avoid giving steroids with ritonavir!!

the issue recently came up in terms of adverse effects (ie, iatrogenic cushings) in patients on hiv cocktail containing ritonivir and use of even local steroids (the issue being that ritonivir 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, esp since prior studies have found that these 2 drugs in particular have the highest tissue-to-blood levels -- 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.  see my recent review of the hiv recommendations in jama. if unable to switch away from ritonavir, i would preferentially try the lowest dose of beclomethasone.

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 infection 2013 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 ritonivir 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 (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. if that were not feasible, makes sense to use the ones not implicated above and at the lowest dose you can (with the rather large caveat that the identified cases are possibly found because of the more frequent use of inhaled fluticasone or injected triamcinolone in the population, instead of their really being the bad actors here). 

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