cardiovascular complications of hiv and its treatment
DESCRIPTION
Relative Risk of CVD Among People Living with HIV: A systematic review and meta-analysis Study Relative risk (95% CI) Weight HIV+ vs. HIV- Obel (2007) 1.39 (0.81, 2.39) 4.72 Triant (2007) 1.75 (1.51, 2.03) 46.62 Lang (2010) 1.50 (1.30, 1.73) 48.67 Overall (I-squared = 18.4%, p = 0.294) 1.61 (1.43, 1.81) 100.00 0.1 1 10 (b) Study Relative risk (95% CI) Weight Obel (2007) 2.12 (1.62, 2.77) 32.95 HIV+ exposed to ART vs. HIV- Benito (2002) 2.40 (1.69, 3.41) 20.54 Klein (2007) 1.78 (1.43, 2.22) 46.51 Overall (I-squared = 13.2%, p = 0.316) 2.00 (1.70, 2.37) 100.00 0.1 1 10 FM Islam, J Wu, J Jansson and DP Wilson. HIV Med. 2012;13:453-68.TRANSCRIPT
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Marshall J. Glesby, MD, PhDProfessor of Medicine, Healthcare
Policy and ResearchWeill Cornell College of Medicine
New York, New York
Cardiovascular Complications of HIV and Its Treatment
FORMATTED: 11/06/15
New Orleans, Louisiana: December 15-17, 2015
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FM Islam, J Wu, J Jansson and DP Wilson. HIV Med. 2012;13:453-68.
Relative Risk of CVD Among People Living with HIV: A systematic review and meta-
analysis
HIV+ vs. HIV-
HIV+ exposed to ART vs. HIV-
(a)Study Relative risk (95% CI) Weight
Obel (2007) 1.39 (0.81, 2.39) 4.72
Triant (2007) 1.75 (1.51, 2.03) 46.62
Lang (2010) 1.50 (1.30, 1.73) 48.67
Overall (I-squared = 18.4%, p = 0.294) 1.61 (1.43, 1.81) 100.00
Obel (2007) 2.12 (1.62, 2.77) 32.95
Benito (2002) 2.40 (1.69, 3.41) 20.54
Klein (2007) 1.78 (1.43, 2.22) 46.51
Overall (I-squared = 13.2%, p = 0.316) 2.00 (1.70, 2.37) 100.00
(b)Study Relative risk (95% CI) Weight
0.1 1 10
0.1 1 10
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Causes of Death
Malignancy
CV event
Hepatic
Pancreatitis
ESRD
Non-AIDS Events Are More Common Than AIDS Events
1 Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. AIDS. 2010;24:1537-48;2 Mocroft A, et al. J Acquir Immune Defic Syndr. 2010;55:262-70.
Clinical Events in EuroSIDA2
ADINon-ADI
n = 12,844
1,025 ADIs*
1,058 non-AIDS events
D:A:D1
Renal 1%
Lactic acidosis/pancreatitis 1%
Bacterial infection 7%
Non-natural 9%
Other/unknown 13%
AIDS-related32%
Liver-related
14%
Non-AIDS cancers12%
CVD-related 11%
*ADIs: AIDS-defining illnesses; ** ESRD: end-stage renal disease.
**
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Tenofovir x 12 weeks
n=8
PlaceboX 12 weeks
n=9
Washout periodX 4 weeks
PlaceboX 12 weeks
TenofovirX 12 weeks
Randomization
Does TDF lower lipids? ACTG A5206: Design• HIV RNA
<400 on stable cART
• TG 150-1000 or non-HDL-C 100-250 mg/dL
Tungsiripat M et al, AIDS 2010;24:1781-4.
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-40-35-30-25-20-15-10
-505
Totalchol
Non-HDL-C
LDL-C HDL-C TG
Tenofovir Placebo
% c
hang
e
P 0.01 0.02 0.04 0.93 0.81
Data from: Tungsiripat M et al, AIDS 2010;24:1781-4.
N = 17
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Stable and Unstable Plaque
Adapted from Heart Center Online http://www.heartcenteronline.com
Multidetector CT can detect features of unstable/ vulnerable plaque
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HIV+ Pts More Likely to Have Plaque with High Risk Features
Multidetector Spiral Coronary CT Angiography
Low at
tenua
tion p
laque
Pos re
modele
d plaq
ue
Spotty
calci
ficati
on
At leas
t one
3-fea
ture p
laque
0102030405060
HIV- (n=101)HIV+ (n=41)
P = 0.02
P = 0.05
P = 0.69
P = 0.02
Matched on major CVD risk factors.Median age 45, 48
sCD163 associated among HIV+ Zanni MV et al, AIDS 2013;27:1263-72
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ATP III vs 2013 ACC/AHA Guidelines in 150 HIV-infected Patients with Cardiac CT Data
05
101520253035
2004 ATP III 2013 ACC/AHA
P = 0.005 P = 0.04
% fo
r who
m s
tatin
s re
com
men
ded
P = 0.01 P = 0.01
Zanni MV, AIDS 2014;28:2061-70
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Effects of Untreated HIV: SMART Study
HIV-infected patients with
CD4+ cell count > 350 cells/mm3
(N = 5472—84% on cART)
Viral Suppression ArmHAART continuously administered
(n = 2752)
Drug Conservation (Treatment Interruption) ArmTreatment stopped when CD4+ cell count
> 350 cells/mm3; restarted when CD4+ cell count < 250 cells/mm3
(n = 2720)
El-Sadr WM, et al. N Engl J Med. 2006;355:2283-2296.
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SMART Study and CV Events
El-Sadr WM, et al. N Engl J Med. 2006;355:2283-2296. Phillips A, et al. Antiviral Ther 2008;13:177-187
Events DC VS RH(DC/VS) 95% CI p-value
Clinical MI, silent MI, CAD requiring invasive procedure or surgery, CVD death
48 31 1.57 1.00–2.46 0.05
+ Peripheral vascular disease, CHF, CAD requiring medication 76 52 1.49 1.04–2.11 0.03
+ Unobserved death from unknown cause 84 54 1.58 1.12–2.22 0.009
Conclusion• Discontinuation strategy associated with higher risk
of CV disease
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DC Patients on cART at Baseline with HIV RNA < 400 (n = 132)
-0.4-0.3-0.2-0.1
00.10.20.30.4
IL-6 HDLp
ΔIL
-6 (p
g/m
l)
ΔH
DLp
(μm
ol/L
)
≤ 400 401 10,000 > 50,000 -10,000 -50,000
Month 1 HIV-RNA (copies/ml)
P = 0.0003 for trend
P < 0.0001 for trend
Duprez DA et al, Atherosclerosis 2009;207:524-9
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Slide 12 of 42Cascade of Events Due to Chronic Immune Activation and Inflammation
Chronic Inflammation
Atherosclerosis, Osteoporosis, Neurocognitive
Degeneration, Frailty, Metabolic Syndrome, etc
Low-level Viral Replication
Secretion of Pro-inflammatory Cytokines
Immune Activation/Senescence
Microbial translocation
Loss of gut CD4s
Viral Co-Infections(CMV, KSHV, HCV, HBV)
Adapted from: Martin DE, Abstract 8023, XVIII International AIDS Conference, Vienna, Austria 20 July 2010
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Copyright © 2012 American Medical Association. All rights reserved.
From: Arterial Inflammation in Patients With HIVSubramanian S et al, JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698
There is increased aortic PET-FDG uptake (red coloration) in a participant infected with HIV compared with a non-HIV FRS-matched control participant. Neither participant had known heart disease. For each participant, the FRS was low with a score of 2 and calcium was not present on the cardiac CT scan. Neither participant was receiving a statin.
FDP accumulates in metabolically active macrophages infiltrating affected vessels
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Target : Background Ratio(n = 27/group)
0
0.5
1
1.5
2
2.5
HIV-infected FRS-Matched Known Atherosclerosis
Mean age: 51.6 54.3 68.9
Subramanian S et al, JAMA. 2012;308:379-386.
sCD163 correlated with TBR among HIV+r= 0.44; p = 0.03
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Statins May Have Favorable Effects on Coronary Artery Plaque in HIV-Infected Patients
Lo J, Lancet HIV 2015;2:e52-63
• 40 pts with subclinical coronary atherosclerosis and aortic inflammation by PET imaging with LDL-C < 130 mg/dL randomized to atorvastatin 20 mg 40 mg or placebo x 12 m
• No significant effect of atorvastatin on arterial inflammation (unusable data on 19)
• Atorvastatin reduced non-calcified plaque volume and high-risk plaque features
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Intervention
Clinical Primary Endpoint
TimeScreening
AndConsent
Asymptomatic HIV+ patients with no history of CVD
Pitavastatin 4mg/dayPlacebo
MICV Death Unstable Angina Arterial Revasc
Secondary Endpoints
Individual components of primary endpoint
All Cause Death
RandomizationR
Incidence/Progression of noncalcified plaque; High-risk plaque
Mechanistic Study
Inflammatory, immunological, metabolic biomarkers
Mechanistic Primary Endpoint
Coronary plaque, vascular inflammation, immune activation
Stroke
Predictors of statin effects
Statin safety and non AIDS comorbidities: DM, Infections, Cancer
All cause death
Figure 4. Schematic overview of REPRIEVE trial design.
Intervention
Clinical Primary Endpoint
TimeScreening
AndConsent
Asymptomatic HIV+ patients with no history of CVD
Pitavastatin 4mg/dayPlacebo
MICV Death Unstable Angina Arterial Revasc
Secondary Endpoints
Individual components of primary endpoint
All Cause Death
RandomizationR
Incidence/Progression of noncalcified plaque; High-risk plaque
Mechanistic Study
Inflammatory, immunological, metabolic biomarkers
Mechanistic Primary Endpoint
Coronary plaque, vascular inflammation, immune activation
Stroke
Predictors of statin effects
Statin safety and non AIDS comorbidities: DM, Infections, Cancer
All cause death
Figure 4. Schematic overview of REPRIEVE trial design.
6 year F/u
(n=6500)
(n=800)
reprievetrial.org
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RCT of Pitavastatin vs Pravastatin % Change in Lipids at Week 52
TC LDL-C HDL-C TG
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
Pitavastatin 4 mg (n=98)
Pravastatin 40 mg (n=90)
P = 0.009 P < 0.001 P = 0.20 P = 0.09
HIV+, LDL 130-220 and TG < 400 after 4 week washout/dietary stabilization
Sponseller CA, CROI 2014, 751LB
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HIV-infected Population controls HIV-infected Population controls0
10
20
30
40
50
60
70
80
Danish Study: ~3 of 4 of MIs in HIV-Infected Individuals Associated with Ever Smoking vs ~1 of 4 in Matched Controls
% of MIs that could be prevented if everyone had same risk as never smokers
% of MIs that could be prevented if everyone had same risk as previous smokers
Rasmussen LD, Cin Infect Dis 2015;60:1415-23
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Summary• Risk stratification tools for the general population are
generally not validated in HIV-infected patients–Reasonable to use Framingham or Pooled Cohort
Equations–Consider counting HIV as a risk factor as per NLA
• Inflammation and immune activation are likely important contributors to atherosclerosis
• Are statins indicated more broadly? –A large clinical endpoint trial (REPRIEVE) is underway