HIV meds, local steroids, and Cushings

Jason Worcester at bmc brought up concerns about steroid injections in patients on certain HIV drugs. i sent out an email/blog 5 years ago on the potentially very severe consequences of topical steroids (inhalation, joint injection) in patients on ritonavir.  a recent search found some similar issues with cobicistat, also a profound cytochrome P450 3A (CYP3A) inhibitor, now used in some HIV cocktails.

so, given the rather frequent prescriptions for inhaled steroids (esp fluticasone) and injected steroids into joints/bursae/trigger points, i thought it would be useful to resend and expand the prior blog (which is appended below)

--a case report of iatrogenic adrenal suppression after using inhaled intranasal fluticasone and cobicistat (in the combo evitegravir, cobicistat, emtricatibine, tenofovir = stribild). see hiv cobicistat cushing ClinMed2016 in dropbox, or Elliot ER. Clinical Medicine. 2016; 16: 412

--and another case report: a 53yo woman on dolutegravir and cobicistat-boosted darunavir who had hip pain, went to ortho clinic, and had 5ml of bupivacaine 0.5% with 40mg of triamcinolone injected into her trochanteric bursa. She was cushingoid 7 days later, had undetectable cortisol level, and was diagnosed with exogenous steroid-induced hypoaldrenalism (see hiv cobicistat steroid cushings BMJcaserep2018 in dropbox, or doi: 10.1136/bcr-2018-226912 )

--and this warning: https://www.gov.uk/drug-safety-update/cobicistat-ritonavir-and-coadminsitration-with-a-steroid-risk-of-systemic-corticosteroid-adverse-effects , a UK safety alert warning that patients on either cobicistat or ritonavir should avoid having coadministered steroids, including intranasal, inhaled and intra-articular routes

i would just add to the commentary below that the array of INSTI-based therapies that do not need ritonavir or cobicistat boosting is impressive, with minimal pill burden, few adverse effects, very high barrier to resistance (except raltegravir) and remarkably robust outcomes.  and, given the increasing likelihood of other chronic diseases accumulating in hiv-positive patients as they get older and the overall common drug-drug interactions with ritonavir or cobicistat, i have switched essentially all of my patients from the newer combos with cobicistat to an INSTI-based regimen as a means to decrease the potential of later medical errors. it may be that certain steroids are safe (eg inhaled budesonide has much lower absorption/blood levels than some of the others, esp fluticasone. see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319197/ ), but given the potential future risks, i still think avoiding ritonavir and cobicistat is the preferable choice. (and this concern is amplified by the fact that inhaled steroids are given out like a presumably healthier version of candy in urgent care centers, EDs, primary care, etc)

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here is blog from 8/1/14 (also on website: https://gmodestmedblogs.blogspot.com/2014/08/avoid-giving-steroids-with-ritonivir_1.html ), which presents even more evidence against ritonavir-based regimens:

the issue recently came up in terms of adverse effects (ie, iatrogenic cushings) in patients on hiv cocktail containing ritonavir and use of even local steroids (the issue being that ritonavir is an extremely potent inhibitor of CYP 3A4 , leading to excessive increases in circulating levels of drugs metabolized through this system). i brought up this question with HIV providers in san francisco (the HIV consult line) and received the following answer:

1. lots of problems with inhaled steroids, esp fluticasone and budesonide. better results with beclomethasone, nasolide and flunisolide (i asked them is that just because fluticasone and budesonide are used more frequently,  and they did not know, but said that the medical literature is replete with examples of cushings in using these drugs. of note, a drug company study did find a 350-fold increase of serum fluticasone levels with ritonavir). probably the best option for many patients is to switch to a non-boosted protease inhibitor HIV cocktail, of which there now are many ones, with (my opinion) dolutegravir-containing ones being the best. if unable to switch away from ritonavir, i would preferentially try the lowest dose of budesonide.

2. in terms of intra-articular steroids, they felt there was no problem and that they do them in their HIV clinic.  BUT, then Kevin Ard (former brigham resident who did his continuity clinic at our health center, now ID-trained HIV specialist) chimed in with the following article refuting this claim (see hiv intraartic steroids and ritonivir cushings2013 in dropbox, or DOI 10.1007/s15010-013-0506-z) -- [thanks, kevin]. this is a case report and review of the literature. major points:

    --the case reported involved a patient with periradicular injection of 20mg of triamcinolone acetonide weekly for 6 weeks for lower back pain, who then developed severe cushingoid facies, central obesity, buffalo hump and proximal muscle weakness of her legs, as well as marked hypokalemia. her HIV treatment included ritonavir 100mg bid for 6 years, with a CD4 of 820 and suppressed viral load. the symptoms of cushings began 6 week after her first injection. work-up confirmed suppressed ACTH and cortisol levels.

     --15 cases reported in the literature with suppression of hypothalamic-pituitary-adrenal (HPA) axis after injection with triamcinolone. of the 15 reported cases, 9 were women, mean dose of injected triamcinolone was 97mg (40-240) and mean number of injections was 1.6 (though only 1 injection in 9 cases), all were on 100-200 mg ritonavir

        --specifically 4 injections were intra-articular (which presumably has less systemic absorption than IM), 3 of these 4 had total dose of only 40 mg. symptoms began 2 weeks after injections and lasted 4-8 months afterwards. 2 patients with epidural injections had avascular necrosis. (so, a single injection of 40mg triamcinolone can lead to complete suppression of the HPA axis for up to 8 months!!)

    --methylprednisolone may be a reasonable therapeutic option (reduced dose methylprednisolone -- 20-40 mg-- was suggested in the radiology literature (ref 9 in the article) and "may present lower risk", but with the caveat that there are insufficient cases to know for sure if this is safe. in that article they suggested checking an am cortisol level 2 weeks after the injection. 

note: this becomes more of an issue given the (rather remarkable and fortunate) aging of the HIV population, as HIV has evolved into a chronic condition, and living longer, as we know, is associated with more musculoskeletal problems.  but, the good news is that for most patients, there are great non-protease inhibitor options. so, seems that the safest thing would be to change the HIV regimen prior to putting someone on inhaled steroids or injectable ones.  

geoff

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