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Panarteritis: beyond the vulnerable plaque Human immunodeficiency virus Stockholm, August 30, 2010 Giuseppe Schillaci Department of Clinical and Experimental Medicine University of Perugia Perugia, Italy

Changing spectrum of CV disease in HIV-infected patients Pre-HAART Pericarditis and pericardial effusion Myocarditis and dilated cardiomyopathy Endocarditis (IV drug users) Cardiac involvement in AIDSrelated turmors HAART Pulmonary arterial hypertension Systemic arterial hypertension CV ischemic disease Restrepo CS et al. RadioGraphics 2006; 26:213-231 Khunnawat C et al. Am J Cardiol 2008;102:635-642

Slow, increasing trend of CV disease as a cause of death in HIV-infected patients Mortality 2000 (n=964) Proportion (%) 0 10 20 30 40 50 60 France Mortality 2005 1 st quarter (n=405) Proportion (%) 0 20 40 60 AIDS Cancer HCV Cardiovascular Bacterial infection Suicide Liver disease Accident Overdose Iatrogenic HBV Metabolic Other infection Unknown 2 2 2 2 2 1 1 3 4 6 7 9 11 47 AIDS Cancer HCV Cardiovascular Suicide Non-AIDS related infection Accident HBV Neurological disorder Overdose Bronchopulmonary disease Renal failure Liver disease Psychiatric illness Antiretroviral treatment Other Unknown Lewden C, et al. Int J Epidemiol 2005;34:121-130 Lewden C et al. J Acquir Immune Defic Syndr 2008;48:590-8 1 1 1 1 1 0 0 2 2 2 2 4 6 9 12 15 39

Non-AIDS-defining illnesses as causes of death The EuroSIDA Group

Incidence of CVD is higher in HIV+ than in HIV- individuals References Size Outcome HIV+ vs HIV- Klein, JAIDS, 02 4,159/39,877 CAD (6.5 vs 3.8/1000 PY) Klein, CROI, 07 5,000/43000 CAD (4.5 vs 2.9/1000 PY) Currier, JAIDS, 03 28,513/3 mill CAD (only in young) Triant, JCEM, 07 3,851/1 mill MI (75%) Obel, CID, 07 3,953/0.4 mill CAD (39-112%)

HIV infection is an independent risk factor for coronary calcifications % 80 60 40 20 HIV+ HIV- HIV+ HIV- P CAC >0 39% 20% 0.01 CAC >100 17% 4% 0.03 0 0 1-100 101-400 401-1000 > 1000 CAC score 247 patients HIV+ 45 controls Hsue P, CROI 2009, Abs. 724

HIV infection is an independent risk factor for cimt similar to traditional CV risk factors 433 HIV+ (FRAM 2) and 5749 control (FRAM 2 & CARDIA) subjects in the age range spanned by the controls (37-78 yrs). Multivariable Analysis of Associated Factors Estimated Effect in mm14 Internal Carotid Common Carotid HIV infection 0.15 mm** 0.033 mm * Male 0.13 mm*** 0.054 mm*** Current smoker 0.17 mm*** 0.020 mm** Past smoker 0.09 mm*** 0.020 mm*** Diabetes 0.12 mm*** 0.026 mm*** Age (per 10 years) 0.16 mm*** 0.073 mm*** SBP (per 10 mmhg) 0.05 mm*** 0.025 mm*** DBP (per 10 mmhg) -0.07 mm*** -0.026 mm*** Total Chol (per 10 mg/dl) 0.009 mm*** 0.004 mm*** HDL (per 10 mg/dl) -0.020 mm*** -0.011 mm*** *p<0.01, **p<.001, ***p<.0001; Significant gender interaction Grunfeld C et al. CROI 2009; abstract 146

HIV & cardiovascular risk Who is the villain? Tobacco smoking & traditional CV risk factors Metabolic alterations Direct damage (PIs) Endothelial dysfunction, proinflammatory cytokines, oxidative stress, immune deficiency Metabolic alterations

Host-related factors Higher prevalence of metabolic abnormalities (dyslipidemia and insulin resistance) and drug consumption (alcohol, cocaine, others) 1-4 Higher smoking rates in HIV+ vs HIV- 5, 6 Body fat changes (lipoatrophy and visceral accumulation) associated with dyslipidemia and insulin resistance 1. Currier JS. Circulation 2008; 2. Mondy KE. AIDS 2008; 3. Bongiovanni M. J Antimicrob Chemother 2008; 4. Lai S. Clin Infect Dis 2008; 5. DAD Study Group. NEJM 2007; 6. Savès M. Clin Infect Dis 2003

Largest observational study to date linked myocardial infarction to ART exposure MIs per 1000 person-yrs (IC95%) Events Person-yrs 8 7 6 5 4 3 2 1 0 D:A:D study No <1 1-2 2-3 3-4 4-5 5-6 6-7 >7 Exposure to ART (years) 16 17 20 41 61 62 51 47 30 11815 7105 9027 12098 14892 14394 11351 7935 5853 RR per year of ART: Univariate: 1.16 [1.11-1.21] Adjusted: 1.16 [1.09-1.23] Total 345 94469 D:A:D study group. NEJM 2003;349:1993-2003

Higher risk of MI with protease inhibitors exposure (but not with non-nucleoside RTI exposure) Number of MIs per 1000 PYFU (IC 95%) 10 8 6 4 2 D:A:D study Adjusted relative rate/year of PI: 1.15 (1.06, 1.25) Adjusted relative rate/year of NNRTI: 0.94 (0.74, 1.19) 0 0 <1 1 2 2 3 3 4 4 5 5 6 Years of exposure to PI or NNRTI >6 Friis-Møller N et al. N Engl J Med 2007;356:1723-35

Classification of antiretroviral drugs RT inhibitors Protease Entry inhibitors inhibitors Integrase NRTI NNRTI inhibitors Fusion inhibitors Co-receptor antagonists AZT ddi d4t 3TC ABC TDF FTC NVP EFV ETV SQV IDV NFV LPV fapv ATV TPV DRV Raltegravir Elvitegravir* T20 Maraviroc Vicriviroc*

Antiretroviral treatment: how to start? Standard: 2 NRTIs + 1 NNRTI or 1 PI/ritonavir Aim: suppression of viremia CD4 recovery

Increase in the risk of myocardial infarction by antiretroviral drugs PI (as a class) DAD 2007 DAD 2008 DAD 2009 FHDB 2009 16% per year (relative to NNRTI) (10%/yr, after adjustment for HTN, dyslipidemia, DM) - - 16% per year (relative to SQV) LPV/r - - 13% per year 37% per year IDV - - 12% per year n.s. APV/fAPV - - n.s. 52% per year ABC - 90% recent exposure ddi - 49% recent exposure 60% recent exposure 41% recent exposure 97% recent exposure n.s. * Recent exposure means current exposure or stopped in the previous 6 months 1. DAD NEJM 2007; 2. DAD Lancet 2008; 3. DAD CROI 2009; 4. FHDB Arch Intern Med 2010

HAART (mostly PIs) atherogenic dyslipidemia enos expression ROS viral load endothelial dysfunction atherosclerosis endothelial dysfunction

HAART: common side effects Rash (nevirapin, abacavir, darunavir, amprenavir ) Liver toxicity (NNRTI, tipranavir) Kidney disease (tenofovir) Anemia (AZT) Pancreatitis (didanosine) Lactic acidosis (stavudine, zidovudine) Insulin resistance/diabetes (AZT, d4t, ddi, PI) Hypertriglyceridemia (ritonavir, efavirenz, stavudine) Hypercholesterolemia (PI/ritonavir, efavirenz) Lipodystrophy Lipo-atrophy (AZT, d4t, ddi) Lipo-hypertrophy (PI/ritonavir)

Part (but not all) of CV risk attributable to PI can be explained by lipids Exposure to PI (per year) RR 1.16 RR 1.10 Exposure to NNRTI (per year) RR 1.05 RR 1.00 0.9 1.0 1.1 1.2 1.3 Relative rate of MI (95% CI) Adjusted for sex, age, cohort, year, prior CVD, family CVD, smoking, body mass index, and the other 3rd drug However, no clear adjustment for NRTI. Thymidine NRTIs have an impact on insulin sensitivity and lipids. Friis-Møller N et al. N Engl J Med 2007;356:1723-35

Abacavir and didanosine-associated CV risk: not fully explained by traditional risk factors Recent * didanosine use Recent * abacavir use No further adjustment 1.49 1.90 Adjustment also for: Latest CD4 Latest HIV RNA Latest Lipids Latest blood pressure Diabetes Fat loss/gain Latest glucose 0.5 1 1.5 2 2.5 3 Adjusted OR (95% CI) 0.5 1 1.5 2 2.5 3 Adjusted OR (95% CI) * Recent = still using or stopped within last 6 months All data depicted are also adjusted for demographic factors, calendar year, cohort, CV risk factors that are unlikely to be modified strongly by cart use and cumulative exposure to other antiretroviral drugs. DAD Study Group. Lancet 2008;371:1417-26

Endotheliumdependent FMD (%) Abacavir use is associated with endothelial dysfunction among patients on ART with HIV suppression Cross-sectional study No data on antiretrovirals other than ABC and other epidemiological characteristics 10 8 6 4 2 P =0.01 0 Ab ac av ir Sp ar in g Reg im en Ab ac av ir Co n tain in g Reg im en After adjustment for age, gender, traditional risk factors, HIV-specific factors, baseline brachial artery diameter, current abacavir use was independently associated with lower FMD (p=0.02) Hsue P, et al. AIDS. 2009;23:2021-2027

Pressure Waves Recorded Along the Arterial Tree Femoral artery Common carotid artery Thoracic aorta Abdominal aorta Iliac artery Ascending aorta velocity distance time

Prognostic value of aortic PWV Event-based studies, 2007 Study Year yrs CV events Setting Result Blacher 1 1998 3.0 death, CV death ESRD Meaume 2 2001 2.5 CV death elderly Laurent 3 2001 9.3 CVD hypertension Boutouyrie 4 2002 5.7 CHD hypertension Laurent 5 2003 7.9 fatal stroke hypertension Health ABC 6 2005 4.6 death, CHD, stroke elderly Rotterdam 7 2006 3.2 stroke general population MONICA-DK 8 2006 9.4 CVD, CHD general population [1] Circulation 1999;99:2434-2439 [5] Hypertension 2003;34:1203-1206 [2] ATVB 2001;21:2046-2050 [6] Circulation 2005;111:3384-3390 [3] Hypertension 2001;37:1236-1241 [7] Circulation 2006;113:657-663 [4] Hypertension 2002;39:10-15 [8] Circulation 2006;113:664-670

Subclinical organ damage in hypertension Left ventricular hypertrophy (EKG or echocardiography) Carotid wall thickening ( 0.9 mm) or plaques Carotid-femoral pulse-wave velocity >12 m/s Ankle/brachial BP index <0.9 Plasma creatinine (M) 1.3-1.5 mg/dl, (W) 1.2-1.4 mg/dl, or estimated GFR <60 ml/min/1.73 m 2, or creatinine clearance <60 ml/min Microalbuminuria (30-300 mg/24h, or albumin-creatinine ratio (M) 22 mg/g, (W) 31 mg/g creatinine) 2007 ESH-ESC guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105-1187

Aortic stiffness in HIV-infected patients treated with protease inhibitors 10 Aortic pulse wave velocity, m s -1 p=0.015 Antiretroviral therapy p<0.001 30 8 6 Metabolic syndrome 20 Metabolic syndrome prevalence % Arterial stiffness 10 0 Controls HIV-infected Control n=32 adult HIV-infected patients treated with protease inhibitors n=32 age-, sex- and BP-matched HIV-uninfected control subjects excluded: hypertension, hypercholesterolemia, diabetes, renal or CV disease HIV Cardiovascular disease Schillaci G, et al. Arterioscler Thromb Vasc Biol 2005;25:2381-2385 0

Aortic PWV, m/s Duration of treatment with PIs and aortic stiffness 10 8 r= 0.42 p=0.016 6 4 0 2 4 6 8 Protease inhibitor treatment duration, years Schillaci G, et al. Arterioscler Thromb Vasc Biol 2005;25:2381-2385

MetSyn & aortic stiffness: putative mechanisms arterial stiffness Ageing Insulin resistance adiposity Pro-inflammatory state oxidative stress leptin insulin TIMPs MMPs NO ET1, Ang II SNS, NE, -adrenergic tone Arterial wall remodeling collagen cross-linking AGEs elastin fragmentation density VSMC hypertrophy growth factors VSMC tone

Waist circumference, cm High aortic pulse wave velocity in hypertension: the role of the metabolic syndrome Aortic PWV Waist circumference p=0.03 10 140 120 9 m/s 100 No Yes Metabolic syndrome 8 7 n=169 never-treated, non-diabetic hypertensive subjects analysis of covariance (adjusted by age and mean arterial pressure) metabolic syndrome defined according to the ATPIII classification Schillaci G, et al. Hypertension 2005;45:1078-1082 80 60 r= 0.35 p<0.001 4 8 12 16 Aortic pulse wave velocity, m/s

Case-control studies investigating arterial stiffness in HIV-infected subjects receiving ART authors no. of subjects parameter results Schillaci, 2005 [1] 32 cases, 32 controls aortic PWV van Wijk, 2006 [2] 37 cases, 14 controls aortic PWV = van Vonderen, 2009 [3] 77 cases, 52 controls carotid stiffness Lekakis, 2009 [4] 34 cases, 28 controls aortic PWV 1. Arterioscler Thromb Vasc Biol 2005;25:2381-2385 2. J Am Coll Cardiol 2006;47:1117-1123 3. J Acquir Immune Defic Syndr 2009;50:153-161 4. Am J Hypertens 2009;22:828-834 Schillaci G, et al. Artery Res 2009;3:100-103

% with a Major CVD Event ART withdrawal increases the risk of CV disease due to acute effects of HIV viremia The Strategies for Management of Anti-Retroviral Therapy trial 6 4 Drug conservation* Viral suppression 2 No. at Risk DC VS 0 0 0.5 1 1.5 2 2.5 3 3.5 4 Years from Randomization 2752 1306 713 379 10 2720 1292 696 377 10 ART discontinuation associated with: Increased immune activation (Tebas P et al. PLoS ONE 2008) Increased adhesion molecules (Papasavvas E et al. AIDS 2008) Increased inflammation (Seoane E et al. J Acquir Immune Defic Syndr 2008) Phillips A, et al. Antivir Ther 2008;13:177-187 * Short-term CD4+ guided episodic use of ART vs continuous therapy

Discontinuation of ART increases the incidence of CV, renal, liver disease between 50% and 5-fold Event OD/death 169 3.4 1.3 Baseline ART Status Naïve 5 2.7 0.5 Experienced, off ART 31 4.4 1.7 On ART 133 3.2 1.3 SMART study Rate DC VS CVD, renal, liver 104 1.8 1.1 Baseline ART Status Naïve 5 2.8 0.5 Experienced, off ART 13 2.0 0.6 On ART 86 1.7 1.2 OR 2.6 5.3 2.6 2.5 1.7 5.1 3.5 1.5 0,1 1 10 Favours DC El-Sadr WM et al. N Engl J Med 2006;355:2283-2296 Favours VS

Relative risk of death Relative risk of death according to immune function and specific cause The Data collection on Adverse events of anti-hiv Drugs (D:A:D) Study Improved immune function decreases the risk of non HIV-related death 100 10 HIV Liver Malignancy Heart 1.0 <50 50 99 100 199 200 349 350 499 Latest CD4+ count (cells/mm 3 ) N=23,000+ 1,248 (5.3%) deaths 2000 2004 (1.6/100 person-yrs) Of these, 82% on ART Incidence of CV-related mortality lower than other non HIV-related deaths Weber R, et al. 12th CROI, Boston 2005, #595 >500

HIV factors are associated with CV death in HIV-infected patients D:A:D Study Group, Smith C. AIDS 2010;24:1537-1548

HIV-related factors HIV systemic inflammation endothelial cell infection cell adhesion molecules 5,6 1 gp120 tat 7 PKC p21-activated kinase-1 reverse cholesterol transport HDL-C 2,3 WBC adhesion endothelial dysfunction ROS oxidative stress 4 1. Takano Y, BBA 2007; 2. Mujawar Z, PLoS Biol 2006; 3. Bukrinsky M, PLoS Med 2007; 4. Kline ER, Am J Physiol Heart Circ Physiol 2008; 5. Torriani FJ, JACC 2008; 6. Francisci D, AIDS 2009; 7. Huang MB, JAIDS 2000

Arterial stiffness in untreated HIV patients p=0.001 10 9 8 m/s Control (n=39) HIV untreated (n=78) 7 6 5 case-control study (matching by age, sex, and BP) exclusion criteria: hypertension, dyslipidemia, diabetes, CKD, obesity, any CVD, any evidence of inflammation over the previous 4 weeks Schillaci G, et al. Hypertension 2008;52:308-313

Case-control studies investigating arterial stiffness in treatment-naïve HIV-infected subjects authors no. of subjects parameter results Schillaci, 2008 [1] 39 cases, 78 controls aortic PWV Baker, 2009 [2] 32 cases, 30 controls aortic PWV Lekakis, 2009 [3] 22 cases, 28 controls aortic PWV Vlachopoulos, 2009 [4] 51 cases, 35 controls aortic PWV = 1. Hypertension 2008;52:308-313 2. J AIDS 2009 Jul 9 [EPub ahead of print] 3. Am J Hypertens 2009;22:828-834 4. Artery Res 2009;3:104-110 Schillaci G, et al. Am J Hypertens 2009;22:817-818

Arterial stiffness in untreated HIV patients p<0.01 p=0.021 p=0.07 9 8 m/s 7 Control HIV untreated HIV treated (n=23) (n=23) (n=23) 6 case-control study (matching by age, sex, and BP) exclusion criteria: hypertension, dyslipidemia, diabetes, CKD, obesity, any CVD, any evidence of inflammation over the previous 4 weeks Schillaci G, et al. Hypertension 2008;52:308-313

Am J Hypertens 2009;22:817-818

BP, mm Hg J AIDS 2010;EPub ahead of print Nondippers, % 130 120 Controls (n=156) HIV (n=52) 50 40 p=0.003 35 110 30 100 20 15 80 70 10 60 8 12 16 20 0 4 8 Time of day, hours 0 HIV- (n=156) HIV+ (n=52)

HIV & CVD Conclusions (1) Increasing importance of atherosclerosis-related disease in HIVinfected persons Higher risk of CV disease in HIV-infected persons relative to non- HIV-infected ones Traditional CV factors account for a substantial part of CV risk in HIV-infected persons Rationale for active identification and aggressive interventions similar to general population

HIV & CVD Conclusions (2) Uncontrolled HIV and other concurrent infections further increase the risk for CV disease rationale for early ART and against discontinuation of ART Individual ARTs and classes (PIs) associated with increased risk of CV disease (mechanisms only partly understood, contribution of ART probably lower than that of traditional RFs & uncontrolled infection) rationale for conducting RCTs and investigating mechanisms consider the metabolic profiles of ARTs, especially in patients with CVD or with estimated 10-year CV risk >10% Arterial stiffness as a promising tool for early detection of CV damage From a purely CV perspective, the benefits of ART clearly outweigh the potential risks

Artery 10 Verona, Italy October 17-19, 2010