Massimo Galli DISC L.Sacco, Università di Milano Sezione di Malattie Infettive Terapia...
-
Upload
ashlie-henry -
Category
Documents
-
view
214 -
download
0
Transcript of Massimo Galli DISC L.Sacco, Università di Milano Sezione di Malattie Infettive Terapia...
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