Cardiovascular Complications of HIV and Its Treatment

Cardiovascular Complications of HIV and Its Treatment FORMATTED: 11/6/15 Marshall J. Glesby, MD, PhD Professor of Medicine, Healthcare Policy and Research Weill Cornell College of Medicine New York, New York New Orleans, Louisiana: December 15-17, 215 Learning Objectives After attending this presentation, participants will be able to: Describe an approach to risk stratification of HIV-infected patients for coronary heart disease Discuss options for managing dyslipidemia in HIV-infected patients Summarize emerging data on the pathogenesis of atherosclerosis in HIV-infected patients Slide 3 of 42 Relative Risk of CVD Among People Living with HIV: A systematic review and meta-analysis (a) Study Relative risk (95% CI) Weight Obel (27) 1.39 (.81, 2.39) 4.72 Slide 4 of 42 Triant (27) 1.75 (1.51, 2.3) 46.62 Lang (21) 1.5 (1.3, 1.73) 48.67 Overall (I-squared = 18.4%, p =.294) 1.61 (1.43, 1.81) 1..1 1 1 (b) Study Relative risk (95% CI) Weight 2.12 (1.62, 2.77) 32.95 Obel (27) Benito (22) 2.4 (1.69, 3.41) 2.54 Klein (27) 1.78 (1.43, 2.22) 46.51 Overall (I-squared = 13.2%, p =.316) 2. (1.7, 2.37) 1..1 1 1 HIV+ vs. HIV- HIV+ exposed to ART vs. HIV- FM Islam, J Wu, J Jansson and DP Wilson. HIV Med. 212;13:453-68. New Orleans, Louisiana: December 15-17, 215 1

Non-AIDS Events Are More Common Than AIDS Events Slide 5 of 42 D:A:D 1 Causes of Death Other/unknown 13% Renal 1% Lactic acidosis/ pancreatitis 1% Bacterial AIDS-related infection 7% 32% Non-natural 9% Liverrelated CVD-related 11% 14% Clinical Events in EuroSIDA 2 n = 12,844 1,25 ADIs* 1,58 non-aids events ADI Non-ADI Malignancy CV event Hepatic Pancreatitis Non-AIDS cancers ESRD** 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. 21;24:1537-48; 2 Mocroft A, et al. J Acquir Immune Defic Syndr. 21;55:262-7. Overview Assessing CVD risk in HIV-infected patients Management of dyslipidemia Emerging role of inflammation Slide 6 of 42 Case 5 year old African-American man with HIV dx 27 h/o PCP (nadir CD4 = 42 cells/mm 3 ) On 1 st regimen of TDF/FTC/EFV with HIV RNA < 2 copies/ml, CD4 518 cells/mm 3 CHD risk factors: smoked minimally in high school, no family hx premature CHD, + hypertension (off and on meds) Slide 7 of 42 New Orleans, Louisiana: December 15-17, 215 2

Lipids TC 193, HDL-C 35, LDL-C 136, TG 112 mg/dl No prior lipid values available Sees local dietician, chiropractor Prescribed liver-gall bladder flushes and raw food cleanses Weight is stable (BMI 2.7); BP 122/84 on HCTZ He is asymptomatic but concerned about his risk of heart disease because someone in his support group had a heart attack recently Slide 8 of 42 AHA/ACC 213 Pooled Cohort Risk Calculator Slide 11 of 42 Slide 12 of 42 New Orleans, Louisiana: December 15-17, 215 3

Slide 13 of 42 ATP III Framingham: 7% http://cvdrisk.nhlbi.nih.gov/ D:A:D: 2.5% CHD-5 Other Risk Calculators N Friis-Møller, et al Eur J Cardiovasc Prev Rehabil. 21;17:491-51. Recalibrated: N Friis-Møller, et al, Eur J Prev Cardiol. 215 [Epub ahead of print]---cd4, cumulative exposure to NRTIs, PIs, current abacavir use Slide 14 of 42 http://hivpv.org/home/tools/tabid/91/ctl/examview/mid/5/eid//lid//default.aspx AHA/ACC 213 Slide 16 of 42 High-Intensity Statin Daily dose lower LDL-C by 5% on average Moderate-Intensity Statin Daily dose lower LDL-C by 3-5% on average Atorvastatin 4-8 mg Rosuvastatin 2-4 mg Atorvastatin 1-2 mg Rosuvastatin 5-1 mg Simvastatin 2-4 mg Pravastatin 4-8 mg Lovastatin 4 mg Fluvastatin XL 8 mg Fluvastatin 4 mg bid Pitavastatin 2-4 mg New Orleans, Louisiana: December 15-17, 215 4

Slide 17a of 42 non-hdl-c LDL-C J Clin Lipidol. 215;9:129-69 Slide 17b of 42 May count HIV as an ASCVD risk factor Jacobson TL et al, National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2 J Clin Lipidol [in press] non-hdl-c LDL-C non-hdl = 158 LDL-C = 136 J Clin Lipidol. 215;9:129-69 EFV RAL: SWITCH-ER Study Randomized, double-blind, cross-over study of 57 subjects on EFV RAL 4 mg bid + EFV placebo, or RAL placebo + EFV 6 mg daily 2 weeks on each regimen Change on RAL P-value Total cholesterol -16 mg/dl <.1 Triglycerides -18 mg/dl.36 LDL-C -8 mg/dl.4 HDL-C -4 mg/dl.5 LDL/HDL -.1.97 Nguyen A, AIDS 211;25:1481-87 Slide 18 of 42 New Orleans, Louisiana: December 15-17, 215 5

% change SINGLE Trial: TDF/FTC/EFV vs ABC/3TC/DTG Total cholesterol ABC/3TC + TDF/FTC/EFV DTG +17.1 +24. HDL-C +5.2 +7.9 LDL-C +8.5 +13.1 Triglycerides +17.7 +18.6 Slide 19 of 42 Dolutegravir prescribing information http://www.accessdata.fda.gov/drugsatfda_docs/label/213/2479lbl.pdf HIV RNA <4 on stable cart TG 15-1 or non-hdl-c 1-25 mg/dl Does TDF lower lipids? ACTG A526: Design Tenofovir x 12 weeks n=8 Randomization Placebo X 12 weeks n=9 Slide 2 of 42 Washout period X 4 weeks Placebo X 12 weeks Tenofovir X 12 weeks Tungsiripat M et al, AIDS 21;24:1781-4. 5 N = 17 Slide 21 of 42-5 -1-15 -2-25 Tenofovir Placebo -3-35 -4 Total chol Non- LDL-C HDL-C HDL-C TG P.1.2.4.93.81 Data from: Tungsiripat M et al, AIDS 21;24:1781-4. New Orleans, Louisiana: December 15-17, 215 6

Median Values (mg/dl) Lipid Changes: E/C/F/TAF vs E/C/F/TDF Studies GS-US-292-14 and GS-US-292-111: 2 15 1 5 189 16 177 163 Fasting Lipids from Baseline to Week 48 E/C/F/TAF E/C/F/TDF Baseline Baseline Week 48 Week 48 115 11 19 14 51 48 Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=.42) 44 1 Total Cholesterol LDL HDL Triglycerides 44 p <.1 p <.1 p <.1 p=.27 p=.84 114 95 18 Sax PE. Lancet 215; 385:266-15 5 4 3 2 1 3.7 3.7 3.6 3.6 TC:HDL Ratio Slide 22 of 42 Abacavir and MI: Update from D:A:D channeling since 28 (less use in higher risk pts) Results (to 2/1/13): 941 MI / 367,559 pt-yrs. --.26/1 pt-yrs Current ABC use.47 No current ABC use.21 RR 1.98; no by time period or after adjustment for lipids/htn/etc. Sabin C, CROI 214 #747LB Slide 23 of 42 Abacavir Use and Risk of Myocardial Infarction in NA-ACCORD = all ART users excluding those on ABC at study entry D:A:D Replication Full Study Population Restricted Study Population = ART naïve persons who initiated ART (but not necessarily ABC in first regimen) Adjusted for cumulative ABC exposure, age, sex, race, HIV risk factor, calendar year, BMI, smoking, years since HAART initiation and cohort.. 1. 2. 3. 4. Adjusted Hazard Ratio Palella F, CROI 215 #749 Slide 24 of 42 Adjusted for age, sex, race, HIV risk factor, calendar year, cigarette smoking, HCV, hypertension, diabetes mellitus, renal impairment, high total cholesterol, high TGs, statin use, CD4 cell count, HIV RNA, h/o clinical AIDS, previous PI use, and cohort New Orleans, Louisiana: December 15-17, 215 7

Slide 25 of 42 No Association of Abacavir Use with MI: Findings of an FDA Meta-Analysis Conflicting data from previous datasets regarding potential association of ABC use with increase risk of MI Analysis: 26 controlled trials in which ABC use was randomized Academic Center Trials NIH (ACTG) Trials Manufacturer Trials All Trials Ding X, et al. J Acquir Immune Defic Syndr 212; 61:441-7. See also Cruciani M, 211 AIDS;25:1993-24 MI Frequency Mantel-Haenszel Risk (Events/Subjects) Difference, % (95% CI) Abacavir No Abacavir -.53.31 1.16 6/72 4/863 -.45.3.51 -.43 -.11.21 -.26.8.27 -.8 -.6 -.4 -.2.2.4.6.8 1. 1.2 1.4 12/1985 6/2341 24/528 9/161 9/2367 22/484 Stable and Unstable Plaque Slide 26 of 42 Multidetector CT can detect features of unstable/ vulnerable plaque Adapted from Heart Center Online http://www.heartcenteronline.com Slide 27 of 42 HIV+ Pts More Likely to Have Plaque with High Risk Features Multidetector Spiral Coronary CT Angiography 6 5 4 3 2 1 P =.2 Low attenuation plaque P =.5 Pos remodeled plaque P =.69 Spotty calcification P =.2 At least one 3-feature plaque scd163 associated among HIV+ Zanni MV et al, AIDS 213;27:1263-72 HIV- (n=11) HIV+ (n=41) Matched on major CVD risk factors. Median age 45, 48 New Orleans, Louisiana: December 15-17, 215 8

% for whom statins recommended Slide 28 of 42 ATP III vs 213 ACC/AHA Guidelines in 15 HIVinfected Patients with Cardiac CT Data 35 3 25 2 15 P =.1 P =.1 P =.5 P =.4 1 5 No coronary plaque Coronary plaque No coronary plaque or plaque w/ no HRM features 24 ATP III 213 ACC/AHA Plaque w/ 1-2 HRM features Zanni MV, AIDS 214;28:261-7 Slide 29 of 42 Effects of Untreated HIV: SMART Study HIV-infected patients with CD4+ cell count > 35 cells/mm 3 (N = 5472 84% on cart) Drug Conservation (Treatment Interruption) Arm Treatment stopped when CD4+ cell count > 35 cells/mm 3 ; restarted when CD4+ cell count < 25 cells/mm 3 (n = 272) Viral Suppression Arm HAART continuously administered (n = 2752) El-Sadr WM, et al. N Engl J Med. 26;355:2283-2296. Slide 3 of 42 New Orleans, Louisiana: December 15-17, 215 9

ΔIL-6 (pg/ml) ΔHDLp (μmol/l) SMART Study and CV Events Events DC VS Clinical MI, silent MI, CAD requiring invasive procedure or surgery, CVD death + Peripheral vascular disease, CHF, CAD requiring medication + Unobserved death from unknown cause RH (DC/VS) 95% CI p-value 48 31 1.57 1. 2.46.5 76 52 1.49 1.4 2.11.3 84 54 1.58 1.12 2.22.9 Slide 31 of 42 Conclusion Discontinuation strategy associated with higher risk of CV disease El-Sadr WM, et al. N Engl J Med. 26;355:2283-2296. Phillips A, et al. Antiviral Ther 28;13:177-187 DC Patients on cart at Baseline with HIV RNA < 4 (n = 132).4.3.2.1 -.1 -.2 -.3 -.4 IL-6 P =.3 for trend P <.1 for trend HDLp 4 41 1, > 5, -1, -5, Month 1 HIV-RNA (copies/ml) Duprez DA et al, Atherosclerosis 29;27:524-9 Slide 32 of 42 Cascade of Events Due to Chronic Immune Activation and Inflammation Loss of gut CD4s Microbial translocation Viral Co-Infections (CMV, KSHV, HCV, HBV) Low-level Viral Replication Secretion of Proinflammatory Cytokines Chronic Inflammation Immune Activation/Senescence Atherosclerosis, Osteoporosis, Neurocognitive Degeneration, Frailty, Metabolic Syndrome, etc Slide 33 of 42 New Orleans, Louisiana: December 15-17, 215 1

From: Arterial Inflammation in Patients With HIV Subramanian S et al, JAMA. 212;38(4):379-386. doi:1.11/jama.212.6698 Slide 34 of 42 FDP accumulates in metabolically 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 212 American Medical Association. All rights reserved. 2.5 Target : Background Ratio (n = 27/group) Mean age: 51.6 54.3 68.9 Slide 35 of 42 2 1.5 1 scd163 correlated with TBR among HIV+ r=.44; p =.3.5 HIV-infected FRS-Matched Known Atherosclerosis Subramanian S et al, JAMA. 212;38:379-386. Slide 36 of 42 Statins May Have Favorable Effects on Coronary Artery Plaque in HIV-Infected Patients 4 pts with subclinical coronary atherosclerosis and aortic inflammation by PET imaging with LDL-C < 13 mg/dl randomized to atorvastatin 2 mg 4 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 215;2:e52-63 New Orleans, Louisiana: December 15-17, 215 11

reprievetrial.org Slide 38 of 42 Time 6 year F/u Asymptomatic HIV+ patients with no history of CVD Placebo R Mechanistic Study (n=65) Pitavastatin 4mg/day (n=8) Screening And Consent Randomization Intervention Coronary plaque, vascular inflammation, immune activation CV Death MI Unstable Angina Stroke Arterial Revasc Mechanistic Primary Endpoint Clinical Primary Endpoint Individual components of primary endpoint All cause death Incidence/Progression of noncalcified plaque; High-risk plaque Secondary Inflammatory, immunological, metabolic biomarkers Endpoints Predictors All Cause of statin Death effects Statin safety and non AIDS comorbidities: DM, Infections, Cancer Figure 4. Schematic overview of REPRIEVE trial design. RCT of Pitavastatin vs Pravastatin % Change in Lipids at Week 52 15 1 5-5 -1-15 -2-25 -3-35 P =.9 P <.1 P =.2 P =.9 TC LDL-C HDL-C TG Pitavastatin 4 mg (n=98) Pravastatin 4 mg (n=9) HIV+, LDL 13-22 and TG < 4 after 4 week washout/dietary stabilization Sponseller CA, CROI 214, 751LB Slide 39 of 42 8 7 6 5 4 3 2 Slide 4 of 42 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 1 HIV-infected Population controls HIV-infected Population controls Rasmussen LD, Cin Infect Dis 215;6:1415-23 New Orleans, Louisiana: December 15-17, 215 12

D:A:D Cohort Study: Smoking and MIs 33,38 HIV-positive pts in 212 clinics in Europe, the US and Australia 432 myocardial infarctions 5 - IRR 1 -.5-1.73 3.4 Baseline status Never smoked Previous Current 3.73 3. 2.62 2.7 Stopped smoking during follow-up < 1 yr 1-2 yrs 2-3 yrs 3+ yrs Adjusted for: age, sex, cohort, calendar year, ART, FH of CVD, DM, and time-updated lipids and BP assessments. Petoumenos K, HIV Med. 211;12:412-21 Slide 41 of 42 Summary Slide 42 of 42 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 New Orleans, Louisiana: December 15-17, 215 13