Inhaled Corticosteroid Use in HIV-positive Individuals Taking Protease Inhibitors

A Review of Pharmacokinetics, Case Reports and Clinical Management

P Saberi; T Phengrasamy; DP Nguyen

HIV Medicine. 2013;14(9):519-529.

Abstract and Introduction

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.

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Table 1. Pharmacokinetic properties of inhaled/intranasal corticosteroids
	17-BMP (ref.)	BDP	BUD	CIC	FLU	FF	FP	MF	TAA
RRA*	1345 [45]	43 [45]	855 [46]	1212 (Des-CIC) [2]	180 [2]	2990 [47]	1910 [5]	2200 [48]	233 [2]
Lipophilicity^†	ND	1.3 [49]	1.9 [49]	4.08–5.32 [49]	1.1 [49]	ND	3.4–3.46 [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]
Metabolism	ND	Esterase & 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]
F _oral (%)	41 [50]	~0 [50]	10 [52]	<1 [54]	20 [55]	1.26 [63]	<1 [57]	<0.1 [58, 59]	23 [64, 65]

17-BMP, 17-beclomethasone monopropionate (active metabolite of BDP); BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; Des-CIC, des-ciclesonide (active metabolite of CIC); F _oral, 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.
*With dexamethasone as reference (RRA = 100).
^†Based on logarithm of octanol to water partition coefficient.
^‡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).

Table 2. Case reports of inhaled/intranasal corticosteroid–protease inhibitor drug–drug interactions
Case number (ref.)	Year	Age; sex	ART	RTV total daily dose	Other medications	Corticosteroid type Inhaled/nasal Daily dose (μg)	Duration of co-administration before onset	Signs and symptoms	Management	Outcome
1 [8]	2006	1.8 years; female	LPV/RTV, d4T, 3TC	60 mg	TAA ointment	FP Inhaled 220	6.2 months*	Weight gain, ACTH and cortisol suppression	FP taper off	Resolution of cortisol 4 months after taper; repeated ↓ cortisol and ACTH attributable to TAA ointment
2 [9]	2010	4 years; female	RTV- containing regimen	300 mg/m²	NR	BUD Inhaled and nasal 1200	3 months	Facial 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 regimen	235 mg/m²	NR	BUD Inhaled 200	2 years	Facial and truncal obesity, facial hirsutism, dorsocervical fat pad	Switch LPV/RTV to EFV	Morning cortisol ↑ from 8 to 278 mmol/L after 4 weeks
4 [9]	2010	7 years; male	NR	NR	Salmeterol	FP Inhaled 50	2 months	Facial and truncal obesity, dorsocervical fat pad, facial hirsutism	FP changed to BUD; no change; d/c BUD	Morning cortisol ↑ from 5 to 115 mmol/L after 6 weeks
5 [10]	2009	9 years; female	LPV/RTV, ABC, ddI	NR	NR	FP Inhaled 250	NR	Cushing's syndrome	NR	NR
6 [11]	2007	9 years; male	LPV/RTV, ddI, 3TC	108 mg	Montelukast	FP Inhaled 440 and MF Nasal 100	FP: 2 months MF: 11 months	Cushingoid facies, facial hirsutism, weight gain	Taper and d/c FP and MF over 4 weeks	Resolution of symptoms 2 weeks after completion of taper
7 [8]	2006	9.5 years; male	LPV/RTV, 3TC, TDF	133 mg	NR	FP Inhaled 220	6.2 months*	Cushing's syndrome	d/c FP; initiate prednisone taper	Resolution of symptoms within 3 months
8 [10]	2009	10 years; female	LPV/RTV, ABC	NR	Topical BDP	FP Inhaled 1000	NR	Cushing's syndrome	NR	NR
9 [8]	2006	11.4 years; female	LPV/RTV, d4T, 3TC	133 mg	NR	FP Inhaled 220	6.2 months*	Cushing's syndrome	d/c ART and FP; initiate EFV, ddI, FTC	Resolution of symptoms within 3 months
10 [12]	2006	12 years; female	3TC, ZDV, LPV/RTV	134 mg	Salmeterol, albuterol, montelukast, fluconazole, azithromycin, cotrimoxazole, dexamethasone (IV × 13 days)	FP Inhaled 500–1000	60 days	Weight gain, ↑ abdominal girth, striae, hirsutism, nausea, vomiting, diarrhoea, poor appetite, epigastric pain, easy bruising, livedo reticularis, malaise	Change 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/RTV	200 mg	NR	FP Inhaled 200	24 weeks	Fatigue, weight gain, cushingoid facies, rash, insulin resistance	Taper FP and d/c and start montelukast	Resolution of symptoms, cortisol, ACTH, and insulin levels 3 months after FP d/c
12 [14]	2007	14 years; female	ddI, TDF, ATV, RTV	100 mg	Salmeterol, motelukast	FP Inhaled 500	2 weeks	Weight gain, striae, cushingoid facies, facial hirsutism,	d/c ATV, RTV and FP; hospitalization for adrenal insufficiency; HCT × 2 weeks	Resolution
13 [12]	2006	15 years; female	3TC, ABC, LPV/RTV	200 mg	Salmeterol, prednisone (× 10 days)	FP Inhaled 1000	13 weeks	Weight gain, cushingoid facies, striae, hirsutism, central adiposity	↓ FP to 500 μg and then 200 μg	Normalized cortisol level and ceased weight gain 2 months after ↓ FP
14 [10]	2009	16 years; male	Fos-APV, RTV, ZDV, TDF	NR	NR	FP Inhaled 500	NR	Cushing's syndrome	NR	NR
15 [15]	2007	16 years; female	3TC, d4T, RTV	NR	Salmeterol	FP Inhaled 500	3 months	Weight gain, acne, striae, amenorrhoea, fatigue, facial oedema, hypercholesterolaemia, amenorrhoea, ↑ appetite	Change RTV to EFV	Resolution of symptoms in 30–60 days; normalized cortisol in 5 months
16 [8]	2006	16.8 years; male	LPV/RTV, ABC, AZT, 3TC	200 mg	NR	FP Inhaled 250	6.2 months*	Cushing's syndrome	d/c all medications	Resolution within 3 months
17 [8]	2006	20.9 years; male	ATV, RTV, ddI, TDF	100 mg	NR	FP Inhaled 200	6.2 months*	Cushing's syndrome	d/c FP	Resolution within 3 months
18 [16]	2005	27 years; female	LPV/RTV, SQV	200 mg	Salmeterol, methadone, benzodiazepine	FP Inhaled 1000	10 weeks	Weight gain, myopathy, central adiposity, striae, dorsocervical fat pad	d/c FP; initiate oral steroids	Resolution
19 [17]	2009	29 years; female	ATV, RTV-containing regimen	NR (presumably 100 mg)	NR	FP Inhaled 2000	1 month	Weight gain, facial plethora, severe myalgias, amenorrhoea	Change ATV/RTV to NVP-containing regimen	Resolution 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, 3TC	1200 mg	Cutaneous corticosteroid preparation	FP Nasal 200	6 months	Cushingoid facies, adrenal failure	Change RTV to NVP	Resolution; adverse effect seen with RTV rechallenge
21 [10]	2009	31 years; female	LPV/RTV, 3TC, TDF	NR (presumably 200 mg)	NR	FP Inhaled 1000	NR	Cushing's syndrome	NR	NR
22 [19]	1999	32 years; male	RTV, ZDV, 3TC	NR	NR	FP Nasal 400	5 months	Weight gain, cushingoid facies	d/c FP	Resolution of adrenal function and morphological changes in 5 weeks
23 [20]	2002	33 years; male	d4T, 3TC, APV, RTV	200 mg	Terbutaline, salmeterol	FP Inhaled 1000	5 months	Cushingoid facies, weight gain, acne, candida oesophagitis	d/c FP	Resolution of clinical symptoms in 2 months
24 [21]	2010	37 years; female	TDF, FTC, LPV/RTV	200 mg	Salmeterol	FP Inhaled 250	4–7 months	Weight gain, hyperpigmentation, mild oedema of shins, striae, HTN	d/c FP	Resolution 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, d4T	NR (presumably 200 mg)	NR	FP Inhaled 2000	10 days	Cushingoid facies, ↑ appetite	d/c FP and start BDP	Resolution of symptoms and cortisol level in 3 weeks (adverse effect seen with FP rechallenge)
26 [19]	1999	39 years; male	SQV, RTV, d4TC, NVP	NR	NR	BDP Inhaled 400–800 and FP Nasal 800	18 months	Mild cushingoid facies	d/c FP	NR
27 [10]	2009	42 years; male	LPV/RTV, 3TC, d4T	NR (presumably 200 mg)	NR	FP Inhaled 2000	NR	Cushing's syndrome	NR	NR
28 [23]	2005	43 years; male	LPV/RTV, APV, ddI	200 mg	NR	FP Inhaled 500	2 years	Rib fractures, central weight gain, striae, facial plethora, acne, dorsocervical fat pads, ↑ appetite, weakness, bruising, irritability, depression	d/c FP; hypocortisolism prompted initiation of oral prednisolone taper	Resolution of dorsocervical fat pads and facial plethora in 5 months
29 [23]	2005	43 years; male	RTV, ZDV, NVP	100 mg	Ketoconazole	FP Inhaled 500	1–2 months	Facial rash, ↑ truncal and abdominal fat, facial plethora, muscle wasting, depression; severe lumbar osteoporosis	d/c FP; hypocortisolism prompted initiation of oral prednisolone taper	Resolution of cortisol level 6 months later
30 [23]	2005	43 years; male	LPV/RTV, ABC	200 mg	NR	FP Inhaled 500	6 weeks	Severe muscle cramping, abdominal obesity, facial plethora, bruising	d/c FP; initiate low-dose oral prednisolone	Clinical features evident 2 months later
31 [24]	2003	44 years; male	ABC, ddI, LPV/RTV	266.4 mg	NR	FP Inhaled 2000	2 months	Weight gain, facial and truncal obesity, striae	Change FP to montelukast	Resolution of symptoms in 1 month
32 [25]	2002	45 years; male	EFV, SQV, RTV	800 mg	Albuterol, prednisone (× 5 days)	FP Inhaled 880	20 days	Weight gain, ↓ CD4, dorsocervical fat pad, distended abdomen, striae	Slow taper and d/c of FP over 3 months	Resolution of symptoms and ↑CD4 over 5 months
33 [26]	2012	45 years; male	ATV, RTV, ABC, 3TC, TDF	NR (presumably 100 mg)	Formoterol	BUD Inhaled 160	2 months	Low morning cortisol and low/normal ACTH	d/c BUD and initiate montelukast	Normalized cortisol level in 2 months
34 [27]	2001	47 years; male	ZDV, ddI; then d4T, ddI, IDV	NA	Oral steroids (3 courses × 7 days)	BUD Inhaled 1600–3200	6 months	Abdominal 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/RTV	NR (presumably 200 mg)	Fluconazole, omeprazole, cotrimoxazole, salmeterol	FP Inhaled 1000	4 weeks	Hoarseness, facial oedema, weight gain, parotid swelling	d/c FP	Normalized cortisol and ACTH after 4 weeks; gradual resolution of symptoms
36 [28]	2012	48 years; female	DRV, RTV, FTC, EFV	NR	Formoterol, montelukast	BUD Inhaled 1600	18 months	Worsening 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 RAL	Normalized cortisol level; unchanged cushingoid features that may have been caused by lipohypertrophy
37 [23]	2005	49 years; male	RTV, SQV, ZDV, 3TC	200 mg	Salmeterol, prednisolone (× 10 days)	FP Inhaled 1000	NR (< 6 weeks)	Abdominal distension, facial plethora, presyncope, HTN, fatigue, osteoporosis	Changed RTV and SQV to EFV; hypocortisolism prompted initiation of oral prednisolone taper	Resolution 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 plethora	d/c FP	Resolution of clinical features by 4 months
39 [29]	2012	52 years; male	RTV-containing regimen	NR	Salmeterol	FP Inhaled 500	5 years	Vertebral fracture and deformaties, osteoporosis, hypogonadism	Taper FP	NR
40 [32]	2012	52 years; male	RTV, ATV, EFV	NR (presumably 100 mg)	Fluconazole	FP Inhaled 500–1000	>2 months	Fatigue, weakness, cramping, mouth sores, hoarseness, oropharyngeal candidiasis, ↑ blood glucose, ↓ CD4	D/c FP, initiate HCT replacement	Resolution of symptoms in several weeks; CD4 increased in 1–2 months
41 [23]	2005	53 years; male	LPV/RTV, ABC, NVP	200 mg	Rosiglitazone	FP Inhaled 1000	Shortly after	Facial plethora, bruising, osteopenia	d/c FP	Resolution of symptoms after 4 months
42 [13]	2011	55 years; female	ZDV, 3TC, LPV/RTV	200 mg	Salmeterol	FP Inhaled 1000	3 weeks	Fatigue, weight gain, cushingoid facies	Taper 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, TDF	NR (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 extremities	Taper FP and start HCT	Total hip replacement therapy
44 [26]	2012	60 years; male	SQV, 3TC, NFV, ZDV	NA	Salmeterol	FP Inhaled 1000	1.5 years	Gynaecomastia, facial oedema, relapsing anal HSV, diarrhoea	Change ART to ATV, RTV, 3TC, TDF; developed cellulitis, weakness, oedema, weight gain, cushingoid face, parotid swelling, ↓ CD4 8 weeks later; d/c ART	Resolution 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 regimen	NR	Salmeterol	FP Inhaled 500	12 months	Central obesity, cushingoid facies, HTN, muscle weakness dorsocervical fat pad, ↑ weight	d/c FP; initiate oral prednisolone taper	Resolution of symptoms
46 [17]	2009	65 years; female	LPV/RTV-containing regimen	NR (presumably 200 mg)	NR	FP Inhaled 500	6 months	Weight gain, cushingoid facies, ↑ abdominal, neck and face fat, myopathy, acnea, striae, severe osteoporosis	d/c FP; initiate low-dose HCT	Resolution of morphological changes in 6 months
47 [13]	2011	65 years; female	ZDV, 3TC, LPV/RTV	200 mg	Salmeterol	FP Inhaled 500	6 months	Weight gain, fatigue, facial swelling	Taper and d/c FP	Resolution 2–3 months after d/c FP
48 [31]	2005	66 years; male	ZDV, 3TC, IDV, RTV	200 mg	Salmeterol, prednisolone (oral; 5 courses over 12 months)	FP Inhaled 1000	12 months	Bilateral foot drop, fatigue, ↓ concentration, memory loss, easy bruising, central obesity, oesophageal candidiasis	↓ FP dose by half	NR
49 [31]	2005	66 years; male	ddI, d4T, APV, RTV, ABC	200 mg	Salmeterol	FP Inhaled 1000	6 months	Bilateral leg pain, weight gain in face and abdomen, thinning of skin, muscle weakness, oral candidiasis, cushingoid facies	Change FP to BUD (800 μg/day) and cortisone	Resolution in 6–12 months; later developed fracture of right neck of femur and avascular necrosis
50 [17]	2009	66 years; male	ATV, RTV-containing regimen	NR (presumably 100 mg)	NR	FP Inhaled 500	1–3 month	Vertebral pain, faciotroncular obesity, dorsocervical fat pad, myopathy, depression, HTN	d/c FP; initiate oral HCT	Resolution after 5 months
51 [17]	2009	66 years; male	LPV/RTV-containing regimen	NR (presumably 200 mg)	NR	FP Inhaled 500	3–12 months	Severe HTN, diabetes, myopathy, easy bruising, hypertriglyceridaemia, hyperlactataemia, obesity	d/c ART; resolution of lactate in 3 weeks; restart RTV; developed KS and osteoporosis; d/c FP after 2 years; start HCT	Normalized cortisol and ACTH in 1 month; resolution of symptoms after 5 months

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.
*Case series reported as mean duration of co-administration.