Iatrogenic Cushing's syndrome after triamcinolone plus ritonavir-boosted atazanavir

Jakeman, Bernadette; Conklin, Jessica; Bouchonville, Matthew F.; Thornton, Karla

doi:10.1331/japha.2015.14114

Cited by 7 publications

(7 citation statements)

References 23 publications

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“…Cases of iatrogenic adrenal suppression presenting in PLWH in an immunodeficient state with a normal CD4 count have previously been described but this is not observed in our patient 26 28 30 31. Jakeman et al reported oral candidiasis and herpes manifesting as a part of the immune suppression associated with exogenous glucocorticoid excess 32. Other clinical signs include hypertension, hyperglycaemia and adrenal insufficiency 19 31 33…”

Section: Discussionmentioning

confidence: 61%

“…The literature also reveals other symptoms and signs of this drug–drug reaction which are important to be aware of, but has not presented in our patient. Jakeman et al reported oral candidiasis and herpes manifesting as a part of the immune suppression associated with exogenous glucocorticoid excess in a similar intrabursal injection into the shoulder 32. Other clinical signs include hypertension, hyperglycaemia and adrenal insufficiency 10 29 30…”

Section: Discussionmentioning

confidence: 99%

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Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction between cobicistat and intrabursal triamcinolone

et al. 2018

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We report a diagnosis of exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction (DDI) between intrabursal triamcinolone and the pharmacokinetic booster cobicistat. A 53-year-old woman living with HIV, managed with dolutegravir and cobicistat-boosted darunavir, presented to the orthopaedic clinic with worsening hip pain. She was diagnosed with greater trochanteric pain syndrome (GTPS) of the hip and was treated with intrabursal injection of bupivacaine and triamcinolone. Seven days following this injection, she presented with Cushingoid features, an undetectable cortisol and was diagnosed with exogenous steroid-induced hypoadrenalism. Cobicistat is a cytochrome P450 3A inhibitor and in this case inhibited clearance of intrabursal triamcinolone, leading to exogenous glucocorticoid excess and adrenal suppression. This is the first report to describe this predictable DDI with cobicistat following intrabursal glucocorticoid injection. This case highlights the complexities in managing non-HIV-related chronic morbidities in people living with HIV.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction between cobicistat and intrabursal triamcinolone

et al. 2018

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“…With the development of triamcinolone-induced Cushing’s syndrome, weight gain and cushingoid facial changes are usually the leading symptoms ( 2 ). Time to development of symptoms following triamcinolone injection has been reported to range from one week to five months ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

“…One option includes replacing RTV with a non-PI-based regimen. Individual case reports have also substituted RTV for an unboosted PI ( 10 ), a choice not applicable for pediatric patients or integrase inhibitors such as for raltegravir ( 2 , 13 ). Hydrocortisone replacement therapy may be initiated while awaiting HPA recovery.…”

Section: Discussionmentioning

confidence: 99%

Acute development of Cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy

Dubrocq

Estrada

Kelly

et al. 2017

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom), didanosine, ritonavir and atazanavir presented with bilateral axillary striae, increased appetite, fatigue, facial swelling and acute weight gain. Two months prior to presentation, the patient had received a diagnostic and therapeutic intra-articular triamcinolone injection in the knee for pain relief and subsequently became progressively swollen in the face, developed striae bilaterally at the axillae, experienced increased appetite, fatigue and an 8 pound weight gain. During the endocrine workup, suspicion for adrenal insufficiency prompted 24-h urine collection for free cortisol, which was found to be undetectable (below LLQ of 1.0 µg/L). This prompted further evaluation of the hypothalamic–pituitary axis (HPA) by standard dose adrenocorticotropic hormone (ACTH) stimulation test. A 250 µg cosyntropin stimulation test was performed and confirmed HPA axis suppression. Baseline cortisol level was <1 µg/dL and stimulated cortisol level at 30 min was 3.8 µg/dL. The patient was diagnosed with iatrogenic Cushing syndrome and suppression of HPA axis secondary to the drug interaction between ritonavir (RTV) and intra-articular triamcinolone injection. Following endocrine evaluation and workup, the patient was admitted for planned orthopaedic procedure including elective left hamstring lengthening, distal femoral osteotomy and patellar tendon advancement. Taking into consideration the diagnosis of iatrogenic Cushing syndrome, at the start of the surgical procedure, 100 mg IV stress dose of hydrocortisone followed by 50 mg hydrocortisone every 8 h for 24 h was administered. Stress dosing was discontinued 24 h after the procedure. Throughout the hospitalization and upon discharge, the patient continued his ART. From initial presentation, patient has remained clinically stable throughout surgery and postoperative period.Learning points:Drug–drug interaction between ritonavir and triamcinolone can cause Cushing syndrome.Although triamcinolone has a half-life of 3 h, an intra-articular injection may be systematically absorbed for 3 weeks after injection, and adrenal suppression may last as long as 30 days.Co-administration of ritonavir and corticosteroids may result in an increase of plasma levels of corticosteroids levels, as they are both eliminated by CYP3A metabolism, and this interaction has the potential to prolong the half-life of triamcinolone several fold.No specific guidelines are available for the management of iatrogenic Cushing syndrome secondary to ritonavir and corticosteroids.One treatment option includes replacing ritonavir with a non-protease inhibitor-based regimen.Initiating hydrocortisone replacement therapy to prevent an adrenal crisis is also an alternate option.

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“…All of these patients were injected with triamcinolone, except one who was injected with methylprednisolone. [8][9][10][11][26][27][28][29][30] A retrospective review reported an 11% event frequency, with the biggest risk factor being two or more injections within 6 months. 26 Interestingly, a recent randomised controlled trial demonstrated no efficacy advantage of triamcinolone over methylprednisolone for knee osteoarthritis (in a non-HIV population).…”

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confidence: 99%

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

et al. 2016

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Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established. We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations. KEYWORDS : Adrenal insuffi ciency , cobicistat , Cushing's syndrome , HIV , ritonavir IntroductionRitonavir and cobicistat are pharmacokinetic enhancers used in the treatment of HIV infection. They are extremely potent inhibitors of cytochrome P450 3A4 (CYP3A4) activity. Ritonavir, originally developed as an antiretroviral, is used ABSTRACT Iatrogenic Cushing's syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies at sub-therapeutic doses, in combination with HIV protease inhibitors (PIs), to significantly increase their concentrations and allow less frequent and lower dosing.1 Cobicistat was developed more recently and is similar in structure. It is used in combination with PIs or elvitegravir (an integrase inhibitor) 2 but has no antiretroviral activity itself. 3 The downside of this pharmacokinetic manipulation is the significant potential for interactions with CYP3A4 substrates, leading to side effects. CYP3A4 is the dominant isoenzyme of the hepatic cytochrome P450 system and is the primary metabolic step for the degradation of endogenous and most prescribed corticosteroids. The metabolism of these can therefore be decreased by inhibitors such as ritonavir/cobicistat. 4 Subsequent increases in exogenous corticosteroid plasma concentrations and half-life can lead to iatrogenic Cushing's syndrome (ICS) 5 and, at supraphysiological levels, to suppression of adrenocorticotropic hormone (ACTH) and endogenous corticosteroid secretion, potentially resulting in secondary adrenal insufficiency (SAI). There is abundant evidence highlighting this issue. 1,[6][7][8][9][10][11] However, a structured approach to identify and manage potentially affected individuals has not been established. We aim to summarise the current management of ICS/SAI in three large HIV patient cohorts, review the available literature and develop practice recommendations. Of note, cobicistat became available after the evaluation period covered; however, all advice for ritonavir is applicable to i...

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Iatrogenic Cushing's syndrome after triamcinolone plus ritonavir-boosted atazanavir

Cited by 7 publications

References 23 publications

Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction between cobicistat and intrabursal triamcinolone

Exogenous steroid-induced hypoadrenalism in a person living with HIV caused by a drug–drug interaction between cobicistat and intrabursal triamcinolone

Acute development of Cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

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