Case Reports on Corticosteroid–Protease Inhibitor Drug–Drug Interactions
By searching PubMed and the references of pertinent articles, and by contacting relevant drug companies, we identified 51 case reports published in English regarding adverse effects with the use of inhaled (n = 45), intranasal (n = 2), and combination inhaled and intranasal (n = 4) corticosteroids and PIs (Table 2).[8–32] Papers were published between the years 1999 and 2012. There were nine (18%) reported cases in the paediatric population (i.e. patients < 12 years of age)[8–11] and 19 (37%) cases in women,[8–10,12–17,21,28] and the mean age of patients was 36 years (range 1.8–66 years). Ritonavir was part of the antiretroviral regimen in 48 (94%) of the cases and other PIs (indinavir, saquinavir and nelfinavir) in two (4%) of cases,[26,27] and the antiretroviral regimen was not reported in one case (2%). The mean daily dose of ritonavir for paediatric patients was 109 mg/day and the mean dose for adult patients was 224 mg/day (range 100–1200 mg/day). Of the 45 patients who used inhaled corticosteroids alone, 91% used fluticasone[8–10,12–14,16,17,20–26,29,31,32] and 9% used budesonide.[9,26–28] Fluticasone was used by both the patients on intranasal corticosteroids.[18,19] In the four cases of combined inhaled and intranasal corticosteroid use, one patient used inhaled and intranasal budesonide, one used inhaled fluticasone and intranasal mometasone, one used inhaled beclomethasone and nasal fluticasone, and one used inhaled and intranasal fluticasone. The mean daily dose of inhaled fluticasone in the paediatric population was 343 μg/day (range 50–1000 μg/day) and that in adults was approximately 841 μg/day (range 200–2000 μg/day). The mean daily dose of intranasal fluticasone was 400 μg/day (range 200–800 μg/day), with all cases being in adult patients.
As a point of reference, the recommended maximum daily doses of fluticasone propionate aerosol inhalation and oral powder inhalation for paediatric patients are 176 and 200 μg/day, respectively, and those for adults are 880 and 2000 μg/day, respectively. The total recommended daily doses of intranasal fluticasone furoate and fluticasone propionate in adults are 110 and 200 μg/day, respectively. Therefore, the mean doses used in both the paediatric and the intranasal adult cases were substantially higher in comparison to the recommended maximum daily doses of fluticasone; however, the inhaled doses in the adult case reports were within the recommended daily dose range.
The duration of corticosteroid–PI co-administration prior to the onset of symptoms was highly variable, ranging from 10 days to 5 years (mean 7.1 months). Symptoms reported also varied, although the most common were typical symptoms associated with Cushing's syndrome, including facial swelling (also known as 'cushingoid facies' or 'moon face'), facial hirsutism, central obesity and weight gain, dorsocervical fat pad (also known as 'buffalo hump'), striae and easy bruising. A reduction in CD4 cell count and oropharyngeal candidiasis was reported in several studies.[20,25,26,31,32] Adverse effects seemed to be more severe in those ≥ 60 years of age and included osteonecrosis of hips, vertebral and femoral fractures and severe hypertension.
Common methods of clinical management which resulted in the resolution of symptoms consisted of tapering and eventually discontinuing the inhaled/intranasal corticosteroid, discontinuation of the inhaled/intranasal corticosteroid and initiation of a slow taper of the oral corticosteroid, or changing the PI-based regimen to a nonnucleoside reverse transcriptase inhibitor-based regimen. Among 43 cases with a reported outcome, 95% had resolution of symptoms and normalization of cortisol or adrenocorticotropic hormone (ACTH) levels within a mean of 12.1 weeks (range 2–24 weeks) and 10.1 weeks (range 3–24 weeks), respectively.
HIV Medicine. 2013;14(9):519-529. © 2013 Blackwell Publishing