Cushing's syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops

Abstract

Treatment of HIV infection with antiretroviral therapy (ART), particularly the protease inhibitors, may be associated with syndromes of abnormal fat accumulation known as lipodystrophy [1]. Protease inhibitor-associated lipodystrophy shares common clinical features with Cushing's syndrome, including the development of central, visceral obesity and enlargement of the dorsocervical fat pad [2]. Cushing's syndrome due to co-administration of the protease inhibitor ritonavir with inhaled fluticasone has been well documented [3]. Recently, cases of Cushing's syndrome occurring in patients treated with ritonavir and epidural or intra-articular triamcinolone have also been reported [4,5]. Here, we describe the first case of Cushing's syndrome secondary to the co-administration of ritonavir with corticosteroid eye drops. A 51-year-old woman with HIV presented to our clinic with weight gain and a 1-month history of right hip pain. Her CD4 cell count was 1070 cells/μl and her HIV viral load was less than 50 copies/ml. On examination, she was noted to have central adiposity and enlargement of the dorsocervical fat, but no peripheral lipoatrophy. An MRI scan of the hip showed avascular necrosis. Her ART included tenofovir disproxil (as fumarate) 300 mg with emtricitabine 200 mg (Truvada) once daily, ritonavir 100 mg once daily and atazanavir 300 mg once daily. Because of previous bilateral cytomegalovirus retinitis, complicated by immune recovery uveitis with severe, chronic, cystoid macular oedema, she was also using dexamethasone 0.1% eye drops six times daily, and betamethasone 0.1% eye ointment at night, in both eyes. Courses of oral prednisolone and/or intravenous methylprednisolone had been administered on six occasions over the preceding 5 years, but no oral or parenteral steroids were prescribed during the 8 months prior to presentation. A tetracosactide (Synacthen) stimulation test showed marked suppression of the pituitary–adrenal axis, with a baseline cortisol of less than 25 nmol/l rising to only 37 nmol/l 30 min after administration of tetracosactide 250 μg (normal response at 30 min, > 570 nmol/l). Adrenocorticotropic hormone (ACTH) was undetectable. The presence of adrenal axis suppression with low ACTH, in the context of Cushingoid features and avascular necrosis of the hip, suggested ongoing exposure to high systemic levels of exogenous corticosteroids. Ritonavir and atazanavir were substituted with efavirenz 600 mg once daily, while continuing the steroid eye drops. Oral hydrocortisone 15 mg daily was added to avoid precipitating crisis due to adrenal insufficiency. Over the following year, the patient's weight declined, with marked improvement in her adrenal function. Subsequent testing of stored serum samples revealed elevated levels of dexamethasone at presentation (1.4 –1.7 nmol/l) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/l) (Fig. 1). Although prior courses of oral and intravenous corticosteroids may have contributed to adrenal axis suppression, the close temporal correlation between discontinuation of ritonavir, reversal of weight gain and recovery of adrenal function, combined with detectable levels of dexamethasone in the blood, strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular corticosteroids, resulting in adrenal axis suppression and Cushing's syndrome.Fig. 1: Changes in weight, systemic dexamethasone and cortisol secretion in response to discontinuing protease inhibitor therapy. , Weight;, serum dexamethasone level;, basal serum cortisol level;, serum cortisol level 30 min after administration of tetracosactide 250 μg.Ritonavir is an integral part of ART in which it is used at low doses (≤200 mg/day) to increase circulating levels of other protease inhibitors by inhibiting their metabolism by hepatic cytochrome P450 3A4 (CYP3A4). This enables lower, less frequent dosing, enhancing adherence and efficacy in HIV treatment. Fifty percent of licensed drugs are also metabolized by CYP3A4 [6], however, such that concurrent ritonavir administration may lead to toxic elevations in drug levels (http://www.hiv-druginteractions.org). CYP3A4 mediates the metabolism of many synthetic corticosteroids, including dexamethasone and its epimer betamethasone [6]. Co-administration of ritonavir with topical corticosteroids may, therefore, lead to elevated systemic corticosteroid levels, Cushing's syndrome and adrenal axis suppression, even in situations wherein systemic exposure would normally be low [3]. Cases of Cushing's syndrome associated with topical dexamethasone and betamethasone application alone, including as eye drops, have rarely been reported [7–10]. As in this case, co-administration with ritonavir may significantly increase the likelihood of developing such problems. Complications of iatrogenic Cushing's syndrome, including avascular necrosis of the hip and adrenal axis suppression, are serious and not always reversible. Weight gain and central obesity following ART may be suggestive of protease inhibitor-related lipodystrophy, but it is important to exclude other possible causes of adipose excess and redistribution before such a diagnosis is made. Clinicians caring for HIV-infected patients should be aware of the potential for adrenal axis suppression and Cushing's syndrome to develop following co-administration of protease inhibitor-based ART, particularly ritonavir, with a wide range of topical corticosteroids. Acknowledgements E.G.-K. is supported by the National Institute for Health Research (NIHR), Cambridge Biomedical Research Centre (BRC) and the Medical Research Council (MRC). A.M. drafted the manuscript. N.J.M. revised the manuscript and prepared it for submission. K.C. and P.A.R.M edited the manuscript. E.G.-K. provided final approval for submission and is the guarantor. All authors have read and approved the text. No author has any proprietary, financial or other interest in any product mentioned. No author received any financial support for this work. No author has any conflict of interests in this article. The authors would like to thank Craig Webster (Birmingham Heartlands Hospital) and David Church (Addenbrooke's Hospital) for their help with measurement of serum dexamethasone levels.