Alexa Vyain, PharmD

 will be bringing you a new case to review, along with commentary to help you hone your clinical acumen.

DT is a 46-year-old African American woman with HIV, COPD, hypertension, and hyperlipidemia who presents to clinic for routine follow up. Her current medications are listed in the Table. You note that budesonide/formoterol is no longer on the preferred formulary and that fluticasone/salmeterol (Advair) is now preferred. You run a drug interaction check and find that fluticasone/salmeterol is not recommended with darunavir/cobicistat with an “X: avoid combination” warning because of the potential for increased fluticasone concentrations and adrenal suppression.

	What change in therapy would you recommend to avoid the risk that DT could develop adrenal insufficiency and Cushing’s syndrome? Voice your opinion in the comments below, or let us know on our 

	Alexa Vyain, PharmD PGY2 HIV Ambulatory Care/Clinical Pharmacogenetics Resident 

	University of Houston College of Pharmacy

	According to DHHS guidelines, darunavir/cobicistat should not be combined with fluticasone, as coadministration can increase glucocorticoid levels and result in adrenal insufficiency and Cushing’s syndrome.

 To accommodate the formulary change, changes to DT’s antiretroviral therapy can be considered.

	Since all protease inhibitors (PIs) are subject to this drug interaction, it would be ideal to switch from a boosted protease inhibitor to another class. Integrase inhibitors as a class, cause far fewer adverse effects and have fewer drug interactions when used concomitantly with inhaled corticosteroids. Additionally, since this patient has hyperlipidemia and is currently being treated with a protease inhibitor-a class that is known to cause lipid abnormalities-switching from a protease inhibitor may yield more favorable effects on lipid levels.

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	It is important to assess a patient’s ability to adhere to their ART regimen before switching regimens, especially considering that DT is currently on darunavir, a PI with one of the highest genetic barriers to resistance of all antiretrovirals. Additionally, in general when switching medication regimens, it is important to maintain viral suppression without jeopardizing future treatment options.

	Therefore, it is pertinent to have recent laboratory results reflecting DT’s current viral load. The patient’s resistance history with any previous resistance testing should also be reviewed. If there is any doubt that her current regimen has been jeopardized, based on the presence of virologic failure and/or resistance mutations to her current regimen, it would be unwise to change her regimen at this time. However, if DT has sustained virologic suppression, I would feel comfortable switching her protease inhibitor to an integrase strand transfer inhibitor (INSTI) with confidence that she has full activity of all three agents. As it is unlikely for patients to possess inherent INSTI resistance, I would not feel it necessary to order an integrase resistance test at this time.

	With this information in mind, I would elect to transition this patient from darunavir/cobicistat to once daily dolutegravir 50 mg in combination with her current nucleoside reverse transcriptase inhibitor (NRTI) backbone of emtricitabine/tenofovir alafenamide daily. This would keep her at a once-daily regimen, which would support optimal adherence.

	In addition, dolutegravir is largely metabolized by UGT1A1 and to a lesser extent CYP3A4.

 With this in mind, it is likely that by removing her current PI, she may not experience as pronounced of an effect from her current doses of atorvastatin and amlodipine, as the metabolism of both of these drugs is inhibited by PIs via CYP3A4 phase I metabolism. By removing her PI, she may require higher doses of both of these agents to achieve the same therapeutic effect. Although dolutegravir still possesses minor CYP3A4 inhibition, dose adjustments may still be necessary. It is important to monitor her lipids and blood pressure for changes, and make adjustments to these medications as necessary. It would be important to note baseline lipid and blood pressure parameters before changing her antiretroviral regimen as well.

	I would not elect to use elvitegravir, as this INSTI requires boosting by cobicistat, which would present the same drug interaction issues with fluticasone as the boosted PIs. Another option to consider is the new once-daily dosing option of two 600-mg raltegravir tablets once daily, which does not require pharmacokinetic boosting. However I elected to choose dolutegravir because of its lower pill burden and higher chance of insurance coverage, as the new formulation of raltegravir was just FDA approved in May 2017.

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	Lastly, if resistance testing revealed sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs), it would be an option to switch darunavir/cobicistat to an NNRTI such as rilpivirine, as it does not possess any significant drug interactions with her current medication list. I chose dolutegravir instead because it is not only a small pill similar to rilpivirine, but it also does not require administration with a meal like rilpivirine, which could lead to inadequate absorption of the drug if the patient is unable to consistently comply with this administration recommendation. Lastly, INSTIs do have a higher genetic barrier to resistance than most NNRTIs including rilpivirine, which also contributes to my clinical decision. 

	1.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://bit.ly/1fEQrl8.

	2.Tivicay (dolutegravir) [prescribing information]. Research Triangle Park, NC. ViiV; June 2016.

	3.Isentress (raltegravir) [prescribing information]. Whitehouse Station, NJ. Merck & Co; May 2017.

	Justin A. Andrade, PharmD Candidate, 2018, and  Amy M. Cheng, PharmD, AAHIVP

	The medication that puts DT most at risk for adrenal insufficiency and Cushing’s syndrome is the fluticasone component in fluticasone/salmeterol used concomitantly with darunavir/cobicistat. Darunavir is a protease inhibitor (PI) that is commonly boosted with either ritonavir or cobicistat, which are strong CYP3A inhibitors. Thus, substrates of CYP3A4, such as fluticasone and budesonide, can have increased concentrations if taken in combination with darunavir/cobicistat (DRV/c) or darunavir/ritonavir (DRV/r, Prezista/Norvir). There have been multiple case reports showing that PI-based regimens such as DRV/r and DRV/c, when used concomitantly with corticosteroids such as budesonide and fluticasone, can have a suppressive effect on the hypothalamus-pituitary-adrenal axis.

 This suppressive effect is associated with the pharmacokinetic properties seen in fluticasone, such as higher lipophilicity, longer elimination half-life, and a higher glucocorticoid relative receptor binding affinity. As a result, DT would be at a higher risk of developing facial hirsutism, osteoporosis, decreased CD4 cell count, and rapid weight gain as seen in Cushing’s syndrome and adrenergic insufficiency.

 an alternative medication is warranted for COPD treatment in HIV patients who take boosted protease inhibitor regimens co-administered with fluticasone, budesonide, or mometasone.

	Our recommendation would be to adjust the regimen for DT by discontinuing her previous COPD drugs and initiating 2 puffs daily beclomethasone 80 mcg (Qvar), based on the Global Initiative for Chronic Obstructive Lung Disease guidelines.

 Additionally, the DHHS HIV guidelines state there is no significant interaction between beclomethasone (inhaled or intranasal) and DRV/c or DRV/r.

	In an open-label prospective randomized pharmacokinetic and pharmacodynamic study in 30 healthy volunteers, investigators identified an alternative inhaled corticosteroid to fluticasone that can be safely administered with HIV PIs.

 Beclomethasone is a prodrug that is rapidly hydrolyzed by esterases to 17-BMP (active metabolite) and two inactive metabolites. Investigators found that there was no change in 17-BMP after 14 days of inhaled beclomethasone and DRV/r co-administration. While the DHHS HIV guidelines documents a 350-fold increase in fluticasone concentration co-administered with DRV/r and DRV/c. Unfortunately, there has been no data comparing the usage of cobicistat with beclomethasone. However, ritonavir and cobicistat are very similar in that they are CYP3A inhibitors, which is the primary mechanism of DT’s interaction. This leads to the conclusion that beclomethasone is a viable alternative to fluticasone as a preferred inhaled corticosteroid.According to DHHS HIV guidelines, salmeterol concentrations can increase when coadministered with protease inhibitors resulting in salmeterol-associated cardiovascular events. Thus, a safer alternative while maintaining a regimen with an inhaled corticosteroid, long acting beta-2 agonist, and a long acting anticholinergic agent would be to add one puff daily of umeclidinum 62.5 mcg/vilanterol 25 mcg (Anoro Ellipta).

	Alternative considerations include two puffs twice daily of glycopyrrolate 9 mcg/formoterol fumarate 4.8 mcg (Bevespi Aerosphere) or one capsule inhaled twice daily of indacterol 27.5 mcg /glycopyrrolate 15.6 mcg (Utibron Neohaler). None of these agents are major substrates of CYP3A4, thus avoiding a pharmacokinetic interaction with cobicistat in the patient’s HIV regimen.

	1.Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013;114(9):519-529.

	2.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://bit.ly/1fEQrl8.

	3.Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://bit.ly/2tSvEmp.

	4.Boyd SD, Hadigan C, McManus M, Chairez C, Nieman LK, et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361.

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