david a cooper national centre in hiv epidemiology and clinical research

LipodystrophyImpact of HIV

第 22 回日本学会教育セッション　ｴｲｽﾞ2008.11.27

David A CooperDavid A Cooper

National Centre in HIV Epidemiology and National Centre in HIV Epidemiology and

Clinical ResearchClinical Research

The University of New South WalesThe University of New South Wales

Sydney, AustraliaSydney, Australia

David A CooperDavid A Cooper

National Centre in HIV Epidemiology and National Centre in HIV Epidemiology and

Clinical ResearchClinical Research

The University of New South WalesThe University of New South Wales

Sydney, AustraliaSydney, Australia

Lipodystrophy and metabolic Lipodystrophy and metabolic

disorders in HIV diseasedisorders in HIV disease

Lipodystrophy


LipoatrophyLipoatrophy

Lipodystrophy


Fat accumulationFat accumulation

Lipodystrophy


increased levels of IL-6 and TNF- in adipose tissue correlate with1

adipose tissue apoptosis

adipocytes and preadipocytes undergo apoptosis2

adipose tissue fibrosis

adipocytes and preadipocytes are dying and are replaced

repair process fills in the space by laying down collagen

adipose vascularity

macrophage infiltration of adipose tissue

increased levels of IL-18 correlate with limb fat3,4

1. Cervera, et al. Antivir Ther. 2004; 2. McComsey, et al. Antiviral Therapy: 20063. Lindegaard, et al. AIDS. 2004. 4. Lindegaard et al. J Acquir Immun Defic Syndr. 2004;36

Cytokines and tissue inflammation in lipoatrophy

Lipodystrophy


Impact of HIV disease

Effects of RTIs

Effects of PIs

Clinical studies in naïve patients

Switch studies

Intervention

Summary

Lipodystrophy


Impact of HIV diseaseImpact of HIV disease

Effects of RTIs

Effects of PIs


Switch studies

Intervention

Summary



subgroups patient events

relative risk (95% CI)

total 114

CVD, liver or renal death

31

non-fatal CVD 63

non-fatal liver 14

non-fatal renal 7

0.1 1 10favours VS ►

►

favours DC

1.5

1.5

1.4

2.5

1.4

El-Sadr, Neaton et al, CROI 2006

►

SMART:SMART: effect of ART discontinuation effect of ART discontinuation



SMART:SMART: baseline biomarkers and all cause mortality baseline biomarkers and all cause mortality

unadjusted adjusted

marker OR (4th/1st) P-value OR (4th/1st) P-value

hs-CRP 2.0 0.05 2.8 0.03

amyloid A 2.2 0.07 2.6 0.09

amyloid P 0.7 0.39 1.1 0.84

IL-6 8.3 <0.0001 11.8 <0.0001

D- dimer 12.4 <0.0001 26.5 <0.0001

F1.2 1.0 0.92 1.2 0.66

Insight Mtg Tlk 2/6/2008



RR 1 1.8 1.9 2.3 3.1 3.2 3.1 4.4

RR per year of cARToverall 1.17 (previously 1.26)men 1.14women 1.38

incidence of MI per 1000 py

exposure to HAART (years)

0

2

4

6

8

none

10

< 1 1-2 2-3 3-4 4-5 5-6 > 6

all subjects

DAD:DAD: ART effect ART effect

El-Sadr et al, CROI 2005

other independent risk factors: increasing age, male, smoking, prior CVD, family history smoking rate fell from 52% to 45% between 2000 and 2003

Lipodystrophy



Effects of RTIsEffects of RTIs

Effects of PIs


Switch studies

Intervention

Summary

LipodystrophyEffect of RTIs


Potential consequences of mitochondrial dysfunction Potential consequences of mitochondrial dysfunction

• lipodystrophy

• neuropathies• hepatic steatosis• myopathy• pancreatitis• lactic acidosis

• metabolic disease• (LD, IR, TGs)

ARTcytokines

HIV

HIV

• DNA polymerase-• uncoupling• transport• oxidative stress• apoptosis• phosphorylation• proteolytic processing• glycosylation



cause adipocyte toxicity and exhibit synergistic toxicity with PIs (no NNRTI data)

alter expression of oxidative phosphorylation genes

lead to reduced mtDNA (without mtDNA mutations) in adipocytes from lipoatrophic patients

subcutaneous adipocyte apoptosis and focal lipogranulomata in patients receiving NRTI-PI

Effects of NRTIs on adipocytes in vitroEffects of NRTIs on adipocytes in vitro

2nd Lipo workshop, Toronto 2000Domingo et al, AIDS 1999



Changes in adipose tissue gene expression with NRTI exposureChanges in adipose tissue gene expression with NRTI exposure

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

PGC1

p=0.02med % chg +83 [137]

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

NRF1

p=0.01med % chg +25 [116]

0

1

2

3

4

5

6

7

8

mtTFA

p=0.01med % chg +42 [131]

0

0.5

1

1.5

2

2.5

COX1

med % chg-63 [77]

0

3

6

9

12

15

18

COX3

p=0.001

med % chg -88 [54]

0

1

2

3

4

5

6

Cyt b

p=0.005

med % chg -60 [62]

(gene : β actin) x 1000

gene : β actin

baseline

week 2

Cyt bCOX3COX1

PGC1 NRF-1 mtTFA

p=0.002

Mallon et al, CROI 2004



DAD:DAD: recent exposure to ABC and ddI may increase the risk of MI recent exposure to ABC and ddI may increase the risk of MI

Sabin et al, CROI 2008

*recent = still using or stopped within last 6 months**similar to model 2

ZDV

ddI

d4T

3TC

ABC

0.5 0.75 1 1.25 1.5 1.75 2 2.25

RR=1.40, p=0.005

RR=1.63, p=0.0001

adjusted** relative rate (95% CI)

CHD (MI, CV deaths, invasive procedures)n=693

Relationship of recent* use of NRTIs and risk of CHD



NNRTIs and mitochondria In vitroNNRTIs and mitochondria In vitro

El Hadri et al, J Biol Chem. 2004

SREBP-1c

- + D2

100

80

20

0

60

40

*

10080

20

60

40† †

†

PPAR-

EFVday of Culture

- + D4

- + D7

*P<.05†P<.001

mRNA levels (% of control)

mRNA levels (% of control)




Effects of RTIs

Effects of PIsEffects of PIs


Switch studies

Intervention

Summary

LipodystrophyEffect of PIs


Effect of PIs on adipocytes in vitroEffect of PIs on adipocytes in vitro

decreased expression of PPARγ, SREBP-1c, C/EBP-α,

and leptin mRNA1-3

inhibition of glucose uptake1,4

insulin resistance3,5

increased lipolysis; decreased expression of CD36

(fatty acid transporter)1

inhibition of adipogenesis

impaired preadipocyte protein synthesis3,6

impaired adipocyte differentiation2,4,6,7

1. Kannisto et al, AIDS 2003 2. Bastard et al, Lancet 2002 3. Caron et al, Diabetes 2001 4. Janneh et al, AVT 2003

5. Cianflone et al, AVT 2006 6 Roche et al AIDS 2002 7. Vernochet et al, AIDS 2003



Effects of PIs on adipocyte lipid and glucose metabolismEffects of PIs on adipocyte lipid and glucose metabolism

control IDV

day 0

day 6

similar results with PPAR-γ

SREBP-1

control IDV3T3 rat preadipocytes



-50

-30

-10

10

30

50

<1%<1%

- 24%- 24%

percent change

relative to placebo

insulin-stimulated glucose disposal rate

per unit of insulin (mg/Kg/min per IU/mL)

+ 4%

- 34%- 34%

glycogen storage rate

(mg/Kg/min)

LPV/r (n=20) ATV (n=20)

P=N.S.P=N.S.

P=0.006P=0.006P=0.008P=0.008

P=NSP=NS

Effect of ATV and LPV/r on insulin sensitivityEffect of ATV and LPV/r on insulin sensitivity

Noor et al, CROI 2004



RTV 100mg bid or r/LPV (HIV-) x 14 days RTV 100mg bid or r/LPV (HIV-) x 14 days

Shafran et al, HIV Med 2005

p ≤0.01 change from baseline

14 days Rx baseline RTV LPV/r

n= 20 20 20

total cholesterol (mmol/l)

4.3 4.8 5.1

LDL cholesterol (mmol/l)

2.51 2.93 3.11

HDL cholesterol (mmol/l)

1.39 1.32 1.38

triglycerides (mmol/l) 0.87 1.11 1.29

Effect of RTV 100mg bd and LPV/r on lipids in HIV -vesEffect of RTV 100mg bd and LPV/r on lipids in HIV -ves

p <0.05 RTV vs LPV/r at day 14



PI-induced glucose and lipid disturbancesPI-induced glucose and lipid disturbances

insulin resistance

GLUT4 GLUT4 GLUT1GLUT1

decreased fat storage in adipocytes

impaired glucose uptake and utilisationin muscle and adipocytes

increased hepatic lipid and VLDL production and secretion

hyperlipidemia

lipodystrophy

suppressed adipogenesis

TG synthesis, TG synthesis, apoBapoB, VLDL, VLDL

HIV - PIsHIV - PIs lipodystrophy

Lipodystrophy



Effects of RTIs

Effects of PIs

Clinical studies in naïve patientsClinical studies in naïve patients

Switch studies

Intervention

Summary

LipodystrophyClinical studies in naïve patients


Changes in body composition following HAARTChanges in body composition following HAART

% from baseline (median)

Mallon et al, AIDS 2002

-30

-15

0

15

30

0 24 48 72 96 120 144

central abdominal fat

lean mass

limb fat

weeks after HAART



Gilead 903:Gilead 903: total limb fat total limb fat

TDF + 3TC + EFV 128 115d4T + 3TC + EFV 134 117

kilograms

0

2

4

6

8

10

12

96 144

TFV+3TC+EFV

d4T+3TC+EFV

weeks

Gallant et al, IAC 2004



ACTG 5142:ACTG 5142: incidence of lipoatrophy at week 96 by subgroupincidence of lipoatrophy at week 96 by subgroup

51%

40%

12%

33%

16%

6%

0%

10%

20%

30%

40%

50%

60%

d4T ZDV TDF

EFV + 2 NRTIs LPV/r + 2 NRTIs

patients

Haubrich R et al. 14th CROI. 2007; Los Angeles, Calif. Abstract 38.

n= 41 43 63 73 67 50



ACTG 5142:ACTG 5142: lipid changes lipid changes

HDL cholesterol non-HDL cholesterol

8 9

1626

22

43

change in lipid levels

(mg/dL)

total cholesterol triglycerides

32 33

57

46

19

62

0

15

30

45

60

75

p>0.5

p<0.001

p<0.001

p=0.006

p<0.001

p<0.03

p<0.001

p<0.001

p<0.001

p<0.001

p=0.3

p=0.3

EFV + NRTIs

LPV/r + NRTIs

LPV/r + EFV

no difference in use of lipid-lowering Tx between LPV/r and EFVHaubrich et al, CROI 2007



Possible explanations for observed changes Possible explanations for observed changes in limb fat between EFV and LPV/r in limb fat between EFV and LPV/r

EFV contributes to lipoatrophy?

LPV/r protects against lipoatrophy?

differential weight gain between groups (dietary effect?)

other?



Raltegravir 004:Raltegravir 004: lipid effects vs EFV lipid effects vs EFV

mean change from baseline, mg/dL (mmol/L)

RAL* 100-600 mg bid

(n = 160)

EFV 600 mg

qd (n = 38)

P value

total:HDL ratio -0.59 -0.47 .52

cholesterol-2.3 (-.06) +20.7 (+.53) < .001

LDL-C -7.5 (-.19) +3.0 (+.08) .016

triglycerides-1.0 (-.01) +49.5 (+.56) .068

*all raltegravir dose groups combined.

Markowitz et al IAS 2007



gains in limb and trunk fat are observed with all ART within the first ~6 months of therapy

potentially related to viral control and return to health

peripheral fat loss and trunk fat gain do not necessarily occur together

the strongest association with limb fat loss is observed with NRTIs, particularly thymidine analogs

different PIs show different effects on limb fat

NFV makes it worse

ATV has no effect

boosted PIs may increase limb fat mass

trunk fat increases with initiation of all ART, but the exact causes remain unknown

most studies don’t look at visceral fat

SummarySummary

Lipodystrophy



Effects of RTIs

Effects of PIs


Switch studiesSwitch studies

Intervention

Summary

LipodystrophySwitch studies


0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 24 48 72 108

MITOX-ABVRAVE-ABVRAVE-TFVTARHEELA5215Sd4T4030-TFV

Carr et al, JAMA 2002; Martin et al, AIDS 2004; McComsey et al, CID 2004 Moyle et al, CROI 2005; Milinkovic et al, CROI 2005; Murphy et al, CROI 2005

d4T/AZT switching for lipoatrophy:d4T/AZT switching for lipoatrophy: cross study comparisons cross study comparisons

week

BUT... return to normal is +3kg to 5kg in 5-10 years?

change from

baseline (kg)

on-treatment analysis

LipodystrophySwitch studies


ConclusionsConclusions

ARV selection can influence the risk of developing lipoatrophy

among NRTIs, TDF is associated with less limb fat loss than thymidine-containing regimens. Switch studies suggest ABC also has a limited impact on body fat

among PIs, emerging data do not support a class effect on the development of lipoatrophy; switching from a PI provides no additional benefit or protection against LD

NRTIs accompanying PIs or NNRTIs can influence the risk of lipoatrophy

both PIs and EFV produce increases in abdominal fat

recent large clinical trials suggest that among preferred first-line regimens, LPV/r is associated with less lipoatrophy than EFV

Lipodystrophy



Effects of RTIs

Effects of PIs


Switch studies

InterventionIntervention

Summary

LipodystrophyInterventions


If lipid lowering drugs are necessaryIf lipid lowering drugs are necessary

serum LDL cholesterol above

threshold, or triglycerides 2-

5 mmol/L with elevated non-

HDL cholesterol: STATINSTATIN

(pravastatin or atorvastatin)

serum triglycerides

>5 mmol/L: FIBRATE FIBRATE

(gemfibrozil or

fenofibrate)

oror

Approach to lipid disorders and cardiovascular riskApproach to lipid disorders and cardiovascular risk

Dubé et al, CID 2003



study population HIV+ adults with LDL-C > 4 mmol/l and TG > 2.2 mmol/l

Aberg et al, ARHR 2005

fenofibrate(n = 60)

pravastatin(n = 63)

achieved goal (%) NCEP 7% 3%

LDL 13% 14%

HDL 67% 56%

TG 60% 44%

median change (%) LDL -5% -8%

HDL 17% 6%

TG -45% -25%

non-HDL -21% -16%

Effect of lipid-lowering drugsEffect of lipid-lowering drugs



Rosiglitazone:Rosiglitazone: randomised trials outcomesrandomised trials outcomes

Sutinen et al, Antiviral Ther 2003; Carr et al, Lancet 2004Hadigan et al, Ann Intern Med 2004; Cavalcanti et al, CROI 2005

insulin resistance

improved 4/4

total cholesterol

increased 4/4 X

triglycerides increased 4/4 X

limb fat no change 3/4 83 patient years ?

increased 1/4 7 patient years ?



cm2

baseline week 13 week 26

tesamorelin

placebo

-15.2%

+5%

145

150

155

160

165

170

175

180

185

-12.1%

+3%

** P < 0.001 vs placebo

**

**

Tesamorelin:Tesamorelin: visceral fat accumulation visceral fat accumulation



Wohl et al, Clin Infect Dis 2006

Investigational pharmacologic therapiesInvestigational pharmacologic therapies

intervention lipidsinsulin

resistance

central

adipositylipoatrophy

rGH worse worse reduced worse

tesamorelin better no change reduced —

metformin better better reduced worse



Estimating benefits and risksEstimating benefits and risks

patient: 39 year old male, HIV+patient: 39 year old male, HIV+

clinical findingsclinical findings CVD risksCVD risks

CDC B smoker

no IDU cholesterol 5.6 mmol/l

pre-ART: CD4+ 220 HIV-RNA 120,000

HDL-C 1.0 mmol/l

NRTI-PI ART: HIV-RNA ND BP 125/75

CD4+ 380 after 6 months no diabetes (OGTT)

LD+



Estimating benefits and risksEstimating benefits and risks

estimated 10-year CVD risk (Framingham)

no intervention 10%

fibrate 10%

statin (chol 4.1, HDL 1.0) 7%

PI switch to ATV / NVP / EFV 6%

stops smoking 2%

stops smoking and PI switch 1%

unknown risks are

10-year risk of AIDS or death

at 3 years: on HAART 2.4%, off ART 6.1%

risks of PI switch / statin

Lipodystrophy



Effects of RTIs

Effects of PIs


Switch studies

Intervention

SummarySummary

Lipodystrophy


We should focus more on trying to

preventprevent these metabolic complications, as well

as their potential atherogenic

consequences in patients starting

treatment for the first time.

david a cooper national centre in hiv epidemiology and clinical research

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