HIVLipodystrophy: Guidelines Development

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HIV-LipodystrophyGuidelines Development

• Donald Kotler, MD
• Professor of Medicine
• Columbia University College of Physicians and
  Surgeons
• St. Lukes-Roosevelt Hospital Center
• New York, NY

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HIV-Associated Lipodystrophy
Hyperlipidemia
Insulin resistance
Fat atrophy
Fat accumulation
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Lipodystrophy

• Are lipodystrophy and metabolic disorders a
  single syndrome or multiple, overlapping
  syndromes?
• Are these conditions caused by ART, host factors,
  HIV disease, or a combination of factors?

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Guidelines Rationale

• Response to need for cost effective approach to
  diagnosis and management
• Clinical and public health (epidemiologic) needs
• Guidelines will need periodic revision

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Aims Guidelines

• Glucose metabolism
• Lipid metabolism
• Body composition
• Cardiovascular risk
• Lactic acidemia
• Osteopenia

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Glucose Metabolism

• Pre-HAART data
• Phenotype
• Effect of PI in healthy volunteers
• Effects of fat accumulation
• Effects of fat depletion
• Recommendations
• Future directions

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Fasting Glucose vs OGTT
FastingIntolerance
Fasting Diabetes
2-hour Intolerance
2-hour Diabetes
?110, lt126
?126
?140, lt200
?200
1 (3)
0
9 (30)
0
Engelson. 13th IAC 2000 Durban. Abstract
ThPpB 1437.
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Effect of Indinavir Upon Glucose Metabolism

• Design prospective, open-label
• Patients 10 healthy volunteers
• Treatment IDV 800 mg TID x 1 mo
• Measurements insulin resistance, lipids, body
  composition
• Findings insulin resistance rose while lipids
  and body composition did not change

Noor. 2nd Workshop on Lipodystrophy.
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VAT and Insulin Sensitivity
10
r .050P lt.0001
8
6
Insulin Sensitivity(10-4 - min-1/(?U-1 mL)
4
2
0
0
100
150
200
250
300
50
VAT (cm2)
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Lipoatrophy and Insulin Resistance

• Design prospective, cross-sectional
• Subjects 15 HIV with LD, 14 HIV without LD,
  12 controls
• Measurements insulin resistance, body
  composition, soluble TNF receptors
• Findings insulin resistance was reduced more in
  muscle than in fat, and was associated with
  lipoatrophy and increased sTNFR2 levels

Mynarcik. JAIDS 200025312.
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ConsensusInsulin Resistance

• Clinical
• Fasting glucose

• Investigational
• Fasting insulin
• C-peptide
• HOMA
• Oral glucose tolerance test
• HgbA1C (diabetes only)

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Metformin in HIV-Lipodystrophy

• Randomized, controlled trial
• Metformin at 500 mg BID
• Treatment associated with decreased insulin AUC
  during OGTT (P .01)
• Treatment associated with weight loss(P .005),
  decreased blood pressure(P .009)
• Trend towards decreased VAT
• Metformin decreased TPA and PAI-1

Hadigan. JAMA 2000284472.
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Rosiglitazone in Lipodystrophy

• Insulin resistance is common
• Insulin resistance is drug-related
• Insulin resistance precedes fat redistribution
• Insulin resistance is related to microvascular
  disease in other circumstances
• Thiazolidinediones decrease insulin resistance

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Fat Metabolism

• Pre-HAART data
• Phenotype
• Effect of PI in healthy volunteers
• Effects of other ARVs
• Genetic susceptibilities
• Recommendations

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Fat MetabolismPre-HAART Data

• Elevated fasting triglycerides
• Association with elevated de novo synthesis
• Associated with decreased clearance
• Association with serum alpha interferon
• Decreased HDL, LDL, VLDL chol, and apo B
• Increased prevalence of LDL-B
• Apoprotein E2 associated with higher
  triglycerides
• Triglycerides fell with AZT therapy

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Effect of RTVUpon Serum Lipids

• Design double-blind, placebo-controlled
• Patients 21 healthy volunteers
• Treatment RTV for 2 weeks
• Findings RTV treatment led to rises in
  triglycerides, VLDL chol, LDL chol, apo B, and Lp
  (a)

Purnell. AIDS 20001451.
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Evaluation Dyslipidemia

• Fasting lipid profile
• ?8 hr, preferably gt12 hr
• TGs, total and HDL chol, calculated LDL
• Calculated LDL is inaccurate if TGs gt400
• Evaluate prior to therapy
• Repeat 3 to 6 months
• Repeat 1 to 2 months if baseline TGs are elevated
• Screen for other risk factors

Adult ACTG Cardiovascular Disease Focus Group,
5/25/00.
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NCEP GuidelinesTreatment Initiation
Treatment Decisions Based on LDL-Cholesterol
Level

• Initiation Level LDL GoalPatient
  Category (mg/dL) (mg/dL)
• Dietary Therapy
• Without CHD and lt2 risk factors ?160 lt160
• Without CHD and ? 2 risk factors ?130 lt130
• With CHD gt100 ?100 Drug Treatment
• Without CHD and lt2 risk factors ?190 lt160
• Without CHD and ? 2 risk factors gt130 ?100

LDL low-density lipoprotein CHD, coronary
heart disease.
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Treatment of Hyperlipidemia

• Potential for drug-drug interactions between
  statins/fibrates and antvirals
• Atorvastatin, simvastatin, lovastatin,
  benzafibrate, ciprofibrate, fenofibrate, and
  gemfibrozil are metabolized primarily by CYP3A4
• Cerivastatin and fluvastatin are metabolized by
  CYP2C8 and CYP2C9, respectively
• Pravastatin is not primarily metabolized by
  CYP isoenzymes

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Body Fat Redistribution

• Definitions
• Prevalence
• Associations
• Measurements
• Recommendations
• Future directions

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Body Fat Distribution

• Refers to the 3-dimensional localization of
  adipose tissue depots within the body
• Various depots affect metabolism differently
• Compartment size affected by many factors
• Health consequences
• Associations with hyperlipidemia, insulin
  resistance, atherosclerosis
• Association with absolute, not relative,fat
  contents

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Prevalence of Fat Redistribution
Prevalence Estimate
Reference
n/N

Method(s)
Boix et al 1998
5/272
2
SR/CR
Shaw et al 1998
12/961
13
PE
Dong et al 1999
21/116
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SR/PE
Veny et al 1998
35/158
22
PE
Lichtenstein et al 2000
529/1077
49
CR
Miller et al 2000
723/1350
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SR/PE
Carr et al 1998
74/116
64
SR/PE
Carr et al 1999
95/113
84
SR/PE
Prevalence estimates are for combined
lipohypertrophy and lipoatrophy. Abbreviations
SR self-report PE physical examination CR
chart review. Boix. 12th World AIDS Congress,
1998. Abstract 12398. Shaw. J STD AIDS
19989595-599. Dong.J Acquir Immune Def Syndr
Hum Retrovirol 199921107-113. Veny. 38th
Interscience Conference on Antimicrobial Agents
and Chemotherapy 1998. Abstract I-92.
Lichtenstein. 7th Congress on Retroviruses and
Opportunistic Infections 2000. Abstract 23.
Carr. AIDS 199812F51-F58. Carr. Lancet
19993532093-2099.
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Regional Measurements

• Cross-sectional imaging
• CT, MRI
• Whole body and single slice
• Regional DXA
• Anthropometry
• Regional BIA
• Ultrasound

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Abdominal MRI Scans
VAT
VAT
SAT
SAT
Control Subject
Increased VAT
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DXA and Fat Distribution

• Most appendicular fat is SAT
• Change in appendicular fat change in SAT
• Trunk fat is comprised of SAT and VAT
• Mild improvement over anthropometrics in non-HIV
  conditions
• Comparison to anthropometrics in HIV infection
  not reported

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Changes in Trunk Fat vs VAT
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y 0.4564x 0.2556R2 0.7153
6
4
2
Change in VAT (Liters)
0
10
8
6
4
2
0
2
4
6
8
10
2
4
6
8
Change in Trunk Fat (kg)
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Difference vs Average of Predicted and Measured
VAT
3
2
Mean 2SD 1.57
1
Difference Between Measured andPredicted VAT
(Liters)
Mean 0.058
0
6
4
2
0
2
4
6
1
Mean 2SD 1.43
2
3
Average of Measured and Predicted VAT (Liters)
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Changes in Limb Fat vs SAT
10
y 1.7514x 0.13R2 0.6978
8
6
4
2
Change in SAT (Liters)
0
5
4
3
2
1
0
1
2
3
4
5
2
4
6
8
10
Change in Limb Fat (kg)
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Difference vs Average ofPredicted and Measured
SAT
4
Mean 2SD 3.17
3
2
1
Difference Between Measured andPredicted SAT
(Liters)
Mean 0.016
0
10
8
6
4
2
0
2
4
6
8
10
1
2
Mean 2SD 3.0
3
4
Average of measured and predicted SAT (liters)
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Waist vs Hip (Male Controls)
1600
y 0.8577x 166.09R2 0.8086
1400
1200
1000
WC (mm)
800
600
400
200
200
400
600
800
1000
1200
1400
1600
CIC (mm)
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Clinical Significance


Coronary arterydisease
0.938 0.051
0.925 0.054
CVA
0.958 0.051
0.925 0.054
All cause deaths
0.935 0.053
0.925 0.053
Larsson. BMJ 1984.
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Anthropometric Analyses

• WHR predicts adverse consequences in
  epidemiologic studies
• WHR lacks sensitivity and specificity compared to
  CT or MRI, also in HIV
• Waist circumference and sagittal diameter are
  better predictors of VAT by single-slice CT in
  non-HIV
• Multivariate techniques

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Discriminant Function vsVAT by MRI
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40
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Female No Lipo
DF
Female Lipo
30
25
20
0
5
10
VAT vol (L)
DF 0.043WC-0.70WHR
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Evaluation Visceral Fat

• Clinical
• Waist circumference

• Investigational
• Single-cut CT
• Single-cut MRI
• DEXA
• Ultrasound
• BIA (not useful)

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Effect of Discontinuing d4T

• 9-month follow-up
• Increased SAT
• No change in VAT
• Results imply that lipoatrophy is reversible

Saint-Marc. 7th CROI 2000 San Francisco.
Abstract 52.
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LipodystrophyEffect of Exercise

• Design prospective, open label
• 10 men with truncal obesity
• 16-week exercise program
• Results significant decrease in total body and
  truncal fat, no significant change in weight,
  lean mass, or bone density nor adverse effects

Roubenoff. AIDS 1999131373.
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Week
Baseline
12
24
36
48
60
8
6
4
VAT (Liters)
2
0
rhGH dose
6 mg
2 mg
0
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Risk Benefit Analysis ofCAD and HAART
Average calculated increase in CHD events 0.14
per year
? Mortality rates in HIV-infected patients by 50
in the US
Risks
Benefits
CHD coronary heart disease. Adapted from
Grunfeld. 6th CROI 1999 Chicago. Palella.
NEJM 1998338853.
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Evaluation Cardiovascular Risk

• Clinical
• Classic risk factors

• Investigational
• Carotid doppler
• Stress echo
• Noninvasive coronary artery assessment
• Novel metabolic parameters

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Lactic Acidosis

• Liver dysfunction as opposed to lipodystrophy
• Non-specific symptoms, may be fatal
• Reversal with cessation of NRTI therapy
• Mild elevations are common
• Utility of screening lactate is questionable
• 5 mmol/L with symptoms or 10 mmol/L, irrespective
  of symptoms, is significant
• Need care in sample collection
• Routine monitoring not recommended

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Osteopenia/Osteonecrosis

• Previous studies had documented avascular
  necrosis of the femoral head
• May be asymptomatic
• Studies show demineralization in a range that may
  become clinically significant
• Not likely related to PI therapy
• NRTI therapy may affect bone mineral
• Routine screening is not recommended

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