M I C H A E L K A V A N A U G H A P R I L 4 , 2 0 1 4

AIDS CLINICAL ROUNDS

Disclosures

I have no relevant financial relationships with any commercial supporters.

Unlabeled/Investigational products and/or services will be mentioned in this CME offering.

67 y/o Caucasian man with HIV/AIDS, OCT CD4+ 437/14%/VL undetectable who presents to NMCSD ER with complaint of progressive dyspnea and a mild dry cough for the last 7 days

History Continued

Initially, his dyspnea was with stairs Progressed to flat surfaces Baseline can walk a few miles, dyspnea with 1 city block and

then at time of admission at rest for past 1-2 days

Dry cough for 7 days-no sputum or hemoptysis 10 lb weight loss over last 6 weeks Denies any fevers Reports that his home blood pressures have been low

(systolic in 80s) so he stopped taking Lisinopril

Review of Systems

Constitution-no fevers or chills, +fatigue HEENT-no sinus tenderness or rhinorrhea Chest-one episode of substernal chest pain 4 days prior to

admission-none at present, no palpitations Resp-DOE – now at rest shortness of breath, slight dry cough,

no sputum GI-no abdominal pain, baseline chronic diarrhea-slight

improvement recently GU-increased nocturia (baseline 1x/night, now 4x/night over

last 4 week) MSK-Significant improvement in shoulder function after

steroid injection in December Neuro-noncontributory

PMH

HIV+; dx oct2006-presented with AIDS with PCP and was admitted with respiratory distress, requiring corticosteroid therapy which resulted in a flare of KS Currently undetectable on

Truvada/Atazanavir/ritonavir/Raltegravir

Switched from Kaletra/Truvada to RAL/3tc/Ataz/Rit on 16sep 2012, previously on Atripla for short period

Genotype 10/12/06: PI mutations: I13V, M36L, L63P; no clinical resistance

Kaposi Sarcoma s/p systemic chemotherapy (doxorubicin)-Jan07-Nov07

Cryptosporidium-treated with nitazoxanide Sept10

BPH HLD Left Shoulder tendonitis-steroid

injection Dec 2013

HTN C diff-oct06 PCP-oct06; based on BAL giemsa CKD (GFR 50) ED Stage I diastolic dysfunction 3rd degree AV block s/p

pacemaker--2007, pacemaker recently checked OS PVD-jul07

B12 def. gynecomastia SCC L ear s/p MOHS-2008 L ear AK cryotherapy-Dec10 ?ABC hypersensitivity-Jul08 Diarrhea predominant IBS-since

age 45; prior significant diarrhea while on Kaletra

Medical History continued

MEDS Truvada Raltegravir 400mg bid Atazanavir 300mg daily Ritonavir 100mg daily Uroxatral 10mg qd Lipitor 20mg qhs Synthroid 75 Lisinopril 5mg-held for 1 day Fish oil 2 pills (1200mg) qam ASA 81mg qd MVI (Ocuvite)

Allergies-Sulfa Past Surgical History Cholecystectomy 2009 Septoplasty Skin excision for SCC Shoulder injection (Dec 2013)

Social History Married-lives with wife Nonsmoker, No alcohol Retired Navy MCPO

Exposure History

Travel: No travel outside US since 2006 Animals: 2 dogs Food Exposure: noncontributory Soil Exposure: occasional gardening in home, does

not wear a mask Other: Denies sick contacts

Physical Exam

T98.3 P94 R16 BP 132/72 99% RA wt 56 kg GEN: NAD, A&Ox4, WDWN HEENT: PERRL, EOMI, nl sclera, no photophobia, no throat inflammation. NECK: nl thyroid, no neck masses, no JVD HEART: RRR S1/S2, no M/G/R LUNGS: CTA Bilaterally ABD: Soft NT/ND, +BS, no HSM LYMPHATICS: No LE edema, no axillary, groin, neck adenopathy. EXT: No LE edema MUSCULOSKELETAL: no joint effusions or pain, no muscle tenderness DERM: Actinic keratoses on right cheek & on his forehead, also with 2 mm of purple

hyperpigmentation on right cheek. No lesions or sores visible elsewhere. (+) for hyperpigmentation on right forearm from prior Kaposi's sarcoma

NEURO: CN 2-12 grossly intact, no focal deficits PSYCH: no perceived mood disorder, nl demeanor with appropriate behavior. LINES/DEVICES: Clean without signs of infection

Labs/Radiology

CBC 4.9/11.3/33.2/181 N77.4 L16.5 Lytes 131/3.6/93/26/31/1.3/200 Ca 8.9 Mg 2 P 2.1 AST 16 ALT 20 Alk P 68 T bili 2.6 Alb 3.6 total protein 6.5

Normal Chest Xray

Differential

Patient Evaluation

Urine Legionella pneumo Ag neg Urine Streptococcus pneumoniae Ag negative Urine Cultures negative Blood Cultures negative Respiratory Viral Panel-negative Sputum Culture-negative Sputum for silver stain-negative Sputum PCP PCR negative

Hospital Course

CT Chest performed-negative ECG and cardiac enzymes unremarkable No antibiotics provided No bronchoscopy performed Diagnosed with a URI? Also diagnosed with new onset DM-HbA1C 6.6 Diabetic teaching provided No medications initiated

Held Lisinopril as possible source of cough Fatigue improved without significant intervention

Clinic Follow up

Patient reports feeling very well Walking 1-2 miles per day Nocturia has returned to 1x per night (baseline) Diarrhea has remained – actually improved over last 2 months Shoulder feels very well Afebrile No cough or SOB

Blood Pressures off Lisinopril 120s-130s Blood Sugars in 130-166

What Happened?

Another Comparable Case

50 year old male with HIV+ CD4 503/13% VL undetectable, on Truvada, atazanavir/ritonavir (RV168 protocol patient), prior KS (Jan 2012) treated with radiation presents for clinic follow-up with 20 lb weight loss over last 6 months

Pertinent History

Patient had intra-articular steroid injection (Aug 2013)-kenalog in left shoulder (2 years shoulder pain) Developed fatigue, shakiness and drenching night sweats

without fevers Wasting of arms and legs Dyspnea on exertion Abdominal bloating Increased urinary frequency (3x nocturia) A1C increased from 6.3->7 in one month-post-prandial glucose

180 Lost 15 lbs in 4-6 weeks New skin lesions requiring surgical removal

Pertinent History Continued

At time-period annotated on previous, he had a recent decrease in CD4 from 504/19% to 214/11% Started on TMP/SMX Weight loss, change in CD4, history of KS & new skin lesions

Concern of recurrence

Bloating sensation with weight loss Received cholecystectomy

Adrenal insufficiency was “ruled out” by primary care provider

Past Medical History

HIV diagnosed 1996 – genotype 2001 M184V, K103R, L63, M36

Headache syndrome Depression Allergic rhinitis Kaposi’s sarcoma Jan 2012 Radiation x 10

BPH s/p TURP Herpes Resolved hepatitis B FHx Family medical history: Diabetes-maternal side Breast CA maternal aunt

PSH PRK R inguinal hernia repair TURP-1999 Cholecystectomy – Sep 13 Septoplasty

NKDA Social History Denies tobacco + EtOH 4X/week Denies ilicits Currently in monogamous

relationship, partner is seronegative

Works in health systems management

Medications

Atazanavir 300mg po daily Ritonavir 100mg po daily Truvada (tenofovir 300mg +Emtricitabine 200mg)

po daily Fexofenadine 60mg po bid Atorvastatin 20mg po daily Escitalopram 10mg po daily Sumitriptan prn Hydrocortisone TMP/SMX

Physical Exam

T99.2 BP 134/86 P98 R14 Gen well appearing Head-cushingoid with moon like facies Neck-increased fat on posterior neck and upper back Oral cavity normal Lymph nodes-no abnormalities noted Lungs cta (b) CV RRR no murmur Abd +bs, soft, NT, ND, well healed surgical scars Musculoskeletal-arm thinning (b) Neuro CN II-XII intact Skin scattered purple plaques on arms, legs and bilateral feet

Evaluation

CBC 8.1/14.2/42.4/222 N 45.9 L 46.3 E 0.7 Lytes 144/3.6/105/23/10/0.9/104 Ca 8.4 Mg 2.3 Bili 2.1 Prot 6.5 Alk P 52 ALT 43 AST 26 UA SG 1.017 protein neg, gluc neg, pH 6 Skin lesions evaluated by dermatology including bx Negative for KS

AM Cortisol

Cortisol AM Site/Specimen 03 Oct 2013 0910 Cortisol AM SERUM 9.760 <o> mcg/dL

(6.2-19.4) Cortisol AM Site/Specimen 03 Oct 2013 0840 Cortisol AM SERUM 7.210 <o> mcg/dL

(6.2-19.4) Cortisol AM Site/Specimen 03 Oct 2013 0800 Cortisol AM SERUM 0.778 (L) <o>mcg/dL

(6.2-19.4)

Additional Labs

Thyroxine free 1.2 nl HBA1C 7 (previous 6.3) Liver enzymes (September) Alk P 213 ALT 162 AST

33 T bili 2.73 with dbili 0.35

Course continued

As steroid level waned-fatigue worsened Endocrine consult-Diagnosed with Cushing’s

Syndrome with secondary adrenal insufficiency Started on hydrocortisone with taper Recognized that ritonavir may be issue Checked ACTH-low nml 8 (6-50 pg/mL) MRI brain- nondiagnostic Performed cosyntropin stimulation test normal

(7.94->19) in one hour, stopped hydrocortisone

Which of the following is an appropriate screening test for Cushing’s Syndrome?

Urine Cortisol Urine Metanephrines Salivary Metanephrines Cosyntropin (ACTH) stimulation test Serum Metanephrines

Which of the following is an appropriate screening test for Cushing’s Syndrome?

Urine Cortisol Confirmatory with Dexamethasone suppression test

Urine Metanephrines Salivary Metanephrines Cosyntropin (ACTH) stimulation test Serum Metanephrines

Cushing’s Syndrome

Iatrogenic hypercortisolism (most common) Ingested/injected/topical/inhaled steroids & megestrol acetate

Ectopic ACTH syndrome- 20 to small cell lung cancer or adrenal tumors

Cushing’s Disease-pituitary ACTH source Factitious Cushing’s- surreptitious intake of steroids Hypercortisolism can occur Extreme stress (including sepsis) Obesity and polycystic ovary syndrome Severe prolonged major depressive disorder Chronic alcoholism

Clinical Manifestations

Progressive Central obesity Children with generalized obesity and growth retardation

Facial Fat accumulation “Moon facies” Buffalo hump Skin atrophy Easy bruisability Striae Fungal infections Hyperpigmentation-induced by increased ACTH (not

cortisol)-binds melanocyte-stimulating hormone Menstrual irregularities Proximal muscle wasting –catabolism Bone loss-can result in pathological fractures

Manifestations

Manifestations continued

Glucose intolerance Stimulation of gluconeogenesis by cortisol & peripheral insulin

resistance Hyperglycemia in 10-15% of patients

Cardiovascular disease Increased risk of MI and Stroke Hypertension

Thromboembolic disease Neuropsychiatric (labile, depressed, anxiety, panic

attacks) Increased frequency of Infections-inhibited immune

system Ophthalmologic findings-increased IOP & cataracts

Test for Cushing’s Syndrome

Daily urinary cortisol (24 hours best) 10 pm-8 am is acceptable alternative

Late evening salivary cortisol-only beneficial if extremely elevated

Low dose dexamethasone suppression test Should suppress ACTH and subsequently reduce urine cortisol

Test of Adrenal Insufficiency

Morning cortisol level > 11 ug/dL not adrenal suppression <3 ug/dL adrenal suppression

Follow up study is cosyntropin (ACTH) stimulation test

Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?

<5% 10% 25% 33% 66%

Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?

<5% 10% 25% 33% 66%-common sources include CMV,

Mycobacteria tuberculosis, Histoplasmosis, PCP, Toxoplasmosis and Kaposi’s Sarcoma

Adrenal Function in HIV

Higher basal cortisol & lower dehydroepiandrosterone Overt adrenal insufficiency is uncommon Hypercortisolism in the absence of Cushings No treatment required

Hypocortisolism always requires treatment

Comparison with Lypodystrophy with PIs “pseudo Cushings”

Altered body adipose tissue Truncal obesity Peripheral wasting Breast hypertrophy “Buffalo hump” Insulin hypersensitivity Normal cortisol and normal dexamethasone

suppression tests Lack striae and easy bruisability

When combined with corticosteroids, which medication has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?

Etravirine Ritonavir Zidovudine Tenofovir Emtricitabine

When combined with corticosteroids, which medication has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?

Etravirine Ritonavir Zidovudine Tenofovir Emtricitabine

Ritonavir and Clearance of Steroids

Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases Samaras, K, Pett S, Gowers, A et al. J Clin Endo and

Metabolism 2005. Review in 2008 reported 25 cases at that date of

ritonavir and fluticasone combination

Clearance of steroids can be delayed by PI including ritonavir

6 patients reported to develop iatrogenic Cushings following inhaled fluticasone for asthma Adrenal suppression noted in all 6 patients When fluticasone removed-4/6 developed hypocortisolism 3/6 developed osteoporosis with pathological fx (1/6) Exacerbation of DM (1/6)

These patients had prior lipodystrophy delaying diagnosis Fluticasone is lipophilic-prior lipodystrophy may contribute

Wide range of variability of 24-hour urine free cortisol levels Suppressed is suppressed Remained suppressed for > 5 months

Samaras et al 2005 cont.

Cushing’s syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction with a woman with HIV infection. Yoganthan K et al. 2011 Int J STD and AIDS

48 year old HIV+ woman with CD4 812 VL undetectable on darunavir/ritonavir emtricatabine and efavirenz (stable regimen for 3 years) presented with cushingoid features after taking inhaled budesonide for 18 months Iatrogenic Cushings w/ secondary adrenal suppression After cortisols resolved, Cushingoid habitus remained

2010-Prior reported case of budesonide & PIs resulting in Cushings in 37 year old African woman

Budesonide, beclomethasone & triamcinolone recommended as safer options Fluticasone longest half life and most lipophilic

Iatrogenic Cushing’s syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted

darunavir Hall JJ et al. 2013 Int J STD & AIDS

Triamcinololone is metabolized by CYP3A4 Ritonavir has greatest effect on CYP3A4 of the PIs Case: 53 year old woman on darunavir/r who

developed cushinoid symptoms 2 weeks after receiving single triamcinolone dose in left shoulder

Triamcinolone injection (both intra-articular and epidural) related Cushing’s Syndrome has been reported previously (usual dose 40-80 mg)

Follow on HPA axis suppression usually 2-6 months No reports with cobicistat-but significant CYP3A4

Diabetes and Corticosteroids

Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?

Random plasma glucose >200 mg/dl 75 g oral glucose tolerance test (2 hour value)> 150 Fasting plasma glucose>126 Hemoglobin A1C>6.5%

Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?

Random plasma glucose >200 mg/dl 75 g oral glucose tolerance test (2 hour value)> 150 Fasting plasma glucose>126 Hemoglobin A1C>6.5%

Glucocorticoid Induced Diabetes and Adrenal Suppression

Lansang MC, Hustak L. Glucocorticoid-induced diabetes and adrenal suppresion: How to detect and manage them. Cleveland Clinic Journal of Medicine. 2011: 78: 748-756. 9% of patients with RA develop DM within 2 years of steroids All types of glucocorticoid formulations including eye drops Mechanism is insulin resistance in liver

Peak effect 4-6 hours after dose Symptoms (either iatrogenic diabetes or Cushing’s) less likely

if regimen mimics physiology (diurnal variation) Insufficiency (Addison’s)-failure of adrenals or pituitary

Lansang et al. 2011 cont.

Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue

diseases. Ito S et al. Modern Rheumatology 2014.

Mechanism-augmentation of hepatic gluconeogenesis & inhibition of glucose uptake in adipose tissue

Since steroids are administered in am, most hyperglycemia is afternoon post-prandial

Author recommended dividing steroid dosing

References

http://www.uptodate.com/contents/establishing-the-diagnosis-of-cushings-syndrome?source=search_result&search=cushings&selectedTitle=1%7E150 Accessioned 31 March 2014

http://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings-syndrome?source=search_result&search=cushings&selectedTitle=2%7E150 Accessioned 31 March 2014

Samaras, K, Pett S, Gowers, A et al. Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases. J Clin Endo and Metabolism 2005: 90:2005-36.

Lansang MC, Hustak L. Glucocorticoid-induced diabetes and adrenal suppresion: Howe to detect and manage them. Cleveland Clinic Journal of Medicine. 2011: 78: 748-756.

Yoganthan K et al. Cushing’s syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction with a woman with HIV infection. Int J STD and AIDS. 2011:23:520-521.

Hall JJ et al. Iatrogenic Cushing’s syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir. Int J STD & AIDS. 2013: 24:748-756.

Ito S et al. Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases. Modern Rheumatology 2014. 24:52-59.

Gerardo J et al. Prevalence of abnormal adrenocortical function in human immunodefiency virus by low dose cosyntropin test. Int J of STD and AIDS. 2001: 12: 804-810.

Mayo, J et al. Adrenal Function in the Human Immunodeficiency Virus-Infected Patient. Arch Intern Med. 2002: 162: 1095-1098.

Foisy MM. et al. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature.

Questions

Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?

Random plasma glucose >200 mg/dl 75 g oral glucose tolerance test (2 hour value)> 150 Fasting plasma glucose>126 Hemoglobin A1C>6.5%

Which of the following is the most sensitive test for diagnosis of glucocorticoid induced diabetes?

Random plasma glucose >200 mg/dl 75 g oral glucose tolerance test (2 hour value)> 150 Fasting plasma glucose>126 Hemoglobin A1C>6.5%

When combined with corticosteroids, which medications has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?

Etravirine Ritonavir Zidovudine Tenofovir Emtricitabine

When combined with corticosteroids, which medications has been reported to be a contributing factor in iatrogenic Cushing’s Syndrome?

Etravirine Ritonavir Zidovudine Tenofovir Emtricitabine

Which of the following is an appropriate screening test for Cushing’s Syndrome?

Urine Cortisol Urine Metanephrines Salivary Metanephrines Cosyntropin (ACTH) stimulation test Serum Metanephrines

Which of the following is an appropriate screening test for Cushing’s Syndrome?

Urine Cortisol Confirmatory with Dexamethasone suppression test

Urine Metanephrines Salivary Metanephrines Cosyntropin (ACTH) stimulation test Serum Metanephrines

Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?

<5% 10% 25% 33% 66%

Although idiopathic adrenal insufficiency in HIV is rare, what percentage of post-mortem evaluations of the adrenal gland are abnormal?

<5% 10% 25% 33% 66%-common sources include CMV,

Mycobacteria tuberculosis, Histoplasmosis, PCP, Toxoplasmosis and Kaposi’s Sarcoma