Download Managment of Long Term Complications of HIV Antiretrovial

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Current HIV Issues in the US:
Case Studies in Managing Long-Term
Non-ADS Co-Morbidities
Ann Khalsa, MD, MSEd, AAHIVS
Centro de Salud Familiar La Fe CARE Center
Texas-Oklahoma AIDS Education
and Training Center
El Paso, Texas, USA
＝背景の写真は、 Dr
Khalsaが2006年エイズ学会（熊本）来日時に日本で写した紅葉の写真だそうです＝
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Outline
Cases
Co-Morbidities
• Francisco
• Richard
• Juan
• Renal and Bone
• Bone and Androgens
• Diabetes
Case: Francisco
Introduction
• 48 y/o Hispanic MSM
• HIV+ since 1992 on multiple ARVs with
multiple 3-class mutations
• VL<50, CD4>500 on TDF-FTC-LPVr x 3yrs
• Complications:
– Hyperlipidemia, hypertension, GERD on
Omega 3 FFA, ACE inhibitor, PPI
• New onset  CrCl: 45 (eGFR)
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Case: Francisco
Question #1
• Which tests should be ordered to evaluate his
renal insufficiency?
1.
2.
3.
4.
5.
Spot urine protein:creatinine ratio
Serum and urine phosporous
Serum and urine glucose
24 hour urine creatinine clearance
1, 2 and 3
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Case Francisco
Q#1 Results
Test
Result
Normal
Urine spot prt:creat ratio
425 mg/g
<200 mg/g creat
Urine spot creatinine
135 mg/dL
N/A
Urine random phosphorous 118 mg/dL
N/A
Serum creatinine
1.8 mg/dL
~< 1.5 mg/dL
Serum phosphate
2.0 ng/dL
2.5-4.5 mg/dL
Fractional Excretion of Phosphorous (FE PO4):
INTERPRETATION:
(Ur PO4 x Ser Cr x 100) / (Ser PO4 x Ur Cr)
Serum PO4 &  FEPO4:
(118 x 1.8 x 100) / (2.0 x 135) = 79%
= Tubular, eg. Fanconi’s
Elevated FE PO4 = >5%
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Kidney Disease in HIV
• Acute Kidney Injury
– Example hospitaliztion complication
– Infections, medications, liver failure
• ARV Nephrotoxicity
– TDF: proximal tubulopathy
– IDV, ATV: crystalluria, nephrolithiasis
• HIV Associated (HIVAN)
– Advanced HIV, blacks (MYH9 gene)
• Comorbid Disease
– HBV, HCV, DM, HTN
End
Stage
Renal
Disease
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Tenofovir Toxicity:
Proximal Tubulopathy
Classic Presentation
Phosphate wasting
Metabolic acidosis
Euglycemic glycosuria
Evaluation
FE PO4
Serum bicarbonate
Serum & urine glucose
 Creatinine clearance
Proteinuria
MDRD, CG GFR
Spot Ur Prt:Creat
• Most have sub-clinical abnormalities; 1-2% serious toxicity
• Risks: Pre-existing renal insufficiency, genetic
predisposition, concommitant meds (ddI, PI-rtv)
Case Francisco
Question #2
• Which of the following are important in the
managment of his CKD?
1. Consider non-TDF antiretroviral regimen
2. Optimize ACE / ARB inhibitor therapy to control
blood pressure and proteinuria
3. Evaluate for other co-morbidities potentially
underlying his CKD
4. All of the above
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Case Francisco
Q#2 Management
• Co-Mobidities:
– No diabetes mellitus
– Hepatitis B & C serologies negative
• ARV Allergies / Resistance:
– NNRTI: 181C, EFV allergy
– NRTI: 151M mutation complex
– PI: 10I,71V,73S,77I,90M: 1st generation PIs, Ø DRV mut
• Medication changes:
– TDF  RLT; FTC dose monitored (CrCl normalized)
– ACE inhibitor increased (BP & proteinuria normalized)
– NSAID discontinued
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Case Francisco
Question #3
• Given his CKD with phosphate wasting what
other studies should be performed?
1. Serum 25-OH vitamin D
2. DEXA bone density scan
3. 1 and 2
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Case Francisco
Q#3 Results
Bone Mineral Density (BMD)
Dual Energy X-ray Absorptiometry (DEXA) Scores
T-Score
Z-Score
L1
-1.8
-0.7
L2
-1.7
-1.7
L3
-2.2
-2.2
Vitamin D Level
25-OH Vitamin D
Result
Normal
24 ng/ml
32-100 ng/ml
Case Francisco
Question #4
• Does this patient have osteoporosis?
1. Yes
2. No
3. Can’t tell
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Osteoporosis Definitions
• WHO Definition (DEXA):
– Osteoporosis:T-Score  -2.5 Std.Dev.
– Osteopenia : T-Score -1.0 to -2.5 SD
– Normal:
T-Score  -1.0 SD
• Increase risk of fracture by 1.5-3.0 fold
for each 1.0 SD decrease
• Z-Score used in men <50 yrs,
and premenopausal women
Case Francisco
Question #5
• Does this patient have Vitamin D deficiency?
1. Yes
2. No
3. Can’t tell
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Vitamin D Deficiency
• Definitions
– Deficiency:
– Insufficiency:
25 OH Vit D <20 ng/ml
25 OH Vit D 20-30 ng/ml
• Vitamin D Replacement (“filling up the tank”)
– Ergocalciferol 50,000 units orally twice weekly
for 6-12 weeks ( 600,000 units total)
• Vitamin D Maintenance
– Cholecalciferol  800-2000 IU daily
– Ergocalciferol 50,000 units every 2-4 weeks
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Osteomalacia
• Most important differential diagnosis for low BMD
• Impaired bone mineralization
• Symptoms: Weakness, fracture, pain, anorexia,
weight loss
• Major causes: severe vitamin D deficiency,
phoaphate wasting
• Treatment: vitamin D, phosphate; not
bisphosphonates
Case Richard
Introduction
• 51 y/o heterosexual male
• Co-morbidities:
– Hepatitis C with cirrhosis
– Alcoholism
• HIV well-controlled on AZT-3TC-EFV
• Complications:
– Hyperlipidemia, severe lipoatrophy with low BMI
– Diabetes mellitus on glipizide 10mg bid,
HgbA1c 6.8%
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Case Richard
Question #1
• Should this patient be screened for
osteoporosis?
1. Yes
2. No
3. Dont know
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Indications for
Osteoporosis Screening in HIV
•
•
•
•
•
•
•
•
•
Low BMI
Hypogonadism / postmenopausal
Vitamin D deficiency: Osteomalacia
Corticosteroid exposure
Alcoholism
Smoking
Aging
? TDF exposure,
? VL AUC (yrs untreated HIV)
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FRAX WHO Fracture Risk Assessment Tool: 10Year Risk of Fracture
Risk Factors
Age
Gender
Weight & height
Previous fracture
Parent hip fracture
Current smoking
Glucocorticosteroids exposure
Rheumatoid arthritis
Secondary osteoporosis
Alcohol
Femoral neck BMD
Parameters
W: 65 yrs, M: 70 yrs; 50-70 yrs if risks
Female
Low BMI
As an adult, spontaneous or low trauma
(dose dependent)
>3 months @ 5mg prednisolone/day
Confirmed diagnosis
Presence of associated condition
3 units daily (8-10g/u)
Gm/cm2
http://www.shef.ac.uk/FRAX/
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Case Richard
Q#1 Results
Bone Mineral Density (BMD)
Dual Energy X-ray Absorptiometry (DEXA) Scores
L1-L4
Femoral Neck
Total Hip
T-Score
-1.9
-2.8
-2.0
Z-Score
-1.6
-2.0
-1.7
Case Richard
Question #2
• Does this patient have osteoporosis?
1. Yes
2. No
3. Can’t tell
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Osteoporosis Definitions
• WHO Definition (DEXA):
– Osteoporosis:T-Score  -2.5 Std.Dev.
– Osteopenia : T-Score -1.0 to -2.5 SD
– Normal:
T-Score  -1.0 SD
• Increase risk of fracture by 1.5-3.0 fold
for each 1.0 SD decrease
• Z-Score used in men <50 yrs, and
premenopausal women
Case Richard
Question #3
• What is the next step?
1.
2.
3.
4.
Treat with a bisphosphonate
Treat with calcium and viatmin D
Evaluate for secondary causes of low BMD
All (1, 2 and 3)
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Causes of Secondary Low BMD
COMMON IN HIV
Vitamin D Deficiency
25-OH Vitamin D Level
Phosphate Wasting
Serum phosphate (urine fractional excretion)
Hypogonadism
M: testosterone; W: menstrual history; FSH/LH
ADDITIONAL BASIC WORK-UP
Hyperparathyroidism
PTH, serum calcium
Subclinical Hyperthyroidism TSH
OTHERS
•
•
•
•
Deficiencies: Calcium, Celiac Disease, Malabsorption, Malnutrition
Endocrine: Cushing’s Syndrome, Adrenal Insufficiency, Diabetes
Inflammation: HIV, Rheumatoid Arthritis, Inflammatory Bowel Disease,
Heme & CA: Hemophilia, Lymphoma, Multiple Myeloma, Thalassemia
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Case Richard
Q#3 Results
Test
Result
Normal
25-OH Vitamin D
36 ng/ml
>30 ng/ml
Serum phosphate
3.5 ng/dL
2.5-4.5 mg/dL
PTH
Serum Calcium
TSH
18 pg/ml
9.4 mg/dL
0.99 mU/L
8.5-10.5 mg/dL
0.45-4.5 mU/L
Testosterone?
Case Richard
Question #4
• What is the best test for evaluation of
hypogonadism in HIV?
1.
2.
3.
4.
Random total testosterone
Morning total testosterone
Random free testosterone
Morning free testosterone
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Regulation of Testosterone
Only 2% is Free Testosterone
Adapted from Braunstein GD. Basic and Clinical Endocrinology. 5th edition.
Stanford, Conn: Appleton & Lange; 1997:422-452.
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Alterations in SHBG
Decreased SHBG
Increased SHBG
•Moderate obesity
•Nephrotic Syndrome
•Hypothyroidism
•Glucocorticoids, progestins,
anabolic steroids
•Aging
•Hepatic cirrhosis
•Hyperthyroidism
•Anticonvulsants
•Estrogens
•HIV
Diagnosis of Androgen-Deficiency in Symptomatic HIV+ Men:

Obtain “Morning Free Testosterone”
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Case Richard
Q#4 Results
Test
Result
Normal
25-OH Vitamin D
36 ng/ml
>30 ng/ml
Serum phosphate
3.5 mg/dL
2.5-4.5 mg/dL
PTH
Serum Calcium
TSH
18 pg/ml
9.4 mg/dL
0.99 mU/L
8.5-10.5 mg/dL
0.45-4.5 mU/L
AM Free Testosterone
32 ng/dL
46-224 ng/dL
Case Richard
Question #5
• What is the next step?
1. Start testosterone enanthate 200 mg IM every 2
weeks
2. Start testosterone gel 1%, 5 g daily
3. Measure LH & FSH
4. Measure serum prolactin
5. Obtain pituitary MRI
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Select Causes of Low Testosterone
PRIMARY
(Testicular)
•Congenital
•Chemo /
radiation
•Mumps /
viruses
•Trauma
•Certain drugs
SECONDARY
(CNS)
•Acute illnesses
•Pituitary tumor /
infiltration
•Hemochromatosis
•Cushing’s Syndrome
•Cirrhosis
•Morbid obesity
•Certain drugs
MIXED
• AIDS
• Liver failure
• Uremia
• Alcoholism
• Aging
• Corticosteroids
Suggested Monitoring During
Testosterone Treatment
Test
Symptom
Assessment
Testosterone
Level
PSA/DRE
Hematocrit
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1-2
3-6
Annually Goal/Comments
months months
Response versus
X
X
X
adverse effects
Acute illnesses
Mid-normal range
X
X
X
Urology eval:
PSA >4 ng/ml or
>1.4 rise in 12 months
X
X
Hold therapy when
hct >54 until safe level
Case Richard
Question #6
• You start patient on testosterone gel 1% (5 g/d)
and calcium 1200 mg/d and vitamin D 800 IU/d.
What else do you recommend?
1. No additional treatment. Repeat DEXA in 1 year.
2. Start bisphosphonate therapy
3. Start recombinant PTH therapy
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Osteoporosis Therapies
BISPHOSPHONATES
Alendronate Risedronate
Ibandronate
Dose
Frequency
Daily
Weekly
Daily
Annually (IV)
Monthly
Quarterly (IV)
Adverse
Effects
• GI: Dyspepsia, pain, nausea
• Jaw osteonecrosis (oversuppression of osteoclasts ?)
Daily
Weekly
Zolendronate
RECOMBINANT PARATHYROID HORMONE
Teriparatide
• Stimulates osteoblastic bone formation
• Dose: daily subcutaneous injection
• Reserved for patients with fractures on
bosphosphonates or continued bone loss
Osteoporosis
Overall Management
• Lifestyle changes:
– Smoking cessation, alcohol reduction, weight
bearing exercise
• Rx options
– Bisphosphonates
– Hormones: estrogen or testosterone
– Parathyroid hormones
• Calcium + Vitamin D
– 1200 mg calcium + 800 IU vitamin D
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Case: Juan
Introduction - 1
• 53 yr Hispanic MSM
• HIV+ x 20 yrs, on ART since 2000
– VL <50: TDF-FTC-EFV
– Mild lipoatrophy: face, buttocks, legs
• Co-morbidities:
– Mild HTN, normal lipids and renal, no smoking
– Strong family history DM
– BMI 27 kg/m2
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Case: Juan
Question #1
The patient’s labs show fasting glucose of
110 mg/dl. What should you do next?
1.Repeat a fasting glucose level
2.Order a 2 hour oral glucose tolerance test
3.Check a HgbA1c level
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Case Juan
Results
• Plasma Fasting Glucose
108 mg/dL
• 2 hour oral glucose tolerance test 167mg/dL
• Hemoglobin A1c
6.4%
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American Diabetes Association
Definitions
Test
Pre-Diabetes
Diabetes
1
Plasma Fasting Glucose
(IFG: Impaired F.G.)
100-125 mg/dL,
confirmed
 125 mg/dL,
confirmed
2
2 hour Oral Glucose
Tolerance Test (OGTT)
(IGT: Impaired G.T.)
140-199 mg/dL
200 mg/dL
3
Random plasma glucose --
 200 mg/dL
w/ symptoms
4
HgbA1c
 6.5% *
6.0-6.5%
HgbA1c for Diabetes Diagnosis – Caveats:
• Confirm with repeat measurement, unless #3 present
• If hemoglobinopathy or increased RBC turnover:
• Not valid, so diagnose with #1 and 2
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HgbA1c Underestimates Glycemia
in HIV+ Patients

450
HIV (n=100)
- - -  Control (n=200)
400

Glucose (mg/dL)
350
300
250
200
150
HgbA1c Discordance
= 29mg/dL
100
50
0
4
5
6
7
8
9
HgbA1c (%)
Kim P, et al. Diabetes Care, 2009; 32:1591-1593.
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Case: Juan
Question #2
The patient is diagnosed with “Pre-Diabetes”. You
recommend?
1.Lifestyle modifications to lose 5-10% of
body weight
2.Lifestyle modifications plus metformin
3.Lifestyle modifications plus pioglitazone
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Evlauation of Glucose Disorders
in HIV-Infected Patients
Fasting Glucose
(at HIV diagnosis, ARV initiation, and annually therafter
< 100 mg/dL
100-125 mg/dL
125 mg/dL
Repeat FG 125 mg/dL
2 hr OGTT
No
Yes
200 mg/dL
< 140 mg/dL
140-199 mg/dL
Normal
Pre-DM: IFG alone
Pre-DM: IFG/IGT
Diabetes Mellitus
Repeat FG
annually
Lifestyle
Modifications
Lifestyle Modifications
Consider Metformin: if other risks
Consider Pioglitazone: if lipoatrophy
Lifestyle Modifications
Rx: Metformin or Pioglitazone
Brown, Clinical Care Options, 2008.
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Metformin
• Associated with 31% reduction in diabetes1
• Recommended for pre-diabetes (IFG & IGT)
with any of the following:2
<60 yrs, BMI >35kg/m2, FH DM (1st-degree relative),
 Triglycerides,  HDL cholesterol, HTN, A1c >6.0%
• Contraindications / Complications:
–
–
–
–
Renal insufficiency
Hepatic failure
Lactic acidosis with antiretrovirals
Worsening of lipoatrophy3
1) Knowler WC, et al. NEJM 2002;346:393-403. 2) Nathan, Diabetes Care 2007. 3) Kohli et al, HIV Med. 2007;8:42-426.
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Pros and Cons of Glitazones
PROS
CONS
• Decreases risk of
developing DM
(82% risk)1
• CVD benefit (pioglit.)
• Modest lipoatrophy
benefit (~200-500gm)
•
•
•
•
•
•
1: Knowler, Diabetes, 2005
Expensive
Weight gain
Fluid retention
CVD risk (rosiglit.)
Osteoporosis
Liver toxicity
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Diabetes Risk Factors
HIV-associated
risk factors
Classic type 2
diabetes risk factors
• Obesity (abdominal)
• Physical Inactivity
• Genetic
– Family history
– Race/ethnicity
• Older age
• Dyslipidemia
Insulin
Resistance
• Peripheral lipoatrophy
• Reduced adiponectin
• Increased liver/muscle
fat
• Inflammatory cytokines
• Low testosterone
• Oxidant stress
• HCV infection
• Protease inhibitors
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Take-Home Application Pointers
Co-Morbidity Management
Renal Disease • Regularly monitor urinalysis and creatinine
clearance;
• Evaluate with FE PO4; spot urine
protein:creatinine
• Optimize management of DM, HTN, HVC, HBV
• Adjust ARVs and other medications
• ACE-I/ARB
Osteoporosis • Screen based on age, hromonal status & risk
factors
• Evaluate for Vit. D (25-OH) and secondary
causes
• Manage with calcium, vit. D, wt-exercise;
d/c smoking & alcohol; bisphosphonates
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Take-Home Application Pointers
Co-Morbidity Management
Hypogonadism
• Screen (free am test.) based on symptoms &
risks
• Evaluate for primary & secondary causes
• Monitor treatment: Hct., PSA & exam, levels
Diabetes
• Monitor fasting glucose; OGTT &/or HgbA1c
• Prevent / treat: diet, exercise, ? ARV changes
• Pioglitazone for lipoatrophy, Metformin for
other risks
Cardiovascular
Disease
•
•
•
•
Agressive lifestyle changes (especially smoking)
Manage co-morbidities (DM, HTN, lipids)
Additive lipid-lowering therapies
Aspirin daily, ? ARV selection or changes