kotler_mds218_final1. 2 hiv-lipodystrophy: guidelines development donald kotler, md professor of...

Kotler_MDS218_final 1


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


HIV-Associated Lipodystrophy

Fat Fat atrophyatrophy

Fat Fat accumulationaccumulation

HyperlipidemiaHyperlipidemia Insulin resistanceInsulin resistance


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?


Guidelines: Rationale

Response to need for cost effective approach to diagnosis and management

Clinical and public health (epidemiologic) needs

Guidelines will need periodic revision


Aims: Guidelines

Glucose metabolism

Lipid metabolism

Body composition

Cardiovascular risk

Lactic acidemia

Osteopenia


Glucose Metabolism

Pre-HAART data

Phenotype

Effect of PI in healthy volunteers

Effects of fat accumulation

Effects of fat depletion

Recommendations

Future directions


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.


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.


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)


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.


Consensus:Insulin Resistance

Clinical

— Fasting glucose

Investigational

— Fasting insulin

— C-peptide

— HOMA

— Oral glucose tolerance test

— HgbA1C (diabetes only)


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.


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


Fat Metabolism

Pre-HAART data

Phenotype

Effect of PI in healthy volunteers

Effects of other ARVs

Genetic susceptibilities

Recommendations


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


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.


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.


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*


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


Body Fat Redistribution Definitions

Prevalence

Associations

Measurements

Recommendations

Future directions


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


*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


Regional Measurements Cross-sectional imaging

— CT, MRI

— Whole body and single slice

Regional DXA

Anthropometry

Regional BIA

Ultrasound


Abdominal MRI Scans

Control Subject Increased VAT

VAT

SAT

VAT

SAT


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


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)


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


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)


–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


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)


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


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


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


Evaluation: Visceral Fat

Clinical

Waist circumference

Investigational

Single-cut CT

Single-cut MRI

DEXA

Ultrasound

BIA (not useful)


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.


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.


0

2

4

6

8Baseline 12 24 36 48 60

VA

T (

Lit

ers)

Week

6 mg 2 mg 0rhGHdose


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.


Evaluation: Cardiovascular Risk

Clinical

Classic risk factors

Investigational

Carotid doppler

Stress echo

Noninvasive coronary artery assessment

Novel metabolic parameters


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


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


For more HIV-related resources, please visit www.hivguidelines.org

kotler_mds218_final1. 2 hiv-lipodystrophy: guidelines development donald kotler, md professor of...

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