1. Cardiovascular Complications of HIV and Its Treatment
Marshall J. Glesby, MD, PhD
Professor of Medicine, Healthcare
Policy and Research
Weill Cornell College of Medicine
New York, New York
FORMATTED: 11/06/15
New Orleans, Louisiana: December 15-17, 2015

2. 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:

3. Non-AIDS Events Are More Common Than AIDS Events
Causes of Death
D:A:D1
Clinical Events in EuroSIDA2
Other/unknown 13%
n = 12,844
1,025 ADIs*
1,058 non-AIDS events
Renal 1%
Lactic acidosis/ pancreatitis 1%
Bacterial infection 7%
AIDS-related 32%
Non-natural 9%
Liver- related 14%
CVD-related 11%
Non-AIDS cancers 12% **
*ADIs: AIDS-defining illnesses; ** ESRD: end-stage renal disease.
1 Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. AIDS. 2010;24: ; 2 Mocroft A, et al. J Acquir Immune Defic Syndr. 2010;55: 3

4. Does TDF lower lipids? ACTG A5206: Design
HIV RNA <400 on stable cART
TG or non-HDL-C mg/dL
Tenofovir
x 12 weeks
n=8
Placebo
X 12 weeks
n=9
Washout period
X 4 weeks
Randomization
Tungsiripat M et al, AIDS 2010;24:

5. N = 17
% change P
Data from: Tungsiripat M et al, AIDS 2010;24:

6. Stable and Unstable Plaque
Multidetector CT can detect features of unstable/ vulnerable plaque
Adapted from Heart Center Online

7. HIV+ Pts More Likely to Have Plaque with High Risk Features Multidetector Spiral Coronary CT Angiography
P = 0.05
P = 0.69
P = 0.02
P = 0.02
Matched on major CVD risk factors.
Median age 45, 48
sCD163 associated among HIV+
Zanni MV et al, AIDS 2013;27:

8. ATP III vs 2013 ACC/AHA Guidelines in 150 HIV-infected Patients with Cardiac CT Data
% for whom statins recommended
Zanni MV, AIDS 2014;28:

9. Effects of Untreated HIV: SMART Study
Slide 30 of 42
Effects of Untreated HIV: SMART Study
Drug Conservation (Treatment Interruption) Arm
Treatment stopped when CD4+ cell count
> 350 cells/mm3; restarted when
CD4+ cell count < 250 cells/mm3
(n = 2720)
HIV-infected patients with CD4+ cell count > 350 cells/mm3
(N = 5472—84% on cART)
Viral Suppression Arm
HAART continuously administered
(n = 2752)
El-Sadr WM, et al. N Engl J Med. 2006;355:

10. SMART Study and CV Events
Slide 31 of 42
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
El-Sadr WM, et al. N Engl J Med. 2006;355: Phillips A, et al. Antiviral Ther 2008;13: 10

11. DC Patients on cART at Baseline with HIV RNA < 400 (n = 132)
Slide 32 of 42
DC Patients on cART at Baseline with HIV RNA < 400 (n = 132)
P = for trend
ΔHDLp (μmol/L)
ΔIL-6 (pg/ml)
P < for trend
≤ , > 50,000
-10, ,000
Month 1 HIV-RNA (copies/ml)
Duprez DA et al, Atherosclerosis 2009;207:524-9

12. Cascade 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
Loss of gut CD4s
Microbial translocation
Viral Co-Infections
(CMV, KSHV, HCV,
HBV)
Adapted from: Martin DE, Abstract 8023, XVIII International AIDS Conference, Vienna, Austria 20 July 2010 12

13. Copyright © 2012 American Medical Association. All rights reserved.
From: Arterial Inflammation in Patients With HIV
Subramanian S et al, JAMA. 2012;308(4): doi: /jama
FDP accumulates in metabolically active macrophages infiltrating affected vessels
FDP accumulates w/in metab active macrophages infiltrating affected vessels
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.
Copyright © 2012 American Medical Association. All rights reserved.

14. Target : Background Ratio (n = 27/group)
Mean age:
sCD163 correlated with TBR among HIV+
r= 0.44; p = 0.03
HIV-infected FRS-Matched Known Atherosclerosis
Subramanian S et al, JAMA. 2012;308:

15. Statins May Have Favorable Effects on Coronary Artery Plaque in HIV-Infected Patients
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
Lo J, Lancet HIV 2015;2:e52-63

16. reprievetrial.org
(n=6500)
6 year
F/u
(n=800)

17. RCT of Pitavastatin vs Pravastatin % Change in Lipids at Week 52
Low Potential for Drug-Drug Interactions; no incr risk DM
HIV+, LDL and TG < 400 after 4 week washout/dietary stabilization
Sponseller CA, CROI 2014, 751LB

18. 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:

19. 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