leukocytosis 
(18,000 WBC/μL with 78% neutrophils) and liver 
enzymes elevation (AST: 81 IU/L, ALT: 501 IU/L, 
GGT: 1,391 IU/L). Serum bilirubin and C-reactive 
protein concentrations were in the normal range. 
Radiography of the spine evidenced multiple os-
teoporotic  vertebral fractures. Measurement of 
446 E. Monge, V. Colombo, A. Giacomelli
hormone concentrations revealed low levels of: 
serum cortisol (2,7 μg/dL; range: 7-25 μg/dL), 
ACTH (4 pg/mL; range: 5-60 pg/mL) and 24-
hour urinary free cortisol (2,7 μg/24 h; range: 36-
127 μg/24 h). Altogether, these findings were con-
sistent with suppression of the hypothalamus-pi-
tuitary-adrenal axis and iatrogenic Cushing’s 
syndrome due to a pharmacologic interaction 
between fluticasone and cobicistat. Cholestatic 
hepatitis was considered to be a consequence of 
Cushing’s syndrome [3]. Therapeutic manage-
ment included: darunavir/cobicistat-switch to 
dolutegravir (an antiretroviral agent that does 
not inhibit the CYP3A4 isozyme), tapering of the 
inhaled corticosteroid and cortisone acetate re-
placement therapy, in order to prevent an adrenal 
crisis.
Although the appropriate treatment strategy, im-
portant consequences were impossible to prevent. 
In detail, the reduction of bone mineral density 
due to Cushing’s syndrome resulted in multiple 
vertebral fractures with spinal cord compression 
requiring surgical intervention. Then, due to the 
extended hospital stay, the patient developed a 
bloodstream infection complicated by spondylo-
discitis due to methicillin-resistant Staphylococcus 
aureus, which was successfully treated. After-
ward, in consideration of paraplegia, the patient 
was sent to a neuro-rehabilitation clinic and lost 
to follow-up ever since.
n DISCUSSION
Inhaled corticosteroids were previously thought 
to be safe, but several cases of iatrogenic Cush-
ing’s syndrome have been reported in the litera-
ture, especially in patients taking drugs that in-
hibit cytochrome P450 (CYP) [4]. Fluticasone nor-
mally has favorable pharmacokinetic properties, 
but, in the presence of CYP inhibitors, it shows 
considerable accumulation because of long half-
life, high lipophilicity and higher binding affinity 
for the glucocorticoid receptor [5]. Patients with 
HIV infection who take regimens containing pro-
tease inhibitors (PIs) or pharmacokinetic enhanc-
er (i.e. booster) are at risk for exogenous corticos-
teroid accumulation in serum: among these med-
ications, ritonavir and cobicistat are the strongest 
CYP3A4 inhibitors. Several cases of Cushing’s 
syndrome due to an interaction between flutica-
sone and ritonavir have been reported in litera-
ture [6-20]. In fewer patients, the inhaled corticos-
teroid responsible for toxicity, when co-adminis-
tered with ritonavir, was budesonide [18, 21-23]. 
Cobicistat is a mechanism-based inhibitor of 
CYP3A that is used in HIV-1 infection as a “boost-
er”of PIs atazanavir and darunavir and the inte-
grase inhibitor elvitegravir. The drug interaction 
Figure 1 - Abdominal distension with red striae.
Figure 2 - Moon facies.
447Iatrogenic Cushing syndrome due to drug interaction
between cobicistat and fluticasone is described 
and expected, but we present herein one of the 
first descriptions of full-blown, iatrogenic Cush-
ing’s syndrome due to this pharmacological inter-
action [24, 25].
In this report the patient had been taking cobicistat 
for more than a year. Then, after seven months 
he started fluticasone inhalation and within two 
months he complained the first symptoms (mus-
cle weakness, abdominal distension, weight gain 
and ankle edema).
Every time a patient receiving cobicistat needs 
treatment with inhaled steroids, clinicians should 
consider switching to an antiretroviral agent 
which doesn’t inhibit CYP (i.e. a non-nucleoside 
reverse transcriptase inhibitor or an unboosted in-
tegrase inhibitor) or using a steroidal medication 
with less potential drug interactions. Beclometha-
sone represents a relatively safer option to flutica-
sone due to its shorter elimination half-life, lower 
glucocorticoid receptor binding affinity, low lipo-
philic activity and lower dependence on CYP for 
its metabolism: when it’s co-administered with an 
enzymatic inhibitor, no drug interaction is expect-
ed [26].
In conclusion, meticulous review of pharmaco-
logic interactions, including topical treatments, 
is warranted before the introduction of any new 
drug to a complex regimen, in order to avoid se-
rious harm to patients. Moreover, active commu-
nication between Infectious Disease Physicians 
and other specialists can contribute to reducing 
clinical errors among patients with HIV infection.
Conflict of interest None 
Acknowledgments
We would like to thank Spinello Antinori, Mario 
Corbellino and Stefano Rusconi for their support.
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Iatrogenic Cushing syndrome due to drug interaction between inhaled fluticasone and cobicistat

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Iatrogenic Cushing syndrome due to drug interaction between inhaled fluticasone and cobicistat

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