Massimo Galli Massimo Galli DISC L.Sacco, Università di MilanoDISC L.Sacco, Università di Milano

Sezione di Malattie InfettiveSezione di Malattie Infettive

Terapia antiretrovirale, Terapia antiretrovirale, alterazioni alterazioni

metaboliche e rischio metaboliche e rischio cardiovascolarecardiovascolare

Terapia antiretrovirale, Terapia antiretrovirale, alterazioni alterazioni

metaboliche e rischio metaboliche e rischio cardiovascolarecardiovascolare

Scomode evidenze…Scomode

evidenze…Il rischio cardiovascolare aumenta in relazione al tempo di esposizione ai PI boosted

Gli NRTI sono gravati da varie tossicità di classe o imputabili alle singole molecole, che hanno comportato restrizioni delle opzioni terapeutiche nei portatori di fattori di rischio cardiovascolare

L’EFV potrebbe contribuire a dare tossicità metabolica

Leonado da Vinci, La battaglia di Anghiari (1503)

ARTEMIS: change in median lipid levels up to Week 96

ARTEMIS: change in median lipid levels up to Week 96

LPV/r baseline

DRV/r Week 96

NCEP cut-off

LPV/r Week 96

DRV/r baseline

Left axis mg/dL; right axis mmol/mL

105

123

105

161

Triglycerides0

0.6

1.1

1.7

2.3

0

50

100

150

200

Med

ian

con

cen

trati

on 156

89

43

182

106

48

158

91

44

193

105

53

0

50

100

150

200

Totalcholesterol

LDL calculated

HDL

0

1.3

2.6

3.9

5.2

Baraldi E, et al. IAS 2009. MOPEB034

ALTAIR: ALTAIR: TDF/FTCTDF/FTC + + EFVEFV or or ATV/rATV/r or or ZDV/ABCZDV/ABC

Metabolic OutcomesMetabolic Outcomes

ALTAIR: ALTAIR: TDF/FTCTDF/FTC + + EFVEFV or or ATV/rATV/r or or ZDV/ABCZDV/ABC

Metabolic OutcomesMetabolic Outcomes

Cooper D et al. IAS 2009 Cooper D et al. IAS 2009 LBPEB09LBPEB09

EFV vs ATV/r p=0.006 p=0.62 p=0.23 p<0.001

EFV vs ZDV/ABC p<0.01 p=0.013 p<0.001 p=0.03

EFV vs ATV/r p=0.006 p=0.62 p=0.23 p<0.001

EFV vs ZDV/ABC p<0.01 p=0.013 p<0.001 p=0.03

Mean Change in Metabolic Parameters at 48 Weeks

mg

/dL

Low/stable rate of CVD as a cause of death in HIV-infected patients

Low/stable rate of CVD as a cause of death in HIV-infected patients

Mortality 2005 1st quarter (n=405)

Mortality 2000 (n=964)

Lewden C, et al. Int J Epidemiol.2005;34:121–130 Lewden C et al. J Acquir Immune Defic Syndr 2008;48:590-8

0 20 40 60

39

15

12

9

6

4

2

2

1

1

1

1

1

0

0

2

2

AIDS

Cancer

HCV

Cardiovascular

Suicide

Non-AIDS related infection

Accident

HBV

Neurological disorder

Overdose

Bronchopulmonary disease

Renal failure

Liver disease

Psychiatric illness

Antiretroviral treatment

Other

Unknown

Proportion (%)

0 20 40 60

47

11

9

7

6

4

2

2

2

2

2

1

1

3

AIDS

Cancer

HCV

Cardiovascular

Bacterial infection

Suicide

Liver disease

Accident

Overdose

Iatrogenic

HBV

Metabolic

Other infection

Proportion (%)

10

30 50

Unknown

FranceFrance

0

1

2

3

4

5

2003 2007 2008 2009

DAD Study: Low and stable incidence of MI in HIV-infected

patients

DAD Study: Low and stable incidence of MI in HIV-infected

patients

Incid

en

ce o

f M

I (p

er

1000 P

YFU

)

No. MI 126 345 517 580

PYFU 36199 94969 157912 178835

NEJM 2003; NEJM 2007; Lancet 2008; CROI 2009

Il sole di Austerlitz ?Il sole di Austerlitz ?

Molti fattori di rischio….Molti fattori di rischio….

DAD French Cohort

MI (n=580)

No MI (n=32728)

MI (n=289)

No MI (n=884)

Age (years) (median) 49 44 47 46 (matched)

Sex, male (%) 91 74 89 89 (matched)

Current smoker (%) 45 29 73 44

Previous CV disease (%) 20 3 0 (defined)

0

Family history CV disease (%)

14 8 19 7

Diabetes mellitus (%) 17 5 16 10

Hypertension (%) 44 19 21 12

Any dislipidemia (%) 75 44 - -

Hypercholesterolemia (%) - - 52 33

10-year Framingham score

Moderate (10-20%) (%) 30 15 - -

High (≥20%) (%) 18 4 - -

Nr CV risk factors

0 (%) - - 1 18

≥3 (%) - - 39 19DAD Study, CROI 2009 (abstract 44LB); French Hospital Database on HIV, CROI 2009 (abstract 43LB)DAD Study, CROI 2009 (abstract 44LB); French Hospital Database on HIV, CROI 2009 (abstract 43LB)

HIV+ patients with MI have higher prevalence of traditional CV risk factors

HIV+ patients with MI have higher prevalence of traditional CV risk factors

Incidence of Smoking is Incidence of Smoking is Increased Increased

among HIV+ among HIV+ vsvs HIV- Patients HIV- Patients

• N=223 HIV+ men and women on PI vs 527 HIV– male

• HIV+ have lower HDL and higher TG

• Predicted risk of CHD > in HIV+ men (RR=1.2) and women (RR=1.6), p<0.0001

APROCO cohort (HIV+)MONICA sample (HIV–)

Savès M et al. Clin Infect Dis 2003.Savès M et al. Clin Infect Dis 2003.

No difference in TC

Glucose 126 mg/dL

p=NS

0

10

20

30

40

50

60

70

p<0.0001

Smoking

p<0.01

Hypertension

Perc

en

t p

ati

en

ts

p=NSp<0.0001

HDL-C <40 mg/dL

LDL-C >160 mg/dL

Period# of AMI

Patient yrs (x 1000)

AMI rate

Unadjusted Hazard Ratio

(95% CI; P value)

Adjusted* Hazard Ratio

(95% CI; P value)

1980-1987HCV- 16 9.391 1.70 2.80 (1.03-

7.64) p=0.0451.78 (0.43-

3.84) p=0.662HCV+ 5 1.048 4.77

1988-1995HCV- 259 105.513 2.45 1.38 (1.14-

1.67) p<0.0011.29 (1.06-

1.58) p=0.012HCV+ 182 53.811 3.38

1996-2004 (HAART era)

HCV- 171 50.863 3.36 1.25 (0.98-1.59) p=0.075

1.25 (0.98-1.61) P=0.072HCV+ 107 25.546 4.19

TotalHCV- 446 165.767 2.69 1.36 (1.17-

1.58) p<0.0011.28 (1.10-

1.49) p=0.002HCV+ 294 80.405 3.66

*Adjusted for HTN, Age, DM and Tobacco Use*Adjusted for HTN, Age, DM and Tobacco Use

Bedimo R et al. World AIDS Conference, Mexico 2008

Chronic hepatitis C increases the risk of myocardial infarction in HIV+ patients

VA patientsVA patients

Peripheral Endothelial Function Decreases after Initiation of cART

Kristoffersen US et al. 49th ICAAC. Abs H-1579.

Time point Mean

Flow-Mediated

Dilation, % (SD)

MeanNitroglycerin-Mediated

Dilation,% (SD)

Baseline (N = 9) 8.7(1.7) 12.8 (1.0)

Month 1 (n = 9) 4.6 (0.9)* 14.3 (1.4)‡

Month 6 (n = 7) 5.1 (0.8)† 14.6 (2.8)§

Hsue et al AIDS 2009, 23: 1059-67

Mean intima-media thicknessMean intima-media thickness

Trafalgar: l’inizio della mischiaTrafalgar: l’inizio della mischia

Incidence 4.4 3.5 4.0 4.9 3.7 4.7(per 1000 PY)Incidence 4.4 3.5 4.0 4.9 3.7 4.7(per 1000 PY)

PIPI NNRTINNRTI1.2

1.2

1.131.13

11

0.90.9

IDV NFV LPV/r SAQ NVP EFV

#PYFU: 68,469 56,529 37,136 44,657 61,855 58,946

#MI: 298 197 150 221 228 221

IDV NFV LPV/r SAQ NVP EFV

#PYFU: 68,469 56,529 37,136 44,657 61,855 58,946

#MI: 298 197 150 221 228 221

RR/year

(95%CI)

RR/year

(95%CI)

Lundgren JD et al., CROI 2009. Abst 44LBLundgren JD et al., CROI 2009. Abst 44LB

Recent data from DAD shows risk of MI with cumulative exposure to IDV and LPV/rRecent data from DAD shows risk of MI

with cumulative exposure to IDV and LPV/r

Incidence 3.8 4.4 5.0 4.2 3.6 4.1 3.5(per 1000 PYFU) DAD CROI 2009DAD CROI 2009

* Adjusted for use of anti-diabetic drugs, anti-hypertensive drugs, lipid-lowering drugs, and ant-platelet drugs or warfarin

Adjusted* hazard ratio of AMI according to exposure to each NRTI in the prior 6 months or any exposure

Quebec Cohort: AMI Risk by NRTIQuebec Cohort: AMI Risk by NRTI

Durand M, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB175.Durand M, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB175.

10

5

0

ABC 6

mo

ABC a

ny

exp

ddI 6 m

oddI any

exp

FTC 6

mo

FTC a

ny

exp

3TC 6

mo

3TC a

ny

exp

d4T 6

mo

d4T a

ny

exp

TD

F 6

mo

TD

F a

ny

exp

ddC 6

mo

ddC a

ny

exp

ZD

V 6

mo

ZD

V a

ny

exp

Haza

rd R

ati

o

(95%

CI)

Statistically Significant

1.5

5 (

1.0

3;2

.32

)1

.69

(1

.17

;2.4

4)

1.4

7 (

0.8

8;2

.45

)

1.6

8 (

1.1

4;2

.49

)

1.5

1

(0.9

8;2

.32

)1

.68

(0

.96

;2.9

4)

1.4

8 (

1.0

3;2

.13

)1

.48

(1

.03

;2.1

2)

1.0

7

(0.5

2;2

.19

)1

.18

(0

.60

;2.3

4)

0.8

4

(0.5

8;1

.22

)1

.31

(0

.90

;1.8

9)

2.1

1

(1.0

7;4

.19

)

1.9

5

(0.4

8;7

.93

)

1.1

3

(0.1

6;8

.10

)

1.1

3 (

0.1

6;8

.10

)

* Adjusted for use of anti-diabetic drugs, anti-hypertensive drugs, lipid-lowering drugs, and * Adjusted for use of anti-diabetic drugs, anti-hypertensive drugs, lipid-lowering drugs, and anti-platelet drugs or warfarinanti-platelet drugs or warfarin

Adjusted* hazard ratio of AMI according to exposure Adjusted* hazard ratio of AMI according to exposure to each PI in the prior 6 months or any exposureto each PI in the prior 6 months or any exposure

55

00

ATV 6

mo

ATV 6

mo

ATV a

ny

exp

ATV a

ny

exp

FPV 6

mo

FPV 6

mo

FPV a

ny

exp

FPV a

ny

exp

IDV 6

mo

IDV 6

mo

IDV a

ny

exp

IDV a

ny

exp

LPV 6

mo

LPV 6

mo

LPV a

ny

exp

LPV a

ny

exp

NFV 6

mo

NFV 6

mo

NFV a

ny

exp

NFV a

ny

exp

RTV 6

mo

RTV 6

mo

RTV a

ny

exp

RTV a

ny

exp

SQ

V 6

mo

SQ

V 6

mo

SQ

V a

ny

exp

SQ

V a

ny

exp

Quebec Cohort: AMI Risk by PIQuebec Cohort: AMI Risk by PI

Durand M, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB175.Durand M, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB175.

Statistically Significant Statistically Significant

1.3

8

1.3

8

(0.8

6;2

.22

)(0

.86

;2.2

2)

1.6

1

1.6

1

(1.0

7;2

.41

)(1

.07

;2.4

1)

1.6

8

1.6

8

(1.1

5;2

.44

)(1

.15

;2.4

4)

1.5

9

1.5

9

(1.1

0;2

.29

)(1

.10

;2.2

9)

1.7

8

1.7

8

(1.2

5;2

.64

)(1

.25

;2.6

4)

1.0

1(0

.47

;2.1

8)

1.0

1(0

.47

;2.1

8)

1.2

7

1.2

7

(0.8

9;1

.82

)(0

.89

;1.8

2)

1.2

2

1.2

2

(0.5

7;2

.63

)(0

.57

;2.6

3)

1.3

2 (

0.4

2;4

.16

)1

.32

(0

.42

;4.1

6)

1.4

8

1.4

8

(0.5

5;4

.01

)(0

.55

;4.0

1)

0.8

4

0.8

4

(0.4

7;1

.49

)(0

.47

;1.4

9)

1.0

0

1.0

0

(0.6

7;1

.49

)(0

.67

;1.4

9)

1.1

5

1.1

5

(0.5

8;2

.28

)(0

.58

;2.2

8)

1.0

6

1.0

6

(0.6

9;1

.62

)(0

.69

;1.6

2)

Haza

rd R

ati

o

Haza

rd R

ati

o

(95%

CI)

(95%

CI)

VA Case Registry:VA Case Registry:Cumulative Abacavir Use and Risk Cumulative Abacavir Use and Risk of Myocardial Infarction and Strokeof Myocardial Infarction and Stroke

Unadjusted HR of AMI for each PY of exposure to each one of the categoriesUnadjusted HR of AMI for each PY of exposure to each one of the categories

Adjusted for most recent estimated GFR (by MDRD method; carried Adjusted for most recent estimated GFR (by MDRD method; carried

forward).forward).

Adjusted for traditional risk factors: age, hyperlipidemia, HTN, type 2 DM, Adjusted for traditional risk factors: age, hyperlipidemia, HTN, type 2 DM,

and tobacco use.and tobacco use.

Cerebrovascular EventCerebrovascular EventCerebrovascular EventCerebrovascular Event

HAART HAART with ABCwith ABC

HAART withHAART withother NRTIsother NRTIs

Non HAARTNon HAARTtherapytherapy

0.80.8

0.90.9

1.01.0

1.11.1

1.21.2

1.31.3

1.41.4

1.51.5

Haza

rd r

ati

oH

aza

rd r

ati

o

Myocardial InfarctionMyocardial InfarctionMyocardial InfarctionMyocardial Infarction

HAART HAART with ABCwith ABC

HAART with HAART with other NRTIsother NRTIs

Non HAARTNon HAART therapy therapy

Haza

rd r

ati

oH

aza

rd r

ati

o

0.80.8

1.01.0

1.21.2

1.41.4

1.61.6

1.81.8

Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.

VA Case Registry: use of ABC or TDF in VA Case Registry: use of ABC or TDF in Last Regimen and risk of AMILast Regimen and risk of AMI

Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.

Unadjusted HR of AMI for each PY of exposure to each one of the Unadjusted HR of AMI for each PY of exposure to each one of the categoriescategories

Adjusted for estimated GFR prior to regimen onset (by MDRD method).Adjusted for estimated GFR prior to regimen onset (by MDRD method).

NRTI n last NRTI n last regimen during regimen during

obs. periodobs. period

ABCABC TFVTFV Both ABC and TFVBoth ABC and TFV

Hazard

rati

oH

azard

rati

o

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

1.41.4

1.61.6

1.81.8

2.02.0

2.22.2

Summary of studies on the association between exposure to abacavir the risk of myocardial

infarction

Summary of studies on the association between exposure to abacavir the risk of myocardial

infarction

•Out of the 418 cases identified, 129 were excluded

– 45 had incomplete medical records

– 36 MIs occurred before the study period

– 2 cases of MI were undated

– 4 cases of MI occurred before the diagnosis of HIV infection

– 6 cases had a MI before being enrolled in the cohort

– 36 cases did not have a confirmed MI

Limitations in the definition of event in the French Cohort: Not all “MIs” are “valid MIs”Limitations in the definition of event in the French Cohort: Not all “MIs” are “valid MIs”

Costagliola D et al. CROI 2009, Abst. 43LB

Impact of Traditional CV Risk Factors and Impact of Traditional CV Risk Factors and HIV Parameters on the Risk of MI in HIV HIV Parameters on the Risk of MI in HIV

PatientsPatients

Lang S et al. EACS 2009.Lang S et al. EACS 2009.

Risk factors of MI in HIV infected patients apart from treatment

Risk factors of MI in HIV infected patients apart from treatment

La battaglia di SolferinoLa battaglia di Solferino

L’indipendenza ha un prezzoL’indipendenza ha un prezzo

Cardiovascular prevention guidelines in daily practice: a

comparison of EUROASPIRE I, II, and III surveys in eight

European countries.

Consecutive patients (men and women </=70 years) were identified after coronary artery bypass graft or percutaneous coronary intervention, or a hospital admission with acute myocardial infarction or ischaemia, and were interviewed at least 6 months later.

Consecutive patients (men and women </=70 years) were identified after coronary artery bypass graft or percutaneous coronary intervention, or a hospital admission with acute myocardial infarction or ischaemia, and were interviewed at least 6 months later.

Koseva et al Lancet 2009, 373: 929-39Koseva et al Lancet 2009, 373: 929-39

Cardiovascular prevention guidelines in daily practice: a comparison of

EUROASPIRE I, II, and III surveys in eight European countries

Koseva et al Lancet 2009, 373: 929-39Koseva et al Lancet 2009, 373: 929-39

These time trends show a compelling need for more effective lifestyle management of patients with coronary heart disease. Despite a substantial increase in antihypertensive and lipid-lowering drugs, blood pressure management remained unchanged, and almost half of all patients remain above the recommended lipid targets. To salvage the acutely ischaemic myocardium without addressing the underlying causes of the disease is futile; we need to invest in prevention

These time trends show a compelling need for more effective lifestyle management of patients with coronary heart disease. Despite a substantial increase in antihypertensive and lipid-lowering drugs, blood pressure management remained unchanged, and almost half of all patients remain above the recommended lipid targets. To salvage the acutely ischaemic myocardium without addressing the underlying causes of the disease is futile; we need to invest in prevention

Una Waterloo….ma c’è anche il punto di vista di WellingtonUna Waterloo….ma c’è anche il punto di vista di Wellington

Grazie per l’attenzioneGrazie per l’attenzione