The Case

A 42-year-old man with acquired immunodeficiency syndrome (AIDS) (CD4 count 198), hip dystocia, and generalized anxiety disorder presented with acute sciatic pain. His human immunodeficiency virus (HIV) regimen (ritonavir-boosted darunavir, tenofovir, and emtricitabine) had been stable, resulting in an undetectable blood plasma viral load. In addition to his antiretroviral therapy, he was also taking clonazepam and escitalopram. After review by his primary care provider, the patient was referred to a spine orthopedist for management of his sciatica. A hip replacement had also been planned for his dystocia, but the sciatica resulted in a delay for his hip arthroplasty.

In response to his complaints, the spine surgeon elected to administer a single injection of epidural triamcinolone. However, one week after the injection, the patient returned to the surgeon's office complaining of fever, anxiety, nausea, abdominal pain, and insomnia. The surgeon advised the patient that these symptoms were not related to the epidural injection or the sciatic pain and referred the patient back to his internist. One week later, the patient was reexamined by the internist and found to have an elevated blood pressure (156/96 mm Hg), anxiety, 5-pound weight gain, and epigastric tenderness. Helicobacter pylori screening, HIV lab work, complete blood count, and chemistry screen revealed a decreased CD4 count to 98, nonfasting blood sugar of 166 mg/dL, and a positive urea breath test [a screening test for H. pylori]. One week of appropriate H. pylori treatment resulted in no improvement in symptoms; in fact, the patient complained of increased insomnia, anxiety, sweats, and weight gain. The diagnosis of Cushing syndrome was considered, and subsequent testing for this syndrome was positive.

The physicians later recognized that HIV medications, particularly ritonavir-associated therapy, are associated with substantial numbers of drug–drug interactions. Ritonavir induces cytochrome P450 (CYP1A2); however, it inhibits the major P450 isoforms (3A4 and 2D6). It was determined that triamcinolone is a 3A4 substrate, and ritonavir has been implicated in Cushing syndrome following oral and other routes of synthetic corticosteroid administration. The spine surgeon had only noted that the patient "is on HIV medication and stable" and did not review each individual medication. In addition, the spine surgeon did not provide a consultation report to the internal medicine team and primary care provider regarding the steroid injection. Only after the medicine and HIV teams questioned the patient regarding recreational steroid use did the patient reveal his recent epidural therapy.

The patient experienced 4 weeks of Cushing-like symptoms, including abdominal pain, insomnia, impotence, anxiety, sweats, and nausea; symptoms improved after adjustment of his HIV medications. These post-epidural events delayed his hip replacement surgery by several months.

The Commentary

Once considered a terminal illness, HIV/AIDS is now a manageable, albeit complex, chronic, outpatient disease.(1) As a result of improved potency, co-formulation, and pharmacokinetic enhancers (such as ritonavir and cobicistat), the handfuls of antiretroviral (ARV) agents that were commonly needed a decade ago have been mostly replaced with 1–2 pills taken once or twice daily. The more patient-friendly attributes of today's ARV regimens, however, do not negate the reality that optimal therapy still requires multiple concomitant antiretrovirals.(2) With the appropriate use of effective ARV therapy, HIV/AIDS patients live significantly longer and thus experience the usual chronic illnesses associated with aging in the 21st century.(3,4) Indeed, 50% of the HIV-infected population in the United States is older than age 50. Consequently, the risks associated with ARV "polypharmacy" are compounded by the treatments associated with the chronic conditions of a graying population, including diabetes mellitus, hypertension, and osteoporosis.(5) The greater the number of pharmacologically active agents, the higher the likelihood for a drug–drug interaction–induced adverse drug event.

Case reports of iatrogenic Cushing-like syndromes in HIV/AIDS patients, similar to this case, have been reported in the dermatologic (6,7), orthopedic (8,9), rheumatologic (10), and pulmonary (11) literature. The presence of these reports in specialty journals is not surprising, considering more HIV/AIDS patients are referred for non-urgent, non-HIV–related health concerns to specialty physicians and surgeons. Although the current case reveals a knowledge deficit regarding the interaction of triamcinolone (as a cytochrome P450 3A4 [CYP3A4] isoform substrate) with the inhibitory effect of ritonavir on that isoform, it also demonstrates several key medication safety issues that are not unique to HIV/AIDS. Ritonavir-associated drug interactions are likely with many commonly prescribed CYP3A4 substrates, including statins, erectile dysfunction agents, benzodiazepines, anticonvulsants, and warfarin. Even clinicians familiar with HIV medicine and ritonavir's complex pharmacologic interactions may not fully appreciate the associated risks.(12)

Useful information regarding drug interactions can be provided by community or health care setting pharmacists. Pharmacists have drug interaction data systems readily available and are particularly well-trained in this area. In addition, many office and institutional medical and/or prescription electronic record programs have drug interaction alerts.(13) Drug interaction information is also readily accessible to consumers and clinicians alike via numerous proprietary programs (e.g., Epocrates, Lexi-Drugs, and Micromedex), from pharmaceutical manufacturers and from multiple public domain (both HIV and non-HIV related) drug interaction Web sites (Table). Many of these public domain information sources provide additional data regarding potential interactions with non-prescription drugs. Patients and clinicians often do not consider non-prescription agents when discussing a medication regimen. Similarly, in light of the current $12 billion vitamins and complementary and alternative medicine supplement market, identification of alternative medicine agents known to interact with ARVs (e.g., St. John's wort) is important. Rapidly expanding hepatitis C treatment options further add to the already complicated concerns regarding clinically significant drug interactions.

Returning to the current case, a drug interaction between ritonavir and triamcinolone caused the Cushing syndrome. Furthermore, the greatly raised steroid levels likely were the etiology of the reduction in CD4 T-cell count from 198 to 98, increasing the risk for opportunistic infections. On top of that, the higher triamcinolone levels and hyperglycemia could have increased the risk for bacterial or fungal infection. While less subtle, the patient's insomnia and anxiety symptoms may well be due to the ritonavir-associated inhibition of escitalopram. The Helicobacter pylori treatment presumably included clarithromycin, and this antibiotic CYP3A4 inhibitor would have increased the ritonavir and triamcinolone levels even more.

The safe introduction of a new agent into an already complicated medication regimen can be challenging even with awareness of drug interactions. In addition, practicing medicine unaware of therapies given by a patient's other providers negates the value of the subspecialist's contributions.(14) Drug list reconciliation should be integral in the continuum of care. A number of proprietary electronic medical record systems, Regional Health Information Organizations, or Health Information Exchanges may be useful to that end. They potentially provide real-time data on recently prescribed and recently dispensed medications. Drug list reconciliation is the most effective method of ensuring medication safety and effectiveness, particularly with multiple prescribers.

Unfavorable drug–drug interactions are to be expected with polypharmacy and concomitant comorbidities. If a particular drug–drug interaction profile is unknown or unfamiliar, a clinician must conscientiously review the possibility for interactions and communicate the finding to the patient and other providers. This important step was clearly not performed in the current case. Even if the orthopedist had been aware of the risk for a triamcinolone–ritonavir interaction, the referring physician did not provide the specialist with important information regarding his ARV therapy. Last, consultation reports were evidently neither provided by the consultant nor sought by the referring clinician.

Even if communication had been significantly better than it was, there is always the chance of a key piece of data falling through the cracks. Accordingly, the use of open-ended questions to elicit the necessary information remains an integral part of the clinician–patient relationship. Questions like: "Is there anything else I should know regarding your health history?" and "Have I forgotten to ask you anything?" will often elicit crucial information. An open and non-judgmental atmosphere that promotes spontaneous, free-flowing information among patients and providers is equally important. On a practical level, patients should be encouraged to carry a complete list of their current medications at all times.

This case illustrates a confluence of epidemiological, clinician practice behaviors, knowledge deficits, and drug–drug interactions. These hazards are not unique to this case; in fact, they are a common set of conditions associated with polypharmacy and chronic disease management.

Take-Home Points

• If you do not regularly prescribe a particular medication, then independently review the possibility for interactions. Sources of drug interaction information are readily available directly from medical and pharmacy colleagues, as well as from proprietary digital programs and public domain resources.
• Elicit from both the patient and his provider(s) the full scope of a patient's current medicinal regimen, including over-the-counter, complementary, and alternative medicine supplements.
• Drug list reconciliation should be routinely performed and patients should be encouraged to carry their most recent list of prescribed medications.
• Use an open-ended interrogatory style to enhance spontaneous and free flow of information from patients.
• Formally communicate and review your therapeutic measures with both patients and your colleagues.

Charles John Gonzalez, MD Associate Medical Director for Science and Policy/Office of the Medical Director New York State Department of Health/AIDS Institute New York, NY

References

1. Press N, Tyndall MW, Wood E, Hogg RS, Montaner JS. Virologic and immunologic response, clinical progression, and highly active antiretroviral therapy adherence. J Acquir Immune Defic Syndr. 2002;31(suppl 3):S112-S117. [go to PubMed]

2. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003;348:1556-1564. [go to PubMed]

3. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289:1107-1116. [go to PubMed]

4. Kirk JB, Goetz MB. Human immunodeficiency virus in an aging population, a complication of success. J Am Geriatr Soc. 2009;57:2129-2138. [go to PubMed]

5. Gandhi TK, Burstin HR, Cook EF, et al. Drug complications in outpatients. J Gen Intern Med. 2000;15:149-154. [go to PubMed]

6. Gupta AK, Bluhm R. Seborrheic dermatitis. J Eur Acad Dermatol Venereol. 2004;18:13-26. [go to PubMed]

7. Borzyskowski M, Grant DB, Wells RS. Cushing's syndrome induced by topical steroids used for the treatment of non-bullous ichthyosiform erythroderma. Clin Exp Dermatol. 1976;1:337-342. [go to PubMed]

8. Grierson MJ, Harrast MA. Iatrogenic Cushing syndrome after epidural steroid injections for lumbar radiculopathy in an HIV-infected patient treated with ritonavir: a case report highlighting drug interactions for spine interventionalists. PM R. 2012;4:234-237. [go to PubMed]

9. Danaher PJ, Salsbury TL, Delmar JA. Metabolic derangement after injection of triamcinolone into the hip of an HIV-infected patient receiving ritonavir. Orthopedics. 2009;32:450. [go to PubMed]

10. Yombi CD, Maiter D, Belkhir L, Nzeusseu A, Vandercam B. Iatrogenic Cushing's syndrome and secondary adrenal insufficiency after a single intra-articular administration of triamcinolone acetonide in HIV-infected patients treated with ritonavir. Clin Rheumatol. 2008;27(suppl 2):S79-S82. [go to PubMed]

11. Clevenbergh P, Corcostegui M, Gérard D, et al. Iatrogenic Cushing's syndrome in an HIV-infected patient treated with inhaled corticosteroids (fluticasone propionate) and low dose ritonavir enhanced PI containing regimen. J Infect. 2002;44:194-195. [go to PubMed]

12. Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, Molina JM. Iatrogenic Cushing's syndrome in HIV-infected patients receiving ritonavir and inhaled fluticasone: description of 4 new cases and review of the literature. J Int Assoc Physicians AIDS Care (Chic). 2009;8:113-121. [go to PubMed]

13. Bright TJ, Wong A, Dhurjati R, et al. Effect of clinical decision-support systems: a systematic review. Ann Intern Med. 2012;157:29-43. [go to PubMed]

14. Giordano SH, Hortobagyi GN. Time to remove the subspecialty blinders: breast cancer does not exist in isolation. J Natl Cancer Inst. 2008;100:230-231. [go to PubMed]

Table

Table. Web sites for consumers and clinicians regarding HIV and drug interactions.