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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
Slide 2 of 42
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
Slide 3 of 42
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.
**
Slide 4 of 42
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.
Slide 5 of 42
-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
Slide 6 of 42
Stable and Unstable Plaque
Adapted from Heart Center Online http://www.heartcenteronline.com
Multidetector CT can detect features of unstable/ vulnerable plaque
Slide 7 of 42
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
Slide 8 of 42
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
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.
Slide 30 of 42
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
Slide 31 of 42
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
Slide 32 of 42
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
Slide 13 of 42
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
Slide 14 of 42
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
Slide 15 of 42
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
Slide 16 of 42
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
Slide 17 of 42
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
Slide 18 of 42
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
Slide 19 of 42
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