Dr Currier received a research grant to UCLA from Theratechnologies (Updated 02/20/17)

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1 Management of Long-Term Complications of HIV Disease With a Focus on Cardiovascular Disease Judith S. Currier, MD Professor of Medicine University of California Los Angeles Los Angeles, California FORMATTED: 02/10/17 New York, New York: February 24, 2017 Financial Relationships With Commercial Entities Dr Currier received a research grant to UCLA from Theratechnologies (Updated 02/20/17) Slide 2 of 41 Slide 3 of 41 Learning Objectives After attending this presentation, learners will be able to: Describe the epidemiology of HIV infection and increased relevance of cardiovascular disease (CVD) Identify biomarkers that have been associated with an increased risk of CVD in HIV populations Discuss how to apply currently available risk calculators for estimating CVD risk in HIV populations

2 Non-AIDS cancers Slide 4 of 41 CVD Osteoporosis Depression Diabetes mellitus Frailty Cognitive disorders Slide P. Reiss Chronic liver disease COPD Chronic renal disease Slide 5 of 41 HIV HIV HIV HIV Legarth, A et al. JAIDS 2016 Slide 6 of 41 Subset of Well Controlled HIV No prior co-morbidities Viral load < 500 Still had reduced survival Compared to matched pop controls Legarth, A et al. JAIDS 2016

3 Long Term Complications of Treated HIV Disease Epidemiology of Non AIDS Events Pathogenesis Interventions: focus on CVD Risk Slide 7 of 41 Slide 8 of % Age > 50 % > 1 NCD Modelling study projected HIV population in Netherlands By % of HIV-infected patients > 3 NCD s 54% of HIV-infected patients will be on medications to treat NCDs Trends in Mortality due to CVD in HIV: US Slide 9 of 41 Proportionate circulatory mortality in HIV-infected women (left) and men (right) aged 25 years and older, 1999 to Adapted from: Feinstein M et al. The American Journal of Cardiology, Volume 117, Issue 2, 2016,

4 Trends in Mortality due to CVD in HIV: US Slide 10 of 41 Adapted from: Feinstein M et al. The American Journal of Cardiology, Volume 117, Issue 2, 2016, HIV+ Individuals in Care No Longer Have Elevated MI Risk compared to controls( ), Kaiser Cohort Cohort to evaluate MI risk from 1996 to 2011 by HIV status Adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval,.7-1.4) in (most recent period) MI Incidence Rates and Rate Ratios for HIV Status Klein DB, et al. Clin Infect Dis. 2015;60(8): Incidence Rate/100,000 py Calendar Year HIV-positive HIV-negative Adjusted Rate Ratio (95% CI) (1.3, 2.6) (1.4, 2.1) (1.0, 1.6) (.9, 1.7) (.7, 1.4) Slide 11 of 41 Cardiac Function Cardiac MRI Studies High burden of myocardial fibrosis, cardiac steatosis among Asx HIV-infected individuals 1-4 Decreased systolic function in HIV compared to controls Increased pericardial fat among HIV-infected individuals with lipo-accumulation Heart Failure Clinical Studies: HIV increases risk of HF, 5,6 27,363 HIV+ 55,125 HIV- free of CVD, HIV status Events HF Rates HF Risk* Heart Failure Preserved Ejection Fraction (EF>=40) HIV ( ) 1.21 ( ) HIV ( ) 1.0 Heart Failure Reduced Ejection Fraction (EF<40) HIV ( ) 1.58 ( ) HIV ( ) 1.0 Slide 12 of 41 1.Holloway CJ et al Circulation 2013, 2. Thiara DK et al JID 2015,3.Diaz-Zamundio M et al J Cardiovasc Magn Reson 2015,4. Chew K CROI White et al. Circulation 2015,6. Butt et al. Archives of Internal Medicine 2011, 7. Secemsky E et al JACC HF 2015

5 What Contributes to the Risk of Non AIDS Events in HIV? Is there a common pathway for all complications? Slide 13 of 41 HOST Genetics Lifestyle Virus/Immune System Antiretroviral Therapy (ART) Understanding the relative contributions of each of these factors to the pathogenesis of specific complications in HIV will help to inform the development of strategies for prevention and treatment Factors Linked to NCD Risk in Treated HIV Measures of innate immune activation (scd14, scd163, monocyte activation) History of low CD4 nadir- area under the curve of chronic inflammation Co-pathogens? CMV immune responses or CMV specific T cell responses Abnormalities in Coagulation Tissue factor expression Slide 14 of 41 Slide 15 of 41 A single measurement of IL-6 or D-dimer predicts Serious Non-AIDS events (SNA)/mortality over next 10yr Grund, PLoS One, 2016, INSIGHT SMART/ESPRIT/SILCAAT Study Group; Ledwaba, PLoS One, 2012

6 Immune Activation and Non-AIDS Complications Higher levels of Innate immune activation predict All cause mortality and individually CVD and thromboembolic disease (Duprez PLoS One 2012) Non-AIDS Cancers and Lymphoma (Breen, Cancer Epidemiol Biomarkers Prev 2011) Osteoporosis (Brown JID 2015) Type 2 Diabetes (Brown, Diabetes Care 2010) Frailty (Erlandson JID 2013) COPD (Attia Chest 2014) Bacterial pneumonia (Bjerk PLoS One 2013) Neurocognitive dysfunction (Burdo AIDS 2103) Adaptive Immune activation T cell activation predicts morbidity/mortality ( Balagopal A, et al JAIDS 2015) Stronger association in studies from resource limited settings (Hunt PW et al AIDS 2011) Slide 16 of 41 Immune Activation Relates to Novel Atherosclerotic Phenotype in HIV Slide 17 of 41 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 Malignancy CVD Non-AIDS AIDS Death Hazard Ratio of Study Endpoints for Plasma Levels of Biomarkers 4 th /1 st Quartile IL-6 stronger predictor of CVD and malignancy than D-dimer but C.I overlap Independent associations of IL-6 were stronger for non-aids related death and all cause death and similar for CVD and non-aids malignancy Slide 18 of 41 Biomarkers IL-6, d-dimer and hs CRP for Clinical Events : SMART and ESPRIT hs-crp D-Dimer IL-6 Adapted from Borges, AH, INSIGHT SMART AND ESPRIT Groups, JID 2016:214 (1 August)

7 Biomarkers Several studies demonstrate that biomarkers such as IL-6, scd14 or the CD4/CD8 ratio may help identify those patients at increased risk for non-aids events Prediction models for combinations of these markers are being tested currently At present these are not ready for widespread clinical use. It is also not clear that they will identify patients you could not already recognize at being of high risk due to traditional risk factors. Stay tuned.. Slide 19 of 41 Slide 20 of 41 Contributions of ART to CVD The toxicity of untreated HIV disease outweighs any excess risk of CVD associated with ART 1 Longer duration of older protease inhibitors (indinavir, lopinavir/r) associated with increased MI risk in observational trials 2,3 ; however no association between ART agents and CT angiographic evidence of plaque 4 Abacavir has been associated with increased relative risk of MI; most consistent findings among patients with other risk factors 5-6 ; mechanism unclear What about other contemporary agents? Slide 21 of El Sadr et al (SMART)NEJM. 2006; 355(22): NEJM 2003 Nov 20;349(21): DAD N Engl J Med Apr 26;356(17): AIDS Oct 23;30(16): Worm (DAD) J Infect Dis 2010; 201: Llibre JM, Hill A. Antiviral Res 2016; 132:

8 A5260: A Clinical Trial to Assess ART and Complications A5257: Phase III, prospective, multi-center, randomized, open-label trial (N=1809) ART-naïve, HIV+ subjects 18 yr, VL 1000 c/ml Slide 22 of 41 Abstract WEAB0106LB Randomized 1:1:1 to three NNRTI-sparing ARV regimens Stratified by screening HIV-1 RNA level ( or <100,000 copies/ml), Framingham 10-year CHD risk score (<6% vs 6% risk), and A5260s participation A5260s Substudy (N=328) No known CVD, diabetes mellitus, or use of lipid-lowering medications Participants followed for 96 weeks after enrollment of last subject FTC/TDF + ATV/r (N=109) FTC/TDF + RAL (N=106) At baseline and week 96 DXA scan (limb fat, trunk fat and lean mass) CT abdomen (visceral and subcutaneous abdominal fat) At baseline Leptin, adiponectin, IL-6, hs-crp, D-dimer, scd14, scd163 FTC/TDF + DRV/r (N=113) Jim Stein, Todd Brown, Grace McComsey, Heather Ribaudo, Carlee Moser, Theo Kelesidis, Michael Dube, Otto Yang How Does ART Impact Biomarkers? ACTG 5260s: ATV/r, RAL, DRV/r RAL Slide 23 of 41 Examined fold change in biomarkers among participants who maintained viral suppression over 96 weeks RAL- associated with a persistent decline in IL-6 where as ATV/r and DRV/r were not DRV D-Dimer declined with ATV/r and DRV/r but not RAL Measures of T cell activation declined in all groups, monocyte activation was inconsistent ACTG 5260s Kelesidis et al. CID 2015 Progression of Carotid Intima Medial Thickness and ART: Slower rate with ATV/r CCA CIMT Carotid Bifurcation CIMT Slide 24 of 41 CCA and bifurcation: significant CIMT progression within each arm (mm/year) Bilirubin levels > 0.6mg/dl at week 4 and 24 associated with slower rate of progression of IMT. Is atazanavir protective against CVD in HIV?

9 More on Atazanavir, Bilirubin and MI risk Cohort studies have evaluated this association CNICS cohort: 22,689 people, 568 MI or ischemic stroke (Crane et al; 2016) Higher bilirubin levels associated with lower risk of T1 MI and stroke, but also with higher risk for T2MI(those due to oxygen supply demand mismatch such is in sepsis) VA study (LaFleur, J et al; 2016) Lower risk of MI for those on ATV regimen (HR 0.66), no difference in stroke rates Atazanavir no longer considered a preferred agent due to higher risk of d/c due to bilirubin Might consider in a patient at high CVD risk Slide 25 of 41 Crane H, et al. Abstract 013 Antiviral Therapy 2016;21 Suppl 1:A15; LaFleur, J et al Abstract 016 Antiviral Therapy 2016;21Suppl 1: A18) CNICS: Lower Risk of Atherosclerotic Events With NNRTI- vs PI-Based ART 651 pts experienced MI or ischemic stroke (IS) Type 1 MI risk and overall atherosclerotic risk lower with NNRTI- vs PIbased initial ART Sensitivity analysis suggested possible trend for atherosclerotic risk with ATV vs other PIs: HR: 0.78 (95% CI: ) HR (95% CI) for risk of event with NNRTI vs PI Type 1 MI: 0.54 ( ) Type 2 MI: 1.07 ( ) All MI: 0.75 ( ) Type 1 MI + IS: 0.65 ( ) HR (95% CI) for risk of event with INSTI vs PI Type 1 MI: 0.79 ( ) All MI: 0.91 ( ) Type 2 MI: 1.09 ( ) Type 1 MI + IS: 0.71 ( ) Slide 26 of 41 Crane HM, et al. International Comorbidities WS Abstract O14.Slide credit: clinicaloptions.com Interventions to Reduce Non-AIDS Events in HIV Lifestyle interventions Smoking cessation Smoking may synergize with HIV to increase mortality Screen and treat for hypertension, diabetes Diet and Exercise (1-3) Earlier ART Slide 27 of 41 1.Lindegaard B, J Clin Edno Metab Troseid M, JAIDS Fitch K AIDS 2012;26:587-97

10 Slide 28 of 41 Young low risk population overall: Median age of 36, 10 year CHD risk was 1.9 Low number of CV events N=12 in immediate and N=14 in deferred Deaths due to CVD: 3 in immediate vs. 1 in deferred Short FU 3 years No apparent difference in vascular function, neurocognitive performance, COPD with early ART Why did early ART not improve everything? (ie. Vascular function, neurocognitive performance, COPD) Early in the course of HIV disease the risk of these events may be too low to see an impact of earlier ART Some of the non-aids conditions may be linked to immunologic changes associated with immunodeficiency ( Hunt, Lee, Sidener JID 2016 (Suppl 2) CD4 nadir and levels of inflammation Slide 29 of 41 CD4 Nadir and Risk of OI s and CVD Slide 30 of 41 JID 2016:214 (Suppl 2) Hunt et al

11 Potential Interventions For CVD in HIV Traditional Risk Modification Strategies Smoking cessation - Antihypertensive - Antidiabetic -ASA -Statins --Other lipid-lowering strategies Immune/Inflammatory Modulators -ART -CCR5 Antagonists - IL Antagonists - Methotrexate - Statins Slide 31 of 41 Low Physical Activity Associated With Higher Risk of Comorbidities in HIV Longitudinal analysis of selfreported PA in pts from CNICS, a multisite US HIV cohort Current analysis included 11,719 pts with 1 PA report 68% of pts reported low or very low PA levels Women, transgender pts more likely to report low, very low PA Higher activity associated with higher CD4+ cell counts, higher HDL cholesterol, lower triglycerides, and lower glucose (P <.05 for each) vs lower PA In longitudinal analysis, moderate, low, and very low PA levels associated with increasing risk of comorbidities vs high PA level Obesity: 1.34 to 1.92 CVD: 1.08 to 2.00 CBVD: 1.41 to 1.75 HTN: 1.21 to 1.53 Diabetes: 1.21 to 2.46 Multicomorbidity: 1.32 to 2.12 Slide 32 of 41 Willig AL, et al. International Comorbidities WS Abstract O12. Slide credit: clinicaloptions.com IL-1β inhibition in HIV Canakinumab is a monoclonal antibody directed against IL-1 β, approved for use in inflammatory diseases including JRA, FMF Currently being studied in a trial of 17,200 HIV negative adults with CVD to test whether reducing inflammation decreases future CVD events (CANTOS) HIV Pilot study NHLBI funded: Hsue, Deeks, Ridker, Tawakol Report on 10 patients on open label canukinamab demonstrated decreased arterial inflammation by FDG-PET after a single infusion with a reduction in IL- 6 but no changes in T cell activation. (Hsue, P. CROI 2017 Abstract 126) Slide 33 of 41 NHLBI R01HL125034

12 Statin use in HIV: Which statement best reflects your current view 1. I follow current AHA/ACC guidance for use of statins without modification for patients with HIV 2. I prescribe statins to patients with HIV without regard to current guidelines 3. I don t know what we should be doing about the use of statins in patients with HIV I follow current AHA/ACC guid... 78% I prescribe statins to patients... 10% 12% I don t know what we should b... Slide 34 of 41 Slide 35 of 41 Many HIV Patients with High-Risk Plaque would not Receive Recommendation for Statins by 2013 Guidelines: CHD risk underestimated by traditional risk scores Zanni AIDS 2014 Slide 36 of 41 Compared observed/expected # CVD Events in HOPS Equation Overall O/E > 10 yr follow-up O/E FRS ACC SCORE 1.72 NR D:A:D FRS most accurate, however many with events not identified Limited numbers (n=692) with > 10 years of follow-up Larger studies needed

13 Assessing and Refining Myocardial Infarction Risk in HIV CNICS Feinstein et al 2016 Slide 37 of 41 Figure Legend: Observed vs Predicted Events Among Subgroups Copyright 2017 American Medical Date of download: 2/6/2017 Association. All rights reserved. JAMA Cardiol. December 21, doi: /jamacardio Slide 38 of 41 Statins Address Both Traditional and Immune Risk Factors in HIV LDL Lowering: Statins lower LDL by similar amounts in patients with and without HIV: (HIV-infected: %; 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 Silverberg Ann Int Med 2009, McComsey CROI 2013, Funderburg JAIDS epub Slide 39 of 41 Newer Statins May Not Increase Glucose and Not Interact with PI s Drug PI Interaction Effects on Glucose LDL Lowering and Dose Pravastatin (40 mg/d) mg/dl, -25% Atorvastatin (20 to 40 mg/d) + +/- -38 mg/dl, -29% Rosuvastatin (10 mg/d) mg/dl -28% Pitavastatin (4 mg/d)* mg/dl, -28% Pitavastatin metabolized primarily by glucuronidation. 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. Sponseller CROI 2014, Aberg Endo 2013, Eckard JID 2014, Stone JACC 2013

14 THE REPRIEVE TRIAL TESTS A STRATEGY TO PREVENT HEART DISEASE IN HIV RANDOMIZED TRIAL TO PREVENT VASCULAR EVENTS IN HIV REPRIEVE is the first large-scale randomized clinical trial to test a strategy for preventing heartrelated disease among people living with HIV. With support from Kowa Pharmaceuticals and Gilead Slide 40 of 41 Slide 41 of 41 Statin clinical endpoint trial in HIV Statins reduce inflammation Pitavastatin has no interactions with ART Patients with treated HIV who do not meet criteria for statins will be randomized to pitavastatin or placebo 6500 patients 100 sites globally Mechanistic Substudy to examine CT Angio outcomes Substudies on sex differences, renal outcomes and muscle function Principal Investigators: Steven Grinspoon, MD, Pamela S Douglas, MD, Udo Hoffmann, MD, MPH, Heather Ribaudo, PhD Funded by NHLBI and NIAID. Supported by KOWA Pharmaceuticals. Summary Non-AIDs events are a growing cause of morbidity and mortality in treated HIV in all settings Inflammation and the Innate immune activation appear to be contributors; biomarkers may have utility in predicting risk and informing interventions Traditional risk factors remain important and should be the focus of interventions Optimal method for predicting CVD risk is undefined at present Novel interventions to reduce inflammation for patients on ART under evaluation Slide 42 of 41

15 Management of Long-Term Complications of HIV Disease With a Focus on Cardiovascular Disease Judith S. Currier, MD Professor of Medicine University of California Los Angeles Los Angeles, California FORMATTED: 02/10/17 New York, New York: February 24, 2017