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

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.

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;24:1537-48; 2 Mocroft A, et al. J Acquir Immune Defic Syndr. 2010;55:262-70. 3

Does TDF lower lipids? ACTG A5206: Design HIV RNA <400 on stable cART TG 150-1000 or non-HDL-C 100-250 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;24:1781-4.

N = 17 % change P 0.01 0.02 0.04 0.93 0.81 Data from: Tungsiripat M et al, AIDS 2010;24:1781-4.

Stable and Unstable Plaque Multidetector CT can detect features of unstable/ vulnerable plaque Adapted from Heart Center Online http://www.heartcenteronline.com

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;27:1263-72

ATP III vs 2013 ACC/AHA Guidelines in 150 HIV-infected Patients with Cardiac CT Data % for whom statins recommended Zanni MV, AIDS 2014;28:2061-70

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;355:2283-2296.

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;355:2283-2296. Phillips A, et al. Antiviral Ther 2008;13:177-187 10

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 = 0.0003 for trend ΔHDLp (μmol/L) ΔIL-6 (pg/ml) P < 0.0001 for trend ≤ 400 401 10,000 > 50,000 -10,000 -50,000 Month 1 HIV-RNA (copies/ml) Duprez DA et al, Atherosclerosis 2009;207:524-9

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

Copyright © 2012 American Medical Association. All rights reserved. From: Arterial Inflammation in Patients With HIV Subramanian S et al, JAMA. 2012;308(4):379-386. doi:10.1001/jama.2012.6698 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.

Target : Background Ratio (n = 27/group) Mean age: 51.6 54.3 68.9 sCD163 correlated with TBR among HIV+ r= 0.44; p = 0.03 HIV-infected FRS-Matched Known Atherosclerosis Subramanian S et al, JAMA. 2012;308:379-386.

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

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

RCT of Pitavastatin vs Pravastatin % Change in Lipids at Week 52 Low Potential for Drug-Drug Interactions; no incr risk DM HIV+, LDL 130-220 and TG < 400 after 4 week washout/dietary stabilization Sponseller CA, CROI 2014, 751LB

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

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