|Home | About | Journals | Submit | Contact Us | Français|
We report the first case of an HIV-1 infected individual undergoing therapy with ritonavir who developed Cushing’s syndrome with profound complications following epidural triamcinolone injections. The case highlights the potential of ritonavir interactions even in local injections of corticosteroid.
A 35 year-old man enrolled in a natural history protocol at the National Institutes of Health (NIH) had a history of HIV-1 infection for 7 years complicated by hepatitis B, Kaposi’s sarcoma, depression and chronic back pain. His HIV-RNA level was suppressed (<50 copies/ml) and CD4+ T cell count was 470/mm3 (28%) on combination lopinavir/ritonavir (400mg/100mg twice daily), emtricitabine and tenofovir (total daily dose of 200mg and 300 mg, respectively), which he had been taking for 2 years. Additional medications included trazodone, rabeprazole, fexofenadine, oxycodone/acetaminophen, gabapentin, oxycodone, and cyclobenzaprine. He developed acute exacerbation of lumbosacral back pain and magnetic resonance imaging revealed a new L4 - L5 disc herniation. As the pain remained intractable despite several weeks of conservative management, he received two sequential epidural injections of triamcinolone acetonide 60 mg and 80 mg (one week apart), with some relief. He returned to the HIV clinic one month later reporting that within a week of injections, he developed facial swelling that he felt was cosmetically disfiguring. Physical examination noted new hypertension with blood pressure of 157/100 mm Hg, dorsocervical fat pad and moon facies with plethora. A subcentimeter laceration on his left index finger had not healed for over four days, and he had a measured weight gain of 1.4 kilograms over the previous month.
Further evaluation noted biochemical evidence of suppression of the hypothalamic-pituitary-adrenal axis, with an undetectable morning plasma cortisol level (< 1 μg/dL, reference range 10–20 μg/dL), suppressed plasma adrenocorticotropic hormone (ACTH, < 5.0 pg/mL, reference range 0–46 pg/mL), and an inadequate response to stimulation with cortrosyn 250 ug (plasma cortisol level of 1.2 μg/dL after 60 minutes). By contrast, the patient had a normal random cortisol level of 10.4 μg/dL (reference range 10–20 μg/dL) two weeks before the first epidural injection. His fasting glucose was elevated at 140 mg/dL, despite previously normal results. Computed tomography of the abdomen did not reveal radiographic evidence of an adrenal mass. Three weeks after the final epidural injection, the patient’s serum triamcinolone acetonide level remained elevated (0.69 μg/dL, Mayo Medical Labs, Rochester, MN). One week later, the patient had thrush on physical examination. His CD4 count had declined from 470 (28%) to 69 cells/mm3 (16%) while his HIV RNA level remained <50 copies/ml. Prophylaxis for Pneumocystis jiroveci pneumonia with trimethoprim-sulfamethoxazole was initiated. The patient developed suicidal ideation two weeks later. His blood pressure at this visit was 161/88. Oral hydrochlorothiazide (12.5 mg daily) was started for hypertension.
As we suspected the role of ritonavir on inhibition of triamcinolone metabolism, his antiretroviral medications were changed at this time to atazanavir, stavudine, and lamivudine. Rabeprazole was discontinued in order to assure adequate absorption of unboosted atazanavir. Three weeks following regimen change, his moon facies began to improve and serum triamcinolone acetonide levels declined from 0.69 μg/dL to 0.07 μg/dL (Figure 1).
Reflux worsened after discontinuing rabeprazole. Since the triamcinolone acetonide level had significantly decreased, it was thought safe to resume the initial regimen of lopinavir and ritonavir, tenofovir and emtricitabine with the protein pump inhibitor. Two weeks after this change, his serum triamcinolone acetonide level increased from 0.07 μg/dL to 0.19 μg/dL, and because of this rise, his antiretroviral medications were then changed to nevirapine, tenofovir and emtricitabine. He was monitored closely for signs and symptoms of adrenal crisis during this period. His serum triamcinolone acetonide level rapidly decreased to undetectable five days after initiation of the nevirapine containing regimen. At the same time, recovery of adrenal suppression was demonstrated by a baseline serum cortisol level of 6.8 μg/dl. The serum cortisol sixty minutes after stimulation with cortrosyn was 20.8 μg/dl. Complete resolution of facial plethora, hypertension, and glucose intolerance occurred five months after the last triamcinolone acetonide injection. Immunologic recovery, however, was slow. His CD4 count increased from 69 (16%) to 250 cells/mm3 (19%) after three months. The patient’s course was further complicated by avascular necrosis of the right femoral head, diagnosed by magnetic resonance imaging eleven months after the last triamcinolone acetonide injection, despite a previously normal study.
Although prolonged Cushing’s syndrome (6–12 months) resulting from epidural administration of methylprednisolone alone has been known to occur in a normal host without HIV infection, such reports are extremely rare (1). Drug-drug interactions are common with antiretroviral therapy, particularly so with antiretrovirals that interact with hepatic metabolizing enzymes, especially cytochrome p450 3A4 (CYP3A4) microsomal oxidation pathway, which is responsible for phase I metabolism of a substantial proportion of xenobiotics. Since its introduction for treatment of HIV-1 infection, the use of ritonavir has resulted in recognition of significant drug interactions arising from the decreased clearance of drugs metabolized by CYP3A4. Although numerous case reports warn against the potentially lethal combination of inhaled fluticasone propionate in patients on low dose ritonavir (2), a similar association with epidural triamcinolone has not been reported to date.
In this patient, ritonavir administration contributed to the development of profound and persistent adrenal suppression due to the significant inhibition of metabolism of 140 mg (322 μM) of triamcinolone acetonide given as epidural injections. Triamcinolone acetonide is typically rapidly metabolized, with an estimated half life of 2–3 hours (3); the acetonide version is less water soluble than other glucocorticoid derivatives, and absorption from intra-articular sites has been reported to continue for 2–3 weeks following injection (4). In this patient, the rate of decline in triamcinolone acetonide levels (Figure 1) from days 22–62 following the last dose of epidural injection approximated linear decay kinetics (slope 0.0154 μg/day, r2=0.992) with a calculated half life of 21.3 days. We infer from these data that the triamcinolone acetonide half-life was prolonged at least 170-fold. Analysis of steroid pharmacokinetics in the presence of ritonavir indicate that the half-life of prednisolone was 33% longer in normal hosts four days after the coadministration of ritonavir (200 mg daily) and prednisone (20 mg, one time dose), and that the magnitude of the interaction was diminished by day fourteen (5). This suggests that some effect on glucocorticoids may have been anticipated, but the inhibition seen in this patient was extreme.
Factors in addition to ritonavir may have influenced triamcinolone levels in this case. Both lopinavir and atazanavir exhibit inhibitory effects on CYP3A, albeit to lesser potency than ritonavir, and the combinations of these drugs likely contributed to net CYP3A inhibition (6,7). The patient had a history of chronic hepatitis B and it is not known whether hepatic injury from hepatitis B infection contributed to relatively slow metabolism of triamcinolone acetonide; no elevations in serum ALT or AST were detected in this patient, although specific effects on drug metabolizing enzymes has not been investigated extensively. Horikke and coworkers (8) have reported a 2-fold decrease in CYP3A4 mRNA in individuals with chronic hepatitis B infection compared with uninfected controls, suggesting a potential effect of hepatitis B on drug metabolism.
The use of nevirapine hastened glucocorticoid clearance, likely due to nevirapine induction of CYP 3A4 (9). Considerable caution to this approach, however, should be emphasized given that adrenal crisis could result from a rapid decline in glucocorticoid levels if it unmasked suppression of pituitary ACTH production by the previous glucocorticoid exposure.
It is important to use the lowest effective glucocorticoid dose for all patients, particularly so for individuals with HIV infection, who are at elevated risk for complications of steroid therapy, including infectious and non-infectious complications (e.g., avascular necrosis). In this context, drug-drug interactions because of cytochrome p450 inhibition may be serious, life threatening or fatal. Progression of Kaposi’s sarcoma has been reported in HIV patients with iatrogenic Cushing’s syndrome, although our patient did not experience this adverse event (10). Marked decrease in circulating lymphocytes in response to glucocorticoids has been previously reported (11), and the relatively slow rebound in peripheral CD4 cells suggests the need for continued caution when corticosteroids are co-administered.
Epidural corticosteroids are frequently prescribed to patients for various indications, including intractable pain. Monitoring drug-drug interactions is a critical aspect of routine evaluation in HIV-1 infected individuals; therapeutic drug monitoring has been proposed (12), although practical limitations preclude feasibility in routine clinical care. Rather, primary physicians and consults should have a heightened sense of awareness for potential interactions, to avoid important adverse effects in patients who receive epidural corticosteroids.
Financial support. This study was supported by the National Institutes of Health and intramural programs of National Institute of Allergy and Infectious Diseases, National Cancer Institute and National Institute of Child Health and Human Development.
Potential conflicts of interest. All authors: No conflicts.