Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management

Authors


Abstract

As a consequence of inhibition of the hepatic cytochrome P450 3A4 isozyme, treatment with HIV protease inhibitors can result in significant drug−drug interactions. One noteworthy interaction is between protease inhibitors and inhaled or intranasal corticosteroids. This interaction can result in adrenal insufficiency and iatrogenic Cushing's syndrome (with symptoms such as rapid weight gain, obesity, facial hirsutism and swelling), as well as hypertension, osteoporosis and decreased CD4 cell count. In this paper, we review and unite pharmacokinetic data, case reports and current research regarding this drug−drug interaction in order to suggest options for the clinical management of HIV-positive patients requiring treatment with protease inhibitors and inhaled or intranasal corticosteroids.

Introduction

Ritonavir is a potent inhibitor of the hepatic cytochrome P450 3A4 (CYP3A4) isozyme and is used at low doses to boost the levels of other protease inhibitors (PIs) for the treatment of HIV infection [1]. As a consequence of this property, the use of ritonavir and other PIs can result in numerous drug−drug interactions. Inhaled and intranasal corticosteroids, such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone and triamcinolone, are mostly substrates of hepatic CYP3A4 and have the potential to interact with ritonavir. These interactions can result in steroid accumulation, adrenal suppression and Cushing's syndrome. Given the widespread use of intranasal and inhaled corticosteroids for allergic rhinitis, asthma and chronic obstructive pulmonary disease, there is a potential for the erroneous prescription and use of these medications in HIV-positive adult and paediatric patients on a PI-containing antiretroviral regimen. The purpose of this article is to review the literature on the pharmacokinetics of inhaled and intranasal corticosteroids and case reports regarding this drug−drug interaction and to suggest options for the clinical management of HIV-positive patients requiring treatment with PIs and inhaled or intranasal corticosteroids.

Pharmacokinetics of corticosteroid inhalers

In the absence of sufficient studies on drug−drug interactions between inhaled/intranasal corticosteroids and PIs, consideration of key pharmacokinetic properties may help us to elucidate which agents may be safer to use when the combination of these two classes is necessary. The extent of corticosteroid metabolism by the CYP3A4 isozyme is a critical factor in determining whether it will be affected by PIs and other CYP3A4 inhibitors. Other important properties that may minimize this drug−drug interaction include [1]: less systemic exposure as measured by glucocorticosteroid relative receptor binding affinity (RRA), which can translate to decreased nasal passage and lung receptor binding and decreased potency [2]; lower systemic oral bioavailability (systemic oral bioavailability is the extent to which the drug reaches the blood) [3]; higher plasma protein binding (Pb), which results in a lower fraction of unbound drug and prevents diffusion of the drug into the tissue [4]; a shorter elimination half-life, which is determined by the volume of distribution and clearance of the drug; and [5] lower lipophilicity, which translates to lower distribution and binding of the drug to the tissue [2].

In Table 1 we summarize and compare pertinent characteristics of inhaled/intranasal corticosteroids in order to identify those that may have a low risk of interaction and adverse effects. Among the available inhaled/intranasal corticosteroids, flunisolide and beclomethasone seem to meet most of the properties mentioned above, such as low RRA, low lipophilicity, short elimination half-life, and less dependence on metabolism by the CYP3A4 isozyme. Of the available corticosteroids, fluticasone exhibits the greatest suppressive effect on the hypothalamic-pituitary-adrenal axis [3]. This is probably a result of its pharmacokinetic properties, such as higher lipophilicity, a longer elimination half-life and a higher glucocorticoid RRA, as well as its relatively exclusive metabolism by CYP3A4 [4-7].

Table 1. Pharmacokinetic properties of inhaled/intranasal corticosteroids
 17-BMP (ref.)BDPBUDCICFLUFFFPMFTAA
  1. 17-BMP, 17-beclomethasone monopropionate (active metabolite of BDP); BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; Des-CIC, des-ciclesonide (active metabolite of CIC); Foral, systemic bioavailability; FF, fluticasone furoate; FP, fluticasone propionate; FLU, flunisolide; MF, mometasone furoate; ND, no data; Pb, protein binding; RRA, relative receptor affinity; TAA, triamcinolone acetonide.
  2. *With dexamethasone as reference (RRA = 100).
  3. Based on logarithm of octanol to water partition coefficient.
  4. Half-life is reported as elimination half-life (half-life with intravenous administration) with the exception of BUD and TAA, which are reported as terminal half-life (half-life with oral or nasal administration).
RRA*1345 [45]43 [45]855 [46]1212 (Des-CIC) [2]180 [2]2990 [47]1910 [5]2200 [48]233 [2]
LipophilicityND1.3 [49]1.9 [49]4.08–5.32 [49]1.1 [49]ND3.4–3.46 [7, 49]2.1–3.49 [7, 49]0.2 [49]
Half-life (h)2.7 [50]0.5 [50]2–3 [51-53]0.36 [54]1–2 [55]15.3 [56]7.8 [57]5 [58, 59]3.6 [60]
Pb (%)94–96 [61]87 [45, 62]85–90 [52, 53]99 [54]80 [55]99.4 [63]99 [57]98–99 [58, 59]68–71 [64, 65]
MetabolismNDEsterase & 3A4 [45, 61, 66]3A4 [52, 53]

CIC: esterase

Des-CIC: 3A4, 2D6 [54]

Glucuronidation, sulfation [55]3A4 [63]3A4 [57]P450 3A4 [58, 59]6 ß-hydroxylation [64, 65]
Foral (%)41 [50]∼0 [50]10 [52]<1 [54]20 [55]1.26 [63]<1 [57]<0.1 [58, 59]23 [64, 65]

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%) [9]. 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 [9], one used inhaled fluticasone and intranasal mometasone [11], one used inhaled beclomethasone and nasal fluticasone [19], and one used inhaled and intranasal fluticasone [30]. 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.

Table 2. Case reports of inhaled/intranasal corticosteroid−protease inhibitor drug−drug interactions
Case number (ref.)YearAge; sexARTRTV total daily doseOther medicationsCorticosteroid type Inhaled/nasal Daily dose (μg)Duration of co-administration before onsetSigns and symptomsManagementOutcome
  1. 3TC, lamivudine; ABC, abacavir; ACTH, adrenocorticotropic hormone; AMP, amprenavir; ART, antiretroviral therapy; ATV, atazanavir; BDP, beclomethasone dipropionate; BUD, budesonide; d/c, discontinue; d4T, stavudine; ddI, didanosine; DRV, darunavir; EFV, efavirenz; Fos-APV, fos-amprenavir; FP, fluticasone propionate; FTC, emtricitabine; HCT, hydrocortisone; HSV, herpes simplex virus; HTN, hypertension; ICS, inhaled corticosteroid; IDV, indinavir; KS, Kaposi's sarcoma; LPV/RTV, lopinavir/ritonavir; MF, mometasone furoate; NA, not applicable; NFV, nelfinavir; NR, not reported; NVP, nevirapine; RAL, raltegravir; RTV, ritonavir; SQV, saquinavir; TDF, tenofovir; TAA, triamcinolone acetonide; ZDV, zidovudine.
  2. *Case series reported as mean duration of co-administration.
 1 [8]2006

1.8 years;

female

LPV/RTV, d4T, 3TC60 mgTAA ointment

FP

Inhaled

220

6.2 months*Weight gain, ACTH and cortisol suppressionFP taper offResolution of cortisol 4 months after taper; repeated ↓ cortisol and ACTH attributable to TAA ointment
 2 [9]2010

4 years;

female

RTV- containing regimen300 mg/m2NR

BUD

Inhaled and nasal

1200

3 monthsFacial lipohypertrophy, truncal obesity, facial hirsutism

↓BUD to 200 μg × 1 week;

morning cortisol < 1 mmol/L; d/c BUD 1 week later

Morning cortisol was 222 mmol/L 3 weeks later
 3 [9]2010

4 years;

female

LPV/RTV- containing regimen235 mg/m2NR

BUD

Inhaled

200

2 yearsFacial and truncal obesity, facial hirsutism, dorsocervical fat padSwitch LPV/RTV to EFVMorning cortisol ↑ from 8 to 278 mmol/L after 4 weeks
 4 [9]2010

7 years;

male

NRNRSalmeterol

FP

Inhaled

50

2 monthsFacial and truncal obesity, dorsocervical fat pad, facial hirsutismFP changed to BUD; no change; d/c BUDMorning cortisol ↑ from 5 to 115 mmol/L after 6 weeks
 5 [10]2009

9 years;

female

LPV/RTV, ABC, ddINRNR

FP

Inhaled

250

NRCushing's syndromeNRNR
 6 [11]2007

9 years;

male

LPV/RTV, ddI, 3TC108 mgMontelukast

FP

Inhaled

440 and

MF

Nasal

100

FP: 2 months

MF: 11 months

Cushingoid facies, facial hirsutism, weight gainTaper and d/c FP and MF over 4 weeksResolution of symptoms 2 weeks after completion of taper
 7 [8]2006

9.5 years;

male

LPV/RTV, 3TC, TDF133 mgNR

FP

Inhaled

220

6.2 months*Cushing's syndromed/c FP; initiate prednisone taperResolution of symptoms within 3 months
 8 [10]2009

10 years;

female

LPV/RTV, ABCNRTopical BDP

FP

Inhaled

1000

NRCushing's syndromeNRNR
 9 [8]2006

11.4 years;

female

LPV/RTV, d4T, 3TC133 mgNR

FP

Inhaled

220

6.2 months*Cushing's syndromed/c ART and FP; initiate EFV, ddI, FTCResolution of symptoms within 3 months
10 [12]2006

12 years;

female

3TC, ZDV, LPV/RTV134 mgSalmeterol, albuterol, montelukast, fluconazole, azithromycin, cotrimoxazole, dexamethasone (IV × 13 days)

FP

Inhaled

500−1000

60 daysWeight gain, ↑ abdominal girth, striae, hirsutism, nausea, vomiting, diarrhoea, poor appetite, epigastric pain, easy bruising, livedo reticularis, malaiseChange LPV/RTV to EFV

Hospitalization for adrenal suppression and Cushing's;

cortisol and ACTH normalized 6 months after LPV/RTV d/c

11 [13]2011

12 years;

female

ZDV, 3TC, LPV/RTV200 mgNR

FP

Inhaled

200

24 weeksFatigue, weight gain, cushingoid facies, rash, insulin resistanceTaper FP and d/c and start montelukastResolution of symptoms, cortisol, ACTH, and insulin levels 3 months after FP d/c
12 [14]2007

14 years;

female

ddI, TDF, ATV, RTV100 mgSalmeterol, motelukast

FP

Inhaled

500

2 weeksWeight gain, striae, cushingoid facies, facial hirsutism,d/c ATV, RTV and FP; hospitalization for adrenal insufficiency; HCT × 2 weeksResolution
13 [12]2006

15 years;

female

3TC, ABC, LPV/RTV200 mgSalmeterol, prednisone (× 10 days)

FP

Inhaled

1000

13 weeksWeight gain, cushingoid facies, striae, hirsutism, central adiposity↓ FP to 500 μg and then 200 μgNormalized cortisol level and ceased weight gain 2 months after ↓ FP
14 [10]2009

16 years;

male

Fos-APV, RTV, ZDV, TDFNRNR

FP

Inhaled

500

NRCushing's syndromeNRNR
15 [15]2007

16 years;

female

3TC, d4T, RTVNRSalmeterol

FP

Inhaled

500

3 monthsWeight gain, acne, striae, amenorrhoea, fatigue, facial oedema, hypercholesterolaemia, amenorrhoea, ↑ appetiteChange RTV to EFVResolution of symptoms in 30–60 days; normalized cortisol in 5 months
16 [8]2006

16.8 years;

male

LPV/RTV, ABC, AZT, 3TC200 mgNR

FP

Inhaled

250

6.2 months*Cushing's syndromed/c all medicationsResolution within 3 months
17 [8]2006

20.9 years;

male

ATV, RTV, ddI, TDF100 mgNR

FP

Inhaled

200

6.2 months*Cushing's syndromed/c FPResolution within 3 months
18 [16]2005

27 years;

female

LPV/RTV, SQV200 mgSalmeterol, methadone, benzodiazepine

FP

Inhaled

1000

10 weeksWeight gain, myopathy, central adiposity, striae, dorsocervical fat padd/c FP; initiate oral steroidsResolution
19 [17]2009

29 years;

female

ATV, RTV-containing regimenNR (presumably 100 mg)NR

FP

Inhaled

2000

1 monthWeight gain, facial plethora, severe myalgias, amenorrhoeaChange ATV/RTV to NVP-containing regimenResolution in 3 months; adverse effects seen with ATV/RTV rechallenge; FP d/c; symptom resolution in 3 months
20 [18]1999

30 years;

male

RTV, ZDV, 3TC1200 mgCutaneous corticosteroid preparation

FP

Nasal

200

6 monthsCushingoid facies, adrenal failureChange RTV to NVPResolution; adverse effect seen with RTV rechallenge
21 [10]2009

31 years;

female

LPV/RTV, 3TC, TDFNR (presumably 200 mg)NR

FP

Inhaled

1000

NRCushing's syndromeNRNR
22 [19]1999

32 years;

male

RTV, ZDV, 3TCNRNR

FP

Nasal

400

5 monthsWeight gain, cushingoid faciesd/c FPResolution of adrenal function and morphological changes in 5 weeks
23 [20]2002

33 years;

male

d4T, 3TC, APV, RTV200 mg

Terbutaline,

salmeterol

FP

Inhaled

1000

5 monthsCushingoid facies, weight gain, acne, candida oesophagitisd/c FPResolution of clinical symptoms in 2 months
24 [21]2010

37 years;

female

TDF, FTC, LPV/RTV200 mgSalmeterol

FP

Inhaled

250

4–7 monthsWeight gain, hyperpigmentation, mild oedema of shins, striae, HTNd/c FPResolution of symptoms in 2 months; symptoms reoccurred in 4 weeks with BUD (320 μg/day) and did not resolve with RTV 100 mg; resolution in weeks after d/c of BUD and start montelukast
25 [22]2004

38 years;

male

LPV/RTV, 3TC, d4TNR (presumably 200 mg)NR

FP

Inhaled

2000

10 daysCushingoid facies, ↑ appetited/c FP and start BDPResolution of symptoms and cortisol level in 3 weeks (adverse effect seen with FP rechallenge)
26 [19]1999

39 years;

male

SQV, RTV, d4TC, NVPNRNR

BDP

Inhaled

400–800 and

FP

Nasal

800

18 monthsMild cushingoid faciesd/c FPNR
27 [10]2009

42 years;

male

LPV/RTV, 3TC, d4TNR (presumably 200 mg)NR

FP

Inhaled

2000

NRCushing's syndromeNRNR
28 [23]2005

43 years;

male

LPV/RTV, APV, ddI200 mgNR

FP

Inhaled

500

2 yearsRib fractures, central weight gain, striae, facial plethora, acne, dorsocervical fat pads, ↑ appetite, weakness, bruising, irritability, depressiond/c FP; hypocortisolism prompted initiation of oral prednisolone taperResolution of dorsocervical fat pads and facial plethora in 5 months
29 [23]2005

43 years;

male

RTV, ZDV, NVP100 mgKetoconazole

FP

Inhaled

500

1–2 monthsFacial rash, ↑ truncal and abdominal fat, facial plethora, muscle wasting, depression; severe lumbar osteoporosisd/c FP; hypocortisolism prompted initiation of oral prednisolone taperResolution of cortisol level 6 months later
30 [23]2005

43 years;

male

LPV/RTV, ABC200 mgNR

FP

Inhaled

500

6 weeksSevere muscle cramping, abdominal obesity, facial plethora, bruisingd/c FP; initiate low-dose oral prednisoloneClinical features evident 2 months later
31 [24]2003

44 years;

male

ABC, ddI, LPV/RTV266.4 mgNR

FP

Inhaled

2000

2 monthsWeight gain, facial and truncal obesity, striaeChange FP to montelukastResolution of symptoms in 1 month
32 [25]2002

45 years;

male

EFV, SQV, RTV800 mgAlbuterol, prednisone (× 5 days)

FP

Inhaled

880

20 daysWeight gain, ↓ CD4, dorsocervical fat pad, distended abdomen, striaeSlow taper and d/c of FP over 3 monthsResolution of symptoms and ↑CD4 over 5 months
33 [26]2012

45 years;

male

ATV, RTV, ABC, 3TC, TDFNR (presumably 100 mg)Formoterol

BUD

Inhaled

160

2 monthsLow morning cortisol and low/normal ACTHd/c BUD and initiate montelukastNormalized cortisol level in 2 months
34 [27]2001

47 years;

male

ZDV, ddI; then d4T, ddI, IDVNAOral steroids (3 courses × 7 days)

BUD

Inhaled

1600–3200

6 monthsAbdominal distension, muscle weakness and pain, cushingoid features

IDV changed to NVP;

d/c BUD

Resolution with d/c of BUD
35 [26]2012

48 years;

male

ZDV, 3TC, LPV/RTVNR (presumably 200 mg)Fluconazole, omeprazole, cotrimoxazole, salmeterol

FP

Inhaled

1000

4 weeksHoarseness, facial oedema, weight gain, parotid swellingd/c FPNormalized cortisol and ACTH after 4 weeks; gradual resolution of symptoms
36 [28]2012

48 years;

female

DRV, RTV, FTC, EFVNRFormoterol, montelukast

BUD

Inhaled

1600

18 monthsWorsening of cushingoid appearance (weight gain, truncal obesity, striae, dorsocervical fat pad)Reduce BUD dose to 800 μg/day and d/c; change DRV/RTV to RALNormalized cortisol level; unchanged cushingoid features that may have been caused by lipohypertrophy
37 [23]2005

49 years;

male

RTV, SQV, ZDV, 3TC200 mgSalmeterol, prednisolone (× 10 days)

FP

Inhaled

1000

NR (< 6 weeks)Abdominal distension, facial plethora, presyncope, HTN, fatigue, osteoporosisChanged RTV and SQV to EFV; hypocortisolism prompted initiation of oral prednisolone taperResolution of physical symptoms over a few months
38 [23]2005

51 years;

male

LPV/RTV- then RTV- containing regimen

200 mg,

then 100 mg

Gliperimide, rosiglitazone

FP

Inhaled

1000

2 months↑ glucose levels, muscle cramps, weakness, wasting, mood changes, abdominal bloating, facial plethorad/c FPResolution of clinical features by 4 months
39 [29]2012

52 years;

male

RTV-containing regimenNRSalmeterol

FP

Inhaled

500

5 yearsVertebral fracture and deformaties, osteoporosis, hypogonadismTaper FPNR
40 [32]2012

52 years;

male

RTV, ATV, EFVNR (presumably 100 mg)Fluconazole

FP

Inhaled

500–1000

>2 monthsFatigue, weakness, cramping, mouth sores, hoarseness, oropharyngeal candidiasis, ↑ blood glucose, ↓ CD4D/c FP, initiate HCT replacementResolution of symptoms in several weeks; CD4 increased in 1–2 months
41 [23]2005

53 years;

male

LPV/RTV, ABC, NVP200 mgRosiglitazone

FP

Inhaled

1000

Shortly afterFacial plethora, bruising, osteopeniad/c FPResolution of symptoms after 4 months
42 [13]2011

55 years;

female

ZDV, 3TC, LPV/RTV200 mgSalmeterol

FP

Inhaled

1000

3 weeksFatigue, weight gain, cushingoid faciesTaper FP and d/c and replace with BUD (400 μg/day)Resolution of symptoms after 3 months
43 [30]2011

60 years;

male

RTV, ATV, ZDV, 3TC, TDFNR (presumably 100 mg)Albuterol, salmeterol

FP

Inhaled

1000

FP

Nasal

200

Inhaled: 2 months

Nasal: 3.2 years

Vertebral fracture, femoral fracture, osteonecrosis of both hips, central obesity muscular atrophy in extremitiesTaper FP and start HCTTotal hip replacement therapy
44 [26]2012

60 years;

male

SQV, 3TC, NFV, ZDVNASalmeterol

FP

Inhaled

1000

1.5 yearsGynaecomastia, facial oedema, relapsing anal HSV, diarrhoeaChange ART to ATV, RTV, 3TC, TDF; developed cellulitis, weakness, oedema, weight gain, cushingoid face, parotid swelling, ↓ CD4 8 weeks later; d/c ARTResolution of symptoms after 3 months; ↓serum cortisol with restart of NFV; FP changed to BUD (160 μg) with resolution of cortisol level
45 [29]2012

60 years;

male

RTV-containing regimenNRSalmeterol

FP

Inhaled

500

12 monthsCentral obesity, cushingoid facies, HTN, muscle weakness dorsocervical fat pad, ↑ weightd/c FP; initiate oral prednisolone taperResolution of symptoms
46 [17]2009

65 years;

female

LPV/RTV-containing regimenNR (presumably 200 mg)NR

FP

Inhaled

500

6 monthsWeight gain, cushingoid facies, ↑ abdominal, neck and face fat, myopathy, acnea, striae, severe osteoporosisd/c FP; initiate low-dose HCTResolution of morphological changes in 6 months
47 [13]2011

65 years;

female

ZDV, 3TC, LPV/RTV200 mgSalmeterol

FP

Inhaled

500

6 monthsWeight gain, fatigue, facial swellingTaper and d/c FPResolution 2–3 months after d/c FP
48 [31]2005

66 years;

male

ZDV, 3TC, IDV, RTV200 mgSalmeterol, prednisolone (oral; 5 courses over 12 months)

FP

Inhaled

1000

12 monthsBilateral foot drop, fatigue, ↓ concentration, memory loss, easy bruising, central obesity, oesophageal candidiasis↓ FP dose by halfNR
49 [31]2005

66 years;

male

ddI, d4T, APV, RTV, ABC200 mgSalmeterol

FP

Inhaled

1000

6 monthsBilateral leg pain, weight gain in face and abdomen, thinning of skin, muscle weakness, oral candidiasis, cushingoid faciesChange FP to BUD (800 μg/day) and cortisoneResolution in 6–12 months; later developed fracture of right neck of femur and avascular necrosis
50 [17]2009

66 years;

male

ATV, RTV-containing regimenNR (presumably 100 mg)NR

FP

Inhaled

500

1–3 monthVertebral pain, faciotroncular obesity, dorsocervical fat pad, myopathy, depression, HTNd/c FP; initiate oral HCTResolution after 5 months
51 [17]2009

66 years;

male

LPV/RTV-containing regimenNR (presumably 200 mg)NR

FP

Inhaled

500

3–12 monthsSevere HTN, diabetes, myopathy, easy bruising, hypertriglyceridaemia, hyperlactataemia, obesityd/c ART; resolution of lactate in 3 weeks; restart RTV; developed KS and osteoporosis; d/c FP after 2 years; start HCTNormalized cortisol and ACTH in 1 month; resolution of symptoms after 5 months

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.

Considerations for clinical management, options for treatment, and future research

It is critical to collect a thorough medication history in patients exhibiting signs and symptoms of Cushing's syndrome. Additionally, it is important to distinguish between lipodystrophy, caused by some antiretroviral medications, and iatrogenic Cushing's syndrome, as they have many overlapping characteristics (e.g. central obesity, weight gain and dorsocervical fat pad) [33]. However, abdominal striae, easy bruising, facial plethora, rapid weight gain, increased appetite and facial hirsutism are commonly related to Cushing's syndrome and peripheral atrophy is more likely to be noted in lipodystrophy. For the diagnosis of adrenal insufficiency, an early morning plasma cortisol level should be obtained followed by a 30-minute synthetic ACTH or cosyntropin stimulation test. A cortisol level > 11 μg/dL is unlikely to be associated with significant adrenal insufficiency; however, levels < 3 μg/dL are strongly suggestive of adrenal insufficiency. A decreased response to the ACTH stimulation test is diagnostic of adrenal insufficiency.

In view of the staggering number of case reports, a previous literature review by Foisy and colleagues clearly advised against the co-administration of fluticasone with ritonavir [34]. However, despite these well-documented cases and the fact that electronic prescribing systems generally provide warnings against the combination of most PIs and some corticosteroids (e.g. fluticasone, mometasone and budesonide), patients continue to inadvertently receive these medications. Most importantly, there is a scarcity of guidance and recommendations regarding the medical management of patients requiring treatment for HIV infection and asthma or allergic rhinitis. Our review suggests that possible options include: (1) initiating or changing the PI to another antiretroviral agent that does not inhibit the CYP3A4 isozyme (such as nonnucleoside reverse transcriptase inhibitors or integrase inhibitors), if this is allowable based on the drug resistance and treatment history; (2) substituting the inhaled/intranasal corticosteroid with another corticosteroid with less potential for drug interactions (we will discuss these options below); and (3) using an alternative medication, such as a leukotriene receptor antagonist (e.g. montelukast), a mast cell stabilizer (e.g. cromolyn), an anticholinergic agent (e.g. ipratropium) or an antihistamine. It is unclear if significant dose reductions in the inhaled/intranasal corticosteroid dose will result in complete resolution or avoidance of this drug−drug interaction [31] and there are reports of cases with an inhaled fluticasone dose as low as 200 μg/day [8, 13]. Those diagnosed with Cushing's syndrome should be evaluated for a potential need to initiate oral steroid replacement and gradual taper [35], being careful to reduce the steroid dose if the PI is continued [36]. Adrenal function recovery may take 9–12 months [35, 37] and serum cortisol levels can be checked every 4–6 weeks [35] to reassess the need for ongoing steroid replacement therapy.

It is noteworthy that this drug−drug interaction is not limited to inhaled and intranasal corticosteroids. Cushing's syndrome has previously been reported when injectable [38, 39] and topical corticosteroids [40, 41] were used in conjunction with CYP3A4 inhibitors. In a recent cohort study, the prevalence of iatrogenic Cushing's syndrome in HIV-positive individuals receiving a ritonavir-containing antiretroviral regimen in addition to inhaled, intranasal or topical corticosteroids (for ≥ 1 month and using ≥ 4.5% of total body surface area) was examined [42]. Approximately 35% of individuals met the diagnosis criteria of iatrogenic Cushing's syndrome, including one patient using topical triamcinolone. The injection of triamcinolone in patients on ritonavir has similarly resulted in the development of Cushing's syndrome [38, 39]. Therefore, this is a potential risk for all individuals on PIs who are chronically using corticosteroids via any route.

Results of one of the few studies to specifically evaluate the drug−drug interaction between corticosteroids and PIs were recently presented [43, 44]. This was a randomized open-label study in HIV-negative healthy adults. The investigators evaluated whether ritonavir alone or darunavir/ritonavir could significantly increase plasma concentrations of beclomethasone 17-monopropionate (17-BMP), the more active metabolite of beclomethasone dipropionate (BDP) [43]. Additionally, they investigated whether inhaled BDP when co-administered with ritonavir or darunavir/ritonavir could significantly influence adrenal function in these participants [44]. For 14 days, 30 subjects received orally inhaled BDP 160 μg twice daily and on day 15, they were randomized (1:1:1) to three groups: group 1 (control) remained on BDP alone for 14 days; group 2 received BDP and ritonavir (100 mg twice daily) for 14 days; and group 3 received BDP and darunavir/ritonavir (600/100 mg twice daily) for 14 days. It was noted that darunavir/ritonavir did not significantly increase the area under the concentration−time curve of 17-BMP and did not cause significant adrenal suppression. Ritonavir alone resulted in a twofold increase in 17-BMP, which was statistically significant; however, given that this increase did not result in significant adrenal suppression, it was not considered clinically consequential. The authors concluded that the use of BDP is preferable to fluticasone in patients receiving a PI and requiring an inhaled corticosteroid. Given the fact that PIs exhibit varying degrees of CYP3A4 inhibition, these promising results with the use of BDP should be interpreted with caution and warrant further research.

However, as we await additional research in this area, we can to some extent be reassured by the fact that evidence from pooled pharmacokinetic data (Table 1), cases reports (Table 2) and prior research [43, 44] suggests that inhaled or intranasal beclomethasone is a relatively safe option in HIV-positive individuals who are receiving PIs. Additionally, based on the pharmacokinetic comparison of these compounds (Table 1), flunisolide appears to have a low risk of drug−drug interactions and may be another potential option in view of its similarly low glucocorticoid RRA, low lipophilicity, short elimination half-life, and weak CYP3A4 metabolism.

The drug−drug interaction between corticosteroids, especially fluticasone, and PIs is significant and deserves close attention and evaluation. Physicians, pharmacists and other health care providers should be further educated about the risks associated with this drug−drug interaction and be provided with alternative options for the treatment and resources for the management of patients. Electronic prescribing systems should frequently be updated to ensure accuracy of warnings for the use of corticosteroids via any route and PIs. Pharmacists should regularly generate lists of patients who may have inadvertently received inhaled/intranasal corticosteroids and PIs and advise prescribing clinicians of appropriate substitutions. Lastly, future research should examine the use of inhaled/intranasal corticosteroids, such as beclomethasone and flunisolide, in HIV-positive individuals receiving commonly prescribed PIs.

Acknowledgements

Conflicts of interest:

The authors have no conflicts of interest to declare. PS receives financial support from National Institute of Mental Health (grant number K23MH097649). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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