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Kotler_MDS218_final 1
Kotler_MDS218_final 2
HIV-Lipodystrophy:Guidelines Development
Donald Kotler, MD
Professor of Medicine
Columbia University College of Physicians and Surgeons
St. Luke’s-Roosevelt Hospital Center
New York, NY
Kotler_MDS218_final 3
HIV-Associated Lipodystrophy
Fat Fat atrophyatrophy
Fat Fat accumulationaccumulation
HyperlipidemiaHyperlipidemia Insulin resistanceInsulin resistance
Kotler_MDS218_final 4
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?
Kotler_MDS218_final 5
Guidelines: Rationale
Response to need for cost effective approach to diagnosis and management
Clinical and public health (epidemiologic) needs
Guidelines will need periodic revision
Kotler_MDS218_final 6
Aims: Guidelines
Glucose metabolism
Lipid metabolism
Body composition
Cardiovascular risk
Lactic acidemia
Osteopenia
Kotler_MDS218_final 7
Glucose Metabolism
Pre-HAART data
Phenotype
Effect of PI in healthy volunteers
Effects of fat accumulation
Effects of fat depletion
Recommendations
Future directions
Kotler_MDS218_final 8
Fasting Glucose vs OGTT
FastingIntolerance
Fasting Diabetes
2-hour Intolerance
2-hour Diabetes
110, <126 126 140, <200 200
1 (3%) 0 9 (30%) 0
Engelson. 13th IAC; 2000; Durban. Abstract ThPpB 1437.
Kotler_MDS218_final 9
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.
Kotler_MDS218_final 10
VAT and Insulin Sensitivity
r = –.050P <.0001
Insu
lin S
en
sit
ivit
y(1
0-4 -
min
-1/(U
-1 m
L)
0
2
4
6
8
10
0 50 100 150 200 250 300
VAT (cm2)
Kotler_MDS218_final 11
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 2000;25:312.
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Consensus:Insulin Resistance
Clinical
— Fasting glucose
Investigational
— Fasting insulin
— C-peptide
— HOMA
— Oral glucose tolerance test
— HgbA1C (diabetes only)
Kotler_MDS218_final 13
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 2000;284:472.
Kotler_MDS218_final 14
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
Kotler_MDS218_final 15
Fat Metabolism
Pre-HAART data
Phenotype
Effect of PI in healthy volunteers
Effects of other ARVs
Genetic susceptibilities
Recommendations
Kotler_MDS218_final 16
Fat Metabolism:Pre-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
Kotler_MDS218_final 17
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 2000;14:51.
Kotler_MDS218_final 18
Evaluation: Dyslipidemia
Fasting lipid profile 8 hr, preferably >12 hr
— TGs, total and HDL chol, calculated LDL
— Calculated LDL is inaccurate if TGs >400
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.
Kotler_MDS218_final 19
NCEP Guidelines:Treatment Initiation
Initiation Level LDL GoalPatient Category (mg/dL) (mg/dL)
Dietary Therapy
Without CHD and <2 risk factors 160 <160
Without CHD and 2 risk factors 130 <130
With CHD >100 100
Drug Treatment
Without CHD and <2 risk factors 190 <160
Without CHD and 2 risk factors >130 100*LDL = low-density lipoprotein; CHD, coronary heart disease.
Treatment Decisions Based on LDL-Cholesterol Level*
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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
Kotler_MDS218_final 21
Body Fat Redistribution Definitions
Prevalence
Associations
Measurements
Recommendations
Future directions
Kotler_MDS218_final 22
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
Kotler_MDS218_final 23
*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 1998;9:595-599. Dong.J Acquir Immune Def Syndr Hum Retrovirol 1999;21:107-113. 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 1998;12:F51-F58. Carr. Lancet 1999;353:2093-2099.
Prevalence of Fat RedistributionPrevalence 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 18 SR/PE
Veny et al 1998 35/158 22 PE
Lichtenstein et al 2000 529/1077 49 CR
Miller et al 2000 723/1350 51 SR/PE
Carr et al 1998 74/116 64 SR/PE
Carr et al 1999 95/113 84 SR/PE
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Regional Measurements Cross-sectional imaging
— CT, MRI
— Whole body and single slice
Regional DXA
Anthropometry
Regional BIA
Ultrasound
Kotler_MDS218_final 25
Abdominal MRI Scans
Control Subject Increased VAT
VAT
SAT
VAT
SAT
Kotler_MDS218_final 26
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
Kotler_MDS218_final 27
Changes in Trunk Fat vs VAT
y = 0.4564x –0.2556R2= 0.7153
–8
–6
–4
–2
00
2
4
6
8
–10 –8 –6 –4 –2 00 2 4 6 8 10
Change in Trunk Fat (kg)
Ch
an
ge
in V
AT
(L
ite
rs)
Kotler_MDS218_final 28
Difference vs Average of Predicted and Measured VAT
–3
–2
–1
00
1
2
3
–6 –4 –2 00 2 4 6
Average of Measured and Predicted VAT (Liters)
Dif
fere
nc
e B
etw
een
Me
asu
red
an
dP
red
icte
d V
AT
(L
iter
s) Mean + 2SD = 1.57
Mean = 0.058
Mean –2SD = –1.43
Kotler_MDS218_final 29
Changes in Limb Fat vs SAT
y = 1.7514x + 0.13R2 = 0.6978
–10
–8
–6
–4
–2
00
2
4
6
8
10
–5 –4 –3 –2 –1 00 1 2 3 4 5
Change in Limb Fat (kg)
Ch
an
ge
in S
AT
(L
ite
rs)
Kotler_MDS218_final 30
–4
–3
–2
–1
00
1
2
3
4
–10 –8 –6 –4 –2 00 2 4 6 8 10
Average of measured and predicted SAT (liters)
Dif
fere
nc
e B
etw
een
Me
asu
red
an
dP
red
icte
d S
AT
(L
iter
s)
Mean + 2SD = 3.17
Mean = 0.016
Difference vs Average ofPredicted and Measured SAT
Mean –2SD = –3.0
Kotler_MDS218_final 31
Waist vs Hip (Male Controls)
y = 0.8577x + 166.09R2= 0.8086
200
400
600
800
1000
1200
1400
1600
200 400 600 800 1000 1200 1400 1600CIC (mm)
WC
(m
m)
Kotler_MDS218_final 32
Clinical Significance
+ –
Coronary arterydisease 0.938 ± 0.051 0.925 ± 0.054
CVA 0.958 ± 0.051
All cause deaths 0.935 ± 0.053
Larsson. BMJ 1984.
0.925 ± 0.054
0.925 ± 0.053
Kotler_MDS218_final 33
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
Kotler_MDS218_final 34
20
25
30
35
40
45
0 5 10
VAT vol (L)
DF Female No Lipo
Female Lipo
Discriminant Function vsVAT by MRI
DF = 0.043*WC-0.70*WHR
Kotler_MDS218_final 35
Evaluation: Visceral Fat
Clinical
Waist circumference
Investigational
Single-cut CT
Single-cut MRI
DEXA
Ultrasound
BIA (not useful)
Kotler_MDS218_final 36
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.
Kotler_MDS218_final 37
Lipodystrophy:Effect 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 1999;13:1373.
Kotler_MDS218_final 38
0
2
4
6
8Baseline 12 24 36 48 60
VA
T (
Lit
ers)
Week
6 mg 2 mg 0rhGHdose
Kotler_MDS218_final 39
Risk: Benefit Analysis ofCAD* and HAART
Average calculated Average calculated increase in CHD increase in CHD
events = 0.14% per events = 0.14% per yearyear
Risks
Benefits
Mortality rates in Mortality rates in HIV-infected HIV-infected
patients by 50% patients by 50% in the USin the US
*CHD = coronary heart disease. Adapted from Grunfeld. 6th CROI; 1999; Chicago. Palella. NEJM 1998;338:853.
Kotler_MDS218_final 40
Evaluation: Cardiovascular Risk
Clinical
Classic risk factors
Investigational
Carotid doppler
Stress echo
Noninvasive coronary artery assessment
Novel metabolic parameters
Kotler_MDS218_final 41
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
Lactic Acidosis
Kotler_MDS218_final 42
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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For more HIV-related resources, please visit www.hivguidelines.org