David A Cooper National Centre in HIV Epidemiology and Clinical Research
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Transcript of 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 エイズ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
第 22 回日本 学会教育セッション エイズ2008.11.27
LipoatrophyLipoatrophy
Lipodystrophy
第 22 回日本 学会教育セッション エイズ2008.11.27
Fat accumulationFat accumulation
Lipodystrophy
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studies
Intervention
Summary
Lipodystrophy
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV diseaseImpact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studies
Intervention
Summary
LipodystrophyImpact of HIV
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyImpact of HIV
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyImpact of HIV
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIsEffects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studies
Intervention
Summary
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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)
LipodystrophyEffect of RTIs
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIsEffects of PIs
Clinical studies in naïve patients
Switch studies
Intervention
Summary
LipodystrophyEffect of PIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of PIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of PIs
第 22 回日本 学会教育セッション エイズ2008.11.27
-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
LipodystrophyEffect of PIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyEffect of PIs
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patientsClinical studies in naïve patients
Switch studies
Intervention
Summary
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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?
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyClinical studies in naïve patients
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studiesSwitch studies
Intervention
Summary
LipodystrophySwitch studies
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studies
InterventionIntervention
Summary
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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 ?
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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+
LipodystrophyInterventions
第 22 回日本 学会教育セッション エイズ2008.11.27
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
第 22 回日本 学会教育セッション エイズ2008.11.27
Impact of HIV disease
Effects of RTIs
Effects of PIs
Clinical studies in naïve patients
Switch studies
Intervention
SummarySummary
Lipodystrophy
第 22 回日本 学会教育セッション エイズ2008.11.27
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.