Hypercortisolism Caused by Ritonavir Associated Inhibition of CYP 3A4 Under Inhalative Glucocorticoid Therapy. 2 Case Reports and a Review of the Literature

Abstract

Recent in vitro and in vivo studies have shown a potent inhibition of cytochrome P450 CYP3A4 through human immune deficiency virus (HIV) protease inhibitors (PIs). The PI ritonavir is described as the most potent compound within these CYP3A4 inhibitors. We present 2 cases who developed the sequelae of glucocorticoid excess following ritonavir therapy and inhalative glucocorticoid treatment: A 60-year-old HIV positive man developed the typical symptoms of Cushing's syndrome and a 52-year-old HIV positive man developed severe osteoporosis.

HIV-associated obstructive lung diseases: insights and implications for the clinician

“…Concomitant use of ritonavir and inhaled corticosteroids results in symptomatic hypercortisolism; the most well described interactions have occurred with the inhaled corticosteroid fluticasone. 62–67 There are a range of hypercortisolism-related symptoms and findings reported in HIV-infected individuals on boosted ritonavir regimens and inhaled corticosteroids (panel 2). 62–67 Most case reports describe interactions between fluticasone and protease inhibitors, but the clinician should be aware that other inhaled corticosteroids including budesonide and, to a lesser extent, beclomethasone, can lead to hypercortisolism symptoms if they are given concomitantly with protease inhibitors.…”

“…62–67 There are a range of hypercortisolism-related symptoms and findings reported in HIV-infected individuals on boosted ritonavir regimens and inhaled corticosteroids (panel 2). 62–67 Most case reports describe interactions between fluticasone and protease inhibitors, but the clinician should be aware that other inhaled corticosteroids including budesonide and, to a lesser extent, beclomethasone, can lead to hypercortisolism symptoms if they are given concomitantly with protease inhibitors. 68–70 The 2013 update of the antiretroviral treatment guidelines 71 advised clinicians to avoid co-administration of ritonavir-based ART with inhaled budesonide or fluticasone, unless the benefits clearly outweighed the risks; however, inhaled beclomethasone was not included in this advice.…”

Inhaled corticosteroid use in HIV‐positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management

“…By searching PubMed and the references of pertinent articles, and by contacting relevant drug companies, we identified 51 case reports published in English regarding adverse effects with the use of inhaled ( n = 45), intranasal ( n = 2), and combination inhaled and intranasal ( n = 4) corticosteroids and PIs (Table ) . Papers were published between the years 1999 and 2012.…”

Clinical Perspective: What Do Addison and Cushing Tell Us About Glucocorticoid Action?

“…Usually Cushing's syndrome is only seen with systemic glucocorticoid exposure, but it is possible to receive enough systemic exposure from injections into the joint, inhaled preparations, or topical preparations [ 8 -10 ]. There were a large number of cases of Cushing's syndrome in HIV patients taking the inhaled glucocorticoid fl uticasone because the commonly used anti-viral medication ritonavir inhibited the body's system of breakdown for the inhaled glucocorticoid, thereby raising levels of the inhaled glucocorticoid in the blood [ 11 ]. Another relevant point is that one cannot rule in or rule out Cushing's disease with the serum cortisol levels alone.…”