1. E. Turner Overton, MD Associate Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama Statins, Rainwater, and Pure Grain Alcohol: Cardiovascular Disease Management in 2016 FINAL: 04/06/16 Washington, DC: April 15, 2016 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA.

2. Slide 2 of 13 Learning Objectives After attending this presentation, participants will be able to: Describe HIV pathogenesis in the setting of viral suppression Demonstrate how end organ disease is unique in the setting of HIV disease. – Cardiovascular Disease as an example. Recognize the potential for statins to prevent non-AIDS events and the need for additional data. From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA.

3. Slide 3 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Atherosclerosis: An Inflammatory Process An atherosclerotic lesion develops as focal thickening of the inner layers of the artery – Vascular endothelial cells – Smooth muscle cells – Immune cells T lymphocytes, macrophages, & neutrophils Plaque formation is triggered by – Arterial wall injury – Lipoprotein deposition – Endothelial activation – Pro-inflammatory molecules Libby et al JACC; 2016, 9: 1091-1103 Early AtherogenesisAdvancing Atheroma Recruitment of inflammatory monocytes Macrophage replication Foam cell formation

4. Slide 4 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. CVD Mortality Higher in HIV-positive, even with Suppressed HIV Virus. Hanna et al. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 729. Freiberg et al. JAMA Intern Med. 2013 Apr 22;173(8):614-22. 145,009 HIV+ subjects reported 2001-2012 71% male, median age 49 yrs – CVD mortality 54% ↑increase (7  13%) Decreasing in gen population aHR 1.54 (95% CI: 1.47-1.62) – Adjusted for age, sex, race/ethnicity, location, and year – Rate if VL > 400cp/mL: 7.7/1000pt yr – Rate if VL suppressed: 3.9/1000pt yr – General population:3.2/1000pt yr Impact of HIV on risk comparable to traditional risk factors including HTN, DM and hyperlipidemia.

5. Slide 5 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Many pathogenic stimuli induce a similar inflammatory response. Interleukins Tumor Necrosis Factor TGF-beta With removal of the stimulus, healing ensues. Inflammation decreases Healing occurs When the stimulus persists Pathogenic responses occur Fibrosis Tissue destruction Altered function Progressive Disease The Inflammation Hypothesis Forrester and Libby. American Journal of Cardiology; 2007, 5: 732–738 END ORGAN DISEASE Persistent HIV Infection

6. Slide 6 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Proportions of monocyte subsets are altered in HIV-1 Funderburg N T et al. Blood 2012;120:4599-4608 -Monocyte populations are altered with HIV infection -Decreased classic monocytes (CD14++CD16-) -Increased CD16+ monocytes (elevated inflammation) -While HAART and virologic control shift monocyte populations towards normal, they remain altered compared with healthy non-HIV infected individuals.

7. Slide 7 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Oxidized LDL is elevated in HIV infection Zidar et al. JAIDS 2015. HIV, Oxidized LDL and Monocytes OxLDL correlates with sCD14 Inflammatory monocytes

8. Slide 8 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. How is HIV Unique? Boccara F, et al. J Am Coll Cardiol. 2013;61:511-523 Unique Features of HIV: Depletion of key regulatory T cell populations Changes in gut mucosal integrity Excess bacterial translocation Promotion of systemic inflammation Lymphocyte activation Monocyte activation Elevated circulating inflammatory biomarkers Neutrophil activation Hypercoagulable state Pro-atherogenic lipid profile

9. Slide 9 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. How to Beat Inflammation Treat early! Continue ART. – Maintain undetectable viremia Stop smoking Maintain normal weight If overweight, lose at least 5-10% of body weight Exercise Have a healthy diet Cut down on alcohol, avoid drugs

10. Slide 10 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. KEY RECOMMENDATIONS Clinicians should be aware that HIV-infected patients are at increased risk for ASCVD. Risk is independent of major established risk factors. A fasting lipid panel should be obtained in all newly identified HIV-infected patients. For primary prevention, HIV infection may be counted as an additional risk factor for risk stratification. Statin therapy is first-line therapy for elevated LDL-C and non-HDL-C. Drug-drug interactions must be considered. Atorvastatin, rosuvastatin, and pitavastatin are preferred agents. High risk condition and residual risk: HIV-infected persons

11. Slide 11 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Suggested Statins in the Setting of ART Ritonavir or Cobicistat Containing Regimens High Intensity StatinModerate Intensity StatinLow Intensity Statin Atorvastatin 20mgAtorvastatin 10mgPravastatin 10-20mg Rosuvastatin 10-20mgRosuvastatin 5mgFluvastatin 10-20mg Pravastatin 40-80mg*Pitavastatin 1mg Simvastatin and lovastatin are contraindicated for patients receiving a PI or cobicistat. *With darunavir, reduce pravastatin to 20-40mg. NNRTI, Raltegravir, or Dolutegravir Containing Regimens High Intensity StatinModerate Intensity StatinLow Intensity Statin Atorvastatin 40-80mgAtorvastatin 10-20mgPravastatin 10-20mg Rosuvastatin 20mgRosuvastatin 10mgFluvastatin 20-40mg Pravastatin 40-80mgPitavastatin 1mg Pitavastatin 2-4mgLovastatin 20mg Lovastatin 40mgSimvastatin 10mg Simvastatin 20-40mg Adapted from Dubé MP. Lipid Management, DOI 10.1007/978-3-319-11161-2_14

12. Slide 12 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Statins: Ideal Strategy to Reduce Non-AIDS and Vascular Events in HIV Traditional effects to lower LDL, effective to lower LDL (-26%), with few AEs (myositis 1.9%) in HIV Silverberg Annals 2009 Pleiotropic effects to reduce monocyte activation, chemo-attraction and vascular inflammation Funderburg CID 2013, Eckard JID 2014 Reduce events even among nonHIV patients with low LDL but increased inflammation Jupiter NEJM 2008 Use is low among HIV patients (19.6% in ACTG), clinicians awaiting results from RCTs ACTG survey

13. Slide 13 of 13 From ET Overton, MD, at Washington, DC: April 15, 2016, IAS-USA. Conclusions HIV and its therapy contribute to cardiac risk along with the traditional host factors Controlling viral replication partially reduces CVD risk. Early ART may significantly mitigate HIV-associated CVD risk. No reliable inflammatory markers to predict risk. Currently available risk scores fail to accurately estimate CVD risk in the setting of HIV infection. Smoking cessation, dietary and exercise interventions are effective. Statins may be of benefit in addition to lipid lowering effects. HOWEVER, more data are needed to inform use in traditional low risk populations.