A 34 year-old HIV-infected male presents with a complaint of increased appetite and weight gain. His weight gain was initially attributed to lipodystrophy related to his HAART, which consisted of Kaletra and Combivir. He returned a month later complaining of worsening depression and difficulty sleeping; he asks about initiating treatment for his depression, for which he had been treated in the remote past. He has no other medical problems except mild asthma, for which he takes Singulair daily and Advair seasonally, though has been using it almost daily for the past 2 months. On exam, his blood pressure was 148/92. He was obese with a central distribution of fat as noted on his prior visit. He had abdominal striae. Cardiovascular and pulmonary exams were normal. On laboratory evaluation he was noted to have glycosuria. An Accucheck done in the office was 214. A clinical diagnosis was made: iatrogenic Cushings syndrome due to ritonavir and fluticasone interaction.

This is an interaction that is increasingly recognized. Fluticasone is a substrate of CYP3A4, and ritonavir is a potent inhibitor of CYP3A4. This leads to decreased clearance of fluticasone and the potential for iatrogenic Cushings or adrenal insufficiency. The effect is most typically seen at fluticasone doses greater than 500mcg per day, and the time to onset of Cushingoid features is typically 2-3 months after drug initiation. Inhaled fluticasone (as in Advair) is a greater culprit than intranasal fluticasone (i.e., Flonase), but both have been implicated. Other inhaled steroids such as budesonide seem to be safer, probably because fluticasone is the most lipophilic and thus has the larger volume of distribution. Note that of the intranasal steroids, however, mometasone (Nasonex) behaves similarly to fluticasone and should also be avoided.

It is important to ask about ritonavir specifically when getting a medication history from patients. It is typically not used as an active drug, but rather to “boost” levels of other protease inhibitors. Because of this, it is sometimes left out of patient-reported HAART regimens. In the patient above, Combivir is a combo of 2 NRTI’s (zidovudine/lamivudine) and Kaletra is lopinavir plus ritonavir.

Cushings syndrome in HIV(+) patients must be distinguished from HAART-associated lipodystrophy. On physical exam, lipodystrophy will not have striae, and Cushings does not present with the peripheral lipoatrophy seen in HAART-associated lipodystrophy. Cushings should be strongly considered in patients presenting with the associated metabolic derangements of corticosteroid excess (such as diabetes and osteopenia / osteoporosis), with new or treatment-resistant hypertension, or with hypokalemia.

Although ritonavir, due to its potency in inhibition of CYP3A4, is probably the drug most likely to contribute to iatrogenic Cushings, other drugs inhibit CYP3A4 and should be considered. These include verapamil, clarithromycin, and the azole antifungals (especially itraconazole, which is especially potent). Most other protease inhibitors also are at least weak inhibitors of CYP3A4, as are ciprofloxacin and amiodarone. Some of these drugs (amiodarone and the azoles, for example) are so notorious for drug-drug interactions that most people carefully review the med list carefully for interactions before starting them. However, how often do you consider this before writing for 6 weeks of ciprofloxacin for osteomyelitis? Also, of the macrolides, clarithromycin is the most potent CYP3A4 inhibitor, and this should be borne in mind when prescribing prophylaxis for HIV patients.

Finally, megestrol (Megace), a progestin with some corticosteroid activity, can contribute to development of Cushings syndrome in patients on inhaled steroids, especially if they are also being exposed from another source as well (such as inhaled steroids). Sudden withdrawal from megestrol can also precipitate adrenal insufficiency, especially in acutely ill patients.