Secondary adrenal suppression and Cushing’s syndrome caused by ritonavir-boosted effects of inhaled fluticasone, injected triamcinolone and topical clobetasol: A case series

NJ Marshall1, K Gurazada2, P Bouloux2, B Khoo2, and MA Johnson1 1. Ian Charleson Centre for HIV medicine, Royal Free London NHS Foundation Trust 2. Department of Endocrinology, Royal Free London NHS Foundation Trust

Background Fluticasone inhaled/nasal (2) Practice Points

• Most glucocorticoids are hepatically metabolised but Fig 1: MRI Spine showing osteoporotic vertebral crush General: there is very limited information on the extent to which fractures in thoracic and lumbar spine and steroid hump • Interactions between glucocorticoids and ritonavir are this occurs and which CYP enzymes are responsible common and can lead to significant morbidity

for this • Due to CYP inhibition by ritonavir, there is likely to be

• Fluticasone is known to be metabolised by CYP 3A4, an increase in systemic exposure from most

and drug-drug interactions (DDI) between ritonavir glucocorticoids irrespective of route of administration, and inhaled or nasal formulations are well described, with the possible exception of beclometasone leading to accumulation of glucocorticoid and • A tapering steroid dose may be required after exposure increasing the risk of iatrogenic Cushing’s syndrome to short term oral glucocorticoid due to the increased and suppression of the Hypothalamic-Pituitary- exposure related to DDI with ritonavir Adrenal axis (HPA-A) • HIV diagnoses and potential for interaction should be • There are 7 cases in the literature describing the stated on all referral letters, especially when referring potential interaction of triamcinolone showing similar patients for X-ray guided glucocorticoid injections outcomes, including avascular necrosis of femoral

heads of femur in 2 cases Fig 4: Potential interactions of ritonavir with available • We describe a series of patients on ritonavir-based Triamcinolone injection corticosteroid preparations (author’s opinion) ART who developed evidence of adrenal suppression Drug Injection PO Inhaled Nasal Top

• Six patients on PI/r-based HAART presented after Fluticasone  na   ■ receiving triamcinolone injections Budesonide na ■ ■ /  ■ na Methods • 4/6 presented with signs of Cushing’s syndrome and Triamcinolone  na na  ■

adrenal suppression Mometasone ■ na ■ ■ ■ • Case series based on 11 patients presenting to the Methylpred ■ ■ na na na • 2/6 were identified very early after injection, before HIV clinic who are known or subsequently discovered Prednisolone ■ ■ na na ■ symptoms of glucocorticoid excess had developed. In to have received a variety of glucocorticoids whilst Hydrocortisone ■ ■ na na  one case (patient 6) ATV/r was switch to raltegravir taking ritonavir-based ART leading to adverse drug- Dexamethasone ■ ■ na na ■ within 3 weeks of injection to expedite clearance of drug interactions (DDI) Beclometasone      triamcinolone. Patient 3 required PI-based HAART Key:  Contraindicated/risk of severe AE, ■ Caution,  minor risk, na not applicable

due to resistance Inhaled steroids and ritonavir:

• Triamcinolone injection was prescribed via the pain Fluticasone inhaled/nasal (1) • Fluticasone inhaler and nasal sprays should be team, neurology, rheumatology and orthopaedic avoided wherever possible • 4 patients presented with symptoms of adrenal specialities, typically from with the hospital • Beclometasone is the preferred inhaled steroid due to suppression after exposure to inhaled (n=4) and/or lack of observed interactions nasal (n=2) fluticasone whilst on ritonavir-based ART

• When beclometasone is ineffective then inhaled • One patient (ID 7) presented with impaired mobility budesonide may be an alternative but used at the due to back pain and proximal muscle weakness, Clobetasol cream lowest dose with titration, counselling, and monitoring which on imaging showed osteoporotic vertebral crush of cortisol fractures in thoracic and lumbar spine (fig 1) • One black-African female presented with Cushing’s syndrome after months of exposure to topical • Steroid sparing therapies should be considered secondary to inhaled fluticasone use with LPV/r. He presented with cushingoid appearance with central clobetasol, used for skin whitening. It is unclear to Injectable steroids: what extent the cream is absorbed but her PI-based obesity and truncal striae, and developed CMV • Triamcinolone should be avoided for patients regimen may have contributed to adrenal suppression viraemia, transaminitis, and influenza AH1N1 during prescribed ritonavir, and potentially other CYP 3A4 inpatient admission inhibitors such as the HCV NS3 protease inhibitors Fig 2: Triamcinolone patients (n=6); HPA axis recovery over 6 months • Methylprednisolone may be a suitable alternative,

350 although there is limited data on DDI and safety

• A morning cortisol should be performed 2 weeks after 250 any glucocorticoid injection with referral to endocrinology if measured cortisol is low

ART modification: 150 Triamcinolone Injection ID • If a glucocorticoid is indicated with high risk of DDI then 1 2 switching to a PI/r sparing regimen should be

Serum cortisol (nmol/L) cortisol Serum 50 3 considered for the duration of glucocorticoid exposure 4 5 • If a PI/r sparing regimens are not possible due to 6 0 significant HIV resistance, a discussion should be had 0m 1m 2m 3m 4m 5m 6m over choice and dose of glucocorticoid, plus planned Cortisol of <80nmol/L: adrenal suppression requiring replacement. Cortisol 80-450nmol/L: possible adrenal suppression, investigate with SST. Cortisol >450nmol/L: adequate response, no further investigation follow up between the HIV team and referring clinician Fig 3: Patient exposed to triamcinolone, fluticasone or clobetsol Hydrocortisone Route of exposure / Duration of ID Age/Sex Glucocorticoid ART regimen Presented with Effect of interaction replacement Change in ART Dose exposure therapy given Conclusions ATV/r/ Fatigue, dizziness on standing, chest 1 47 M Triamcinolone IA 40mg 2 doses Adrenal suppression No No TDF/TFC infection Nausea, vomiting, diarrhea, urine • As we increasingly involve primary care and other 2 47 M Triamcinolone IA 80mg stat LPV/r Adrenal suppression No No infection, worsened type 2 diabetes specialties in our patient’s care we will need to be ATV/r/ 3 65 M Triamcinolone IA 40mg 2 doses No symptoms as early recognition Adrenal suppression Yes No MVC/RAL vigilant for the potential of these interactions, and DRV/r/ Weight gain, moon face, acne, oral Cushing’s syndrome with 4 39 F Triamcinolone IA 40mg 2 doses Yes DRV/r  RAL at month 4 provide colleagues and patient alike with information TDF/FTC OD candiasis, worsening depression adrenal suppression ATV/r/ resources for drug interactions 5 42 M Triamcinolone IA 80mg Stat Severe proximal myopathy Adrenal Suppression No No NVP/TDF ATV/r/ • When patients on ritonavir-based HAART require 6 42 M Triamcinolone IA 40mg 2 doses No symptoms as early recognition Adrenal Suppression Yes ATV/r  RAL at wk3 TDF/FTC glucocorticoids which interact, a multi-disciplinary Back pain (Osteoporotic crush fracture, LPV/r/ Cushing’s syndrome with 7 55 M Fluticasone INH 1000mcg/day 2 yrs see image 1) with overt Cushing’s Yes No approach is necessary to avoid increased morbidity adrenal suppression TDF/FTC syndrome, Aspergilloma

Weight gain, plethoric puffy face, ATV/r/ Cushing’s syndrome with 8 45 M Fluticasone INH 1000mcg/day 2 yrs centripetal obesity, striae, proximal Yes, short term No TDF/TFC adrenal suppression weakness ATV/r/ Tiredness, plethoric facies after ritonavir 8 45 M Fluticasone INH 1000mcg/day 7 days Adrenal Suppression Yes, short term No References TDF/TFC re-commenced INH 400mcg/day + Months ATV/r/ Cushing’s syndrome with 9 71 M Fluticasone Overt Cushing’s syndrome No No nasal spray + weeks TDF/FTC adrenal suppression • Foisy MM et al. HIV medicine 2008;9:389-396 • Mollman et al. Eur J clin pharmacol 1998;53:459-467; Fluticasone / Nasal spray / LPV/r/ 10 42 F 4 weeks No symptoms as early recognition Adrenal suppression No No • Ramanathan R et al. CID 2008;475 betamethasone 0.1% cream SAQ/NVP • Sarita B et al. CROI 2012, Seattle, Session 109, poster 611 Skin whitening Several ATV/r/ Cushing’s syndrome with • Sarita B et al. CROI 2012, Seattle, Session 109, poster 610 11 72 F Clobetsasol Overt Cushing's syndrome Yes No cream months ABC/3TC adrenal suppression • www.hivclinic.ca accessed 10/4/2012