Statin Use and Cardiovascular Disease in HIV Steven K. Grinspoon, MD Professor of Medicine Harvard Medical School Boston, Massachusetts FLOWED: 04/18/16 Los Angeles, California: April 25, 2016 Statin Use and Cardiovascular Disease in HIV Steven Grinspoon, M.D. Professor of Medicine Harvard Medical School IAS USA April 25, 2016 Slide 2 of 36 Financial Relationships With Commercial Entities Dr Grinspoon has served as a consultant to Navidea Biopharmaceuticals, Theratechnologies, Merck & Co, Inc, and Gilead Sciences, Inc. He has received grants and research support to his institution from Gilead Sciences, Inc, Kowa Pharmaceuticals, and Theratechnologies. (Updated 04/25/16) Slide 3 of 36 1
Learning Objectives After attending this presentation, participants will be able to: Describe the current epidemiology of cardiovascular disease (CVD) in HIV Describe the unique pathophysiology of CVD in HIV Describe the potential utility and limitations of statin use to prevent CVD in HIV Slide 4 of 36 Most Epidemiological Studies Suggest that Rates of CVD in HIV are: 6% 1. Equal to that seen in non HIV 38% 50% 6% 2. 10% higher 3. 50-100% higher 4. 200% higher Slide 5 of 36 Current Status of CVD Prevention in HIV Even as rates of death and mortality related to HIV have decreased with use of more potent ART, CVD rates, remain increased among HIV patients and are a leading cause of morbidity and mortality There is limited understanding of the mechanisms and treatment strategies for CVD in HIV No large scale primary CVD prevention strategy has been tested in HIV Slide 6 of 36 2
Effect Size of MI or CHD in HIV vs. non HIV 5/2/2016 CVD Risk in HIV-Infected Patients is Beyond That Predicted by Traditional Risk Factors 2.5 2 1.5 1 Slide 7 of 36 0.5 0 In the VACS cohort, the HR of MI was 1.48 in HIV vs. non-hiv veterans after adjusting for FRS, comorbidities, and substance use (95% CI 1.27-1.72). (Freiberg, 2013) 7% Which of the Following is Not a Common Feature of Coronary Plaque in HIV Patients? 19% 1. Eccentric high risk fatty plaque lesions 74% 2. Inflamed plaque 3. Heavily calcified plaque Slide 8 of 36 Increased Traditional Risk Factors Account for Only a Portion of CVD Risk in HIV A 12 Events Per 1000 PYs 10 8 6 4 2 RR 1.75 P<0.0001 Hypertension Diabetes Dyslipidemia 0 HIV Non-HIV 0 5 10 15 20 25 HIV+ non-hiv+ DM, HTN, and dyslipidemia, though increased, accounted for 25% of excess risk Newer studies suggest importance of genetics, inflammation and immune dysfunction, as non traditional risk factors Slide 9 of 36 Triant JCEM 2007, Rotger Clin Infect Dis. 2013 3
Aortic TBR by PET 5/2/2016 HIV: a State of Immune Activation and Suppression HIV Infection CD4+ T cells Persistent viral infection Microbial translocation Viral reactivation (CMV) and coinfection (HCV) Chronic activation of T cells and monocytes Endothelial cell activation Slide 10 of 36 Acute MI Adapted from Hsue JID 2012 Immune Activation Relates to Novel Atherosclerotic Phenotype in HIV In the general population, MI does not typically result from gradual expansion of subclinical coronary plaque, but rather from rupture of vulnerable high risk plaque in 75% of cases Recent studies in HIV+ patients without known CVD demonstrate that atherosclerotic plaques are indeed: Inflamed Non-calcified, high risk morphology features (vulnerable) Associated with immune activation markers Slide 11 of 36 Increased Arterial Inflammation in HIV 3.0 Control HIV p = 0.0003 p = 0.0003 2.5 2.0 1.5 1.0 Slide 12 of 36 HIV FRS -Matched Controls CVD Controls Subramanian JAMA 2012 4
Aortic (TBR) 5/2/2016 Arterial Inflammation Linked to Immune Activation in HIV Slide 13 of 36 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 ρ=0.53; P-value<0.03 1.2 5.5 6.0 6.5 7.0 7.5 8.0 8.5 Natural Log of scd163 (ng/ml) Inflamed High Risk Plaque Identified by FDG Composed of Activated Macrophages Slide 14 of 36 Rudd Circulation 2002 Increased Rates of Atherosclerosis in HIV by Coronary CT Angiography Slide 15 of 36 Control HIV P value Presence of plaque 34% 59% 0.02 Mean plaque volume (µl) 85 173 0.02 Agatson Score 0 (0, 9.9) 0 (0,17.9) 0.29 Segments with plaque 1.2 2.2 0.03 Non-calcified segments 0.46±0.98 0.99±1.57 <0.05 Calcified segments 0.29±0.81 0.26±0.77 0.87 Any stenosis > 70% 0% 6.5% 0.06 Young HIV-infected men and matched controls Baseline FRS, FH CHD, and smoking rates similar Similar data observed from the MACS cohort Lo AIDS 2010; Post Annals 2014 5
% of subjects with high risk morphology plaque 5/2/2016 Increased High Risk Morphology Plaque in HIV Patients LOW ATTENUATION PLAQUE (LAP) Mean minimal attenuation < 40 Hounsefield Units RC A POSITIVELY REMODELED Plaque segment / (PR) PLAQUE reference segment > 1.05 Slide 16 of 36 RC A Naghavi Circ 2003, Schoenhanger Circ 2000 &JACC 2001; Zanni AIDS 2013 A New Paradigm for Atherogenesis in HIV Persistent Viral Replication Microbial Translocation T-cell activation Monocyte Activation RCA Slide 17 of 36 High Risk Plaque Inflammation Slide 18 of 36 Current Challenges in Preventing and Treating CHD in HIV Understanding the optimal timing and use of ART to maximize effects on immune function and minimize metabolic effects Identifying patients with disease: current risk identification strategies are not adequate Developing a safe and effective strategy for primary prevention, especially for those not identified by current algorithms, but with substantial subclinical disease Developing an intervention that addresses both traditional and immune-related risk factors 6
SMART and START- Effects on CVD SMART- Randomized trial of continuous vs. intermittent ART guided by CD4 count (begun when <250 and stopped when >350). Stringent viral suppression reduced AIDS and CVD events. START- Randomized trial of immediate vs. delayed ART in naïve HIV patients with CD4 > 500 (vs. initiation at CD4 < vs. 350). Earlier initiation reduced AIDS events but not CVD events. Slide 19 of 36 SMART NEJM 2006; START NEJM 2015 Statins Have the Unique Potential to Work in HIV Because: 0% 1. They reduce triglycerides 3% 2. They improve glucose simultaneously with lipids 3% 3. They lower LDL 4. They lower LDL and may have anti-inflammatory effects 94% Slide 20 of 36 Slide 21 of 36 Potential Interventions For CVD in HIV Traditional Risk Modification Strategies - Antihypertensive - Antidiabetic -ASA -Statins Immune/Inflammatory Modulators -ART -CCR5 Antagonists - IL Antagonists - Methotrexate - Statins 7
Statin Effects on CVD in non HIV Population In a meta-analysis of 26 studies with 170,000 patients, statins were shown to reduce events by 22% per 39 mg/dl lowering in LDL Slide 22 of 36 CTT Lancet 2010 2013 ACC/AHA Statin Guidelines Unclear how these guidelines pertain to HIV Patients Need for a discussion between patients and providers Need for more data Slide 23 of 36 Stone Circulation 2013 Many HIV Patients with High-Risk Plaque would not Receive Recommendation for Statin by 2013 Guidelines: CHD risk underestimated by traditional risk scores Slide 24 of 36 Zanni AIDS 2014 8
Statins Reduce Vascular Events in Non HIV Patients with Low LDL and Increased CRP Events/100p-y: Placebo: 1.36 Rosuva: 0.77 HR 0.56 LDL was reduced 47 mg/dl, and should have resulted in a HR of 0.73 based on LDL lowering alone, according to CTTC meta-analysis. Instead JUPITER showed a HR of 0.56, greater than expected based on LDL lowering alone Slide 25 of 36 Ridker N Engl J Med 2008; CTTC Lancet 2010 Statins Address Both Traditional and Immune Risk Factors in HIV LDL Lowering: Statins lower LDL by similar amounts in patients with and without HIV: (HIVinfected: -26.2%; HIV-uninfected: -26.9%) Dampening of Immune Activation: Decrease monocyte activation reflected in decreased circulating levels of scd14 and the macrophage-derived phospholipase Lp-PLA2 Slide 26 of 36 Silverberg Ann Int Med 2009, McComsey CROI 2013, Funderburg JAIDS epub Statins are Generally Safe and Well-Tolerated in HIV Absolute rates of grade 3 or 4 adverse effects on liver and muscle low (Silverberg Ann Int Med 2009) Despite immune suppressant effects, no adverse effects on viral replication (Moncunill AIDS 2005, Negredo AIDS 2006) Slide 27 of 36 9
Percent Change in Noncalcified Plaque Absolute Change in Direct LDL (mg/dl) (ng/ml) 5/2/2016 Newer Statins May Not Increase Glucose and Not Interact with PIs Drug PI Interaction Effects on Glucose LDL Lowering and Dose Pravastatin (40 mg/d) - - -33 mg/dl, -25% Atorvastatin (20 to 40 mg/d) + +/- -38 mg/dl, -29% Rosuvastatin (10 mg/d) + + -28 mg/dl -28% Pitavastatin (4 mg/d)* - - -48 mg/dl, -28% Pitavastatin metabolized primarily by glucoronidation. Minimally metabolized by CYP3A. No known interactions with antiretroviral therapy no dose limitations. Included in 2013 ACC/AHA guidelines as a recommended moderate dose statin. *Among dyslipidemic patients with high starting cholesterol levels. Slide 28 of 36 Sponseller CROI 2014, Aberg Endo 2013, Eckard JID 2014, Stone JACC 2013 110 90 70 50 30 10-10 -30-50 Statin Effects on Coronary Artery Plaque in HIV p =.009 p =.009 40 p <.0001 p <.0001 20 p =.005 p =.005 Placebo Atorvastatin 20 0-20 -40-60 -80 Change in Lp-PLA 2-20 -40-60 -80 Placebo Atorvastatin -100 0 Placebo Atorvastatin Slide 29 of 36 Decreasing non-calcified plaque in proximal left anterior descending (LAD) coronary artery in patient on atorvastatin for 12 months. Lo CROI 2015, Lancet HIV 2015 Need for a Large RCT to Inform Clinical Practice HIV patients with low traditional risk scores are at increased risk for CVD with subclinical plaque and inflammation It is unknown if statins will prevent CVD and should be recommended for the HIV population Though largely well tolerated in small studies, there are no data from large RCTs in HIV investigating efficacy and tolerability How will statins uniquely work in HIV? LDL lowering Effects on inflammatory pathways Slide 30 of 36 30 10
100+ Sites Across US, Thailand and Canada Opened April 2015 www.reprievetrial.org Slide 31 of 36 REPRIEVE Schema Asymptomatic HIV patients with no history of CVD and ASCVD < 10% N=6500, avg. 4-5 yrs 3 visits/year Placebo R Lifestyle Advice Pitavastatin Screening and Consent Randomization Intervention N=800, 2 yrs Mechanistic Study Coronary plaque, vascular Inflammation, immune activation Mechanistic Primary Endpoint CVD Death MI Unstable Angina TIA & Stroke Arterial Revasc PAD Clinical Primary Endpoint Slide 32 of 36 Endpoints Time to first Major Adverse Cardiovascular Event (MI, Stroke, Angina, Revascularization, PAD, CVD death) Secondary Endpoints AIDS events Non AIDS events (liver, kidney, DM) Relationship of immune function and LDL to MACE response Safety Slide 33 of 36 11
Mechanistic Substudy Objectives: To determine: Effects on high risk coronary plaque Effects on immune function in relationship to plaque Green + Red: Noncalcified Plaque Volume: 115 mm 3 Red: Low Attenuation Plaque Volume: 28 mm 3 Slide 34 of 36 34 Novelty First major CVD prevention trial in HIV Largest study to date focused on HIV-related CVD; will inform standard of care Represents a new paradigm of long-term prevention trial for chronic co-morbidities Partnership between NHLBI, NIAID and Office of AIDS Research to fund an important HIV study Slide 35 of 36 Conclusions and Future Directions Traditional and non traditional risk factors contribute to increased CVD risk in HIV, which manifests as inflamed, noncalcified high risk plaque in association with immune activation Modulation of traditional and nontraditional risks is necessary to prevent CVD in HIV Statins may be an effective strategy to prevent CVD in HIV and should be tested in large trials to determine optimal practice patterns Slide 36 of 36 12