Liverpool HIV Interactions

Potential Interaction

Ritonavir (RTV)

_Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but may increase dexamethasone concentrations. A dose reduction of dexamethasone may be necessary with monitoring for symptoms of Cushing’s syndrome. Chronic or high doses of dexamethasone may also decrease ritonavir plasma concentrations due to CYP3A induction with the possible loss of therapeutic effect and development of resistance. Use with caution. Adrenal axis suppression and Cushing's syndrome was reported in a woman receiving atazanavir/ritonavir, tenofovir and emtricitabine with dexamethasone 0.1% eye drops six times daily. Elevated levels of dexamethasone were measured at presentation (1.4-1.7 nmol/L) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/L). The clinical time-course strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular dexamethasone.

Description:

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of dexamethasone. Careful monitoring of therapeutic and adverse effects is recommended when dexamethasone is concomitantly administered with ritonavir.

Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

Coadministration is expected to increase concentrations of dexamethasone. Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Norvir Prescribing Information, AbbVie Inc, December 2016.

A case study was reported of a 15-year-old boy with sight-threatening vernal keratoconjunctivitis (VKC) who was diagnosed with HIV. His VKC was managed with dexamethasone 0.1 % eye drops, twice daily, which after presenting with an epithelial corneal defect was increased to hourly application. Two weeks after increasing the dosage, he developed moon facies, and 6 weeks later he reported increased weight gain and mood changes and on investigation low serum cortisol was found. Surgical intervention and botox allowed the reduction of dexamethasone to three times daily, and his ART was changed to a ritonavir-sparing regimen of unboosted atazanavir (400 mg, once daily), with dolutegravir and zidovudine/lamivudine. Eventually, he was able to replace dexamethasone with tacrolimus 0.1%. Within 12 weeks of changing his ART regimen, his cushingoid appearance and serum cortisol had resolved. The authors hypothesise a drug-drug interaction occurred via inhibition of CYP3A4 and by ritonavir

Ritonavir and topical ocular corticosteroid induced Cushing's syndrome in an adolescent with HIV-1 infection. Rainsbury PG, Sharp J, Tappin A et al. Pediatr Infect Dis J, 2017, 36(5): 502-503.

A case reports describes a 51-year-old woman with HIV who presented with weight gain and a 1-month history of right hip pain. Her ART included tenofovir (300 mg once daily), emtricitabine (200 mg once daily), and atazanavir/ritonavir (300/100 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. 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. 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 250mg (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. Analysis 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). 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.

Cushing’s syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. Molloy A, Matheson NJ, Meyer PAR, et al. AIDS, 2011, 25(10): 1337-1338.

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