Dr Giovanni Guaraldi

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1 15 th Annual Conference of the British HIV Association (BHIVA) 1-3 April 2009, Arena and Convention Centre Liverpool 1-3 April 2009, Arena and Convention Centre Liverpool 15 TH ANNUAL CONFERENCE OF THE BRITISH HIV ASSOCIATION ( BHIVA) Dr Giovanni Guaraldi University of Modena, Italy 1-3 April 2009, Arena and Convention Centre Liverpool 28

BHIVA Plenary SESSION 1 HIV and the ageing population Endothelial function in HIV Giovanni Guaraldi Metabolic Clinic University of Modena and

2 BHIVA Plenary SESSION 1 HIV and the ageing population Endothelial function in HIV Giovanni Guaraldi Metabolic Clinic University of Modena and Reggio Emilia - Italy The Metabolic Clinic model: a patient-centered approach in the management of HIV related non-infectious co-morbidities 29

3 The Metabolic Clinic model: a patient-centered approach in the management of HIV related non-infectious co-morbidities Diabetes Dyslipidaemia Abnormalities of body composition The Metabolic Clinic model: a patient-centered approach in the management of HIV related non-infectious co-morbidities Diabetes Dyslipidaemia Abnormalities of body composition Body Image QoL, depression Sex disfunction Adherence 30

4 The Metabolic Clinic model: a patient-centered approach in the management of HIV related non-infectious co-morbidities Diabetes Dyslipidaemia Abnormalities of body composition Body Image CVD Fatty liver disease QoL, depression Sex disfunction Adherence Osteopenia Osteoporosis Kidney disease A busy day at the Metabolic Clinic An integrated multidisciplinary approach HIV physicians Psychologists Cardiologists Plastic surgeons Lipidologists Diabeticians Nephrologists Nutritionists Physical trainer Endocrinologists 31

A busy day at the Metabolic Clinic An integrated multidisciplinary approach HIV physicians Psychologists Cardiologists Plastic surgeons Lipidologists

5 A busy day at the Metabolic Clinic An integrated multidisciplinary approach HIV physicians Psychologists Cardiologists Plastic surgeons Lipidologists Diabeticians Nephrologists Nutritionists Physical trainer Endocrinologists The Metabolic Clinic data set All: 2241 * Young adults: < 55 yrs if males, < 65 if females 32

6 The Metabolic Clinic data set FMD: 962 CVD: 68 All: Clinical MI 2 Strokes 1 Coronary revascularization * Young persons: < 55 yrs if males, < 65 if females Ageing: a risk factor for CVD 50 D:A:D study Age group Events PYFU 3,834 10,801 20,075 16,900 9,741 6,687 3,899 2,

Surveillance of cardiovascular and cerebrovascular event rates among HIV-infected and HIV-uninfected Californians: 1996-2008 Kaiser Permanente identified hospital myocardial infarction among 20,305

7 Surveillance of cardiovascular and cerebrovascular event rates among HIV-infected and HIV-uninfected Californians: Kaiser Permanente identified hospital myocardial infarction among 20,305 adult HIV+ KP members and among 203,050 year-, age-and sex-matched HIV-KP members from 1996 through June, For the period , MIs among our HIV+ population and were uncommon, occurring at a rate of 3.0 per 1000 person years. During , the rates of MI among HIV+ and HIV- patients converged such that in the difference in rates between the two groups became statistically non-significant L Hurley CROI 2009 # 710 Heterogeneity of vascular lesions in HIV-infected patients VASCULITIS VS ATHEROMA Reina G, Eur J Vasc Endovasc Surg. 2005;29: Wide flogistic infiltration, with lymphomonocytes and plasma cells along all the thickness of the wall and around the vasa vasorum Periard D, Lancet Infect Dis. 2008;8:58 Foamy appearing macrophage cells, sometimes with some additional T lymphocytes, aggregated platelets, localized smooth muscle cells 34

8 Link between small-vessel Vasculitides and Atherosclerosis Why and when vascular occlusion occurs? VASCULITIS VS ATHEROMA Chronic process over many years Ingredients: Host factors (genes?) Lipids Inflammation (Sub)acute process Ingredients: Inflammation Coagulation 35

9 Vascular damage in patients with HIV may be the consequence of a sistemic immune activation process Van Leuven et al. Current Opinion in HIV/AIDS 2007 Endothelial and sub-endothelial immune activation Van Leuven et al. Current Opinion in HIV/AIDS

10 How to assess inflammation impact on atherosclerosis INFLAMMATION Atheroma formation and growth Plaque Plaque instability instability and and rupture rupture Thrombosis EC adh. molecule expression Inflammation Coagulation VCAM-1 hs- CRP IL-6 TNFalfa d-dimer PAI-1 Untreated HIV HIV being suppressed /= =/ Reiss P, modified from CROI 2009 # 152 The endothelial functions 37

11 A case-control Assessment of platelet function in HIV-1 positive and HIV negative individuals Platelet dysfunction was observed at multiple levels in HIVinfected subjects with both clinical and HIV parameters associated. In multivariate regression, a higher CD8% and being HIV+ were independently associated with less ADP-induced and TRAP-induced platelet aggregation respectively while higher neutrophil count and lower diastolic BP were associated with higher collagen EC50. CS Satchell, CROI 2009 # O197 How to monitor natural history of vascular disease in HIV Functional tests Anatomical tests Pulse Wave Velocity (PWV)* Flow Mediated Dilation (FMD) * Independent from traditional cardiovascular risk factors Intima Media Thickness (IMT) Coronary calcium Score (CAC)* 38

FLOW MEDIATED DILATION TEST (FMD) Non invasive shear stress BAD 1 Probe holder Cuff BAD 2 <Requisites: Controlled room temperature 24 C Quiet room 10

12 FLOW MEDIATED DILATION TEST (FMD) Non invasive shear stress BAD 1 Probe holder Cuff BAD 2 <Requisites: Controlled room temperature 24 C Quiet room 10 min rest of the pts FMD=BAD2-BAD1/BAD1 The Metabolic Clinic data set FMD FMD: 962 CVD: 68 All: 2241 * Young persons: < 55 yrs if males, < 65 if females 39

Coronary Calcium Score CAC detection cannot

prone to ropture CAC scoring may be able to

virtue of its strong association with total

Metabolic Clinic data set CAC CVD: 68 CAC: 724

13 Coronary Calcium Score CAC detection cannot localize a stenotic lesion or one that is prone to ropture CAC scoring may be able to globally define a patient s CHD event risk by virtue of its strong association with total coronary atherosclerotic disease burden The Metabolic Clinic data set CAC CVD: 68 CAC: 724 All: 2241 * Young persons: < 55 yrs if males, < 65 if females 40

14 Research questions: 1. Does endothelial function tests identify people vulnerable to CVD? 2. Does endothelial function tests identify antiretroviral-induced CVD toxicity? Research questions: 1. Does endothelial function tests identify people vulnerable to CVD? 2. Does endothelial function tests identify antiretroviral-induced CVD toxicity? 41

15 European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV The intensity of the effort to prevent cardiovascular disease depends on an individual s absolute risk of ischemic heartdisease and should be comprehensive in nature HIV Medicine, 2008;9:72-81 The Metabolic Clinic data set CAC+FMD CVD: 68 FMD: 962 FMD+ CAC= 413 CAC: 724 All: 2241 * Young persons: < 55 yrs if males, < 65 if females 42

16 Count the risk factors 356 young HIV-infected patients Prevalence of single CV Risk Factors Associated CVR factors 94,67% 3,33% Risk stratification: PREDICTIVE ALGORITHMS SCORE PROCAM Italian Heart Tables (ISS) Framingham Framingham+ Risk factors End Point Fatal CVD Coronary HD CVD CVD CVD Definition of HIGH risk >4% >20% >20% >20% >20% or 10-20%+2RF Sex Age BP TC HDL LDL TG Diabetes Smoke Family history 43

Risk stratification: predictive algorithms 356 young HIV infected patients SCORE Procam Framingham ISS 0.01 (93.98%) 0.01* (90.18%) 0.04 (84.05%) SCORE 0.06* (45.63%) 0.13* (49.58%) Procam 0.36* (86.

17 Risk stratification: predictive algorithms 356 young HIV infected patients SCORE Procam Framingham ISS 0.01 (93.98%) 0.01* (90.18%) 0.04 (84.05%) SCORE 0.06* (45.63%) 0.13* (49.58%) Procam 0.36* (86.24%) * p-value < Is Framingham score a good clinical tool? Retrospective review of clinical data from 222 young adults (age less than 55 years for men and less than 65 years for women) hospitalized for acute myocardial infarction over a three-year period. When the 10-year risk of these patients was stratified by the number of risk factors and lowdensity lipoprotein cholesterol level, only 25% met criteria to qualify for pharmacotherapy. 44

Moving From Risk Assessment to Vulnerability Assessment Cardiovascular vulnerable patient = subject susceptible to an acute coronary syndrome or sudden

18 Moving From Risk Assessment to Vulnerability Assessment Cardiovascular vulnerable patient = subject susceptible to an acute coronary syndrome or sudden cardiac death based on plaque, blood and/or myocardial vulnerability Association between Framingham risk and FMD 356 young HIV infected adults Distribution of FMD 45

19 CV risk stratification according to Framingham & FMD 14,61% Association between Framingham risk and CAC 356 young HIV infected adults Distribution of CAC 46

20 CV risk stratification according to Framingham & CAC 14,61% High Risk definition statistical agreement Cohen s Kappa Framingham risk between 10 & 20 + FMD < 10 p-value Framingham risk between 10 & 20 + CAC > (93.26%) <

21 10,377 asymptomatic individuals referred for electron beam tomography (EBT) screening and followed for 5 years for all-cause mortality. Linear regression was used to calculate predicted age and time to death was estimated via a Cox proportional hazard model. Since CAC accumulation is closely linked with atherosclerosis and ageing, a middle aged man with extensive CAC has a coronary age of a much older individual. Using data from MESA cohort, age specific curves for CAC score appropriate for sex and ethnicity have been generated Can we transform the Framingham score into a clinical tool to qualify people who need primary prevention for CVD? 724 HIV-infected patients with CAC score (Low+moderate vs moderate high + high) X 2 Fram Risk vs. FR-CVR: p < X 2 Fram Risk vs. FR-CAC: p < X 2 Fram CVR vs. FR-CAC: p <

22 Can we transform the Framingham score into a clinical tool to qualify people who need primary prevention for CVD? 724 HIV-infected patients with CAC score (Low+moderate vs moderate high + high) X 2 Fram Risk vs. FR-CVR: p < X 2 Fram Risk vs. FR-CAC: p < X 2 Fram CVR vs. FR-CAC: p < Can we transform the Framingham score into a clinical tool to qualify people who need primary prevention for CVD? 724 HIV-infected patients with CAC score (Low+moderate vs moderate high + high) X 2 Fram A Risk 34% vs. increase FR-CVR: p < of new patients X 2 Fram Risk met vs. FR-CAC: criteria p to < qualify X 2 Fram for pharmacotherapy CVR vs. FR-CAC: p <

23 Gender difference in CAC scores CALCIUM SCORE >400 Tot Males Females Tot Fisher test: p-value<0.001 Who may benefit from CAC assessment? The following patients might be reclassified to a higher risk status based on high CAC score 1. Women 2. Patients with intermediate CHD risk FRAMINGHAM CALCIUM SCORE >400 Tot <10% % >20% Tot CAC measurement in asymptomatic patients with intermediate CHD risk (between 10% and 20%) demonstrates incremental risk prediction information in comparison to low CVD risk. In these patients management might be modified. 50

24 Who may benefit from CAC assessment? The following patients might be reclassified to a higher risk status based on high CAC score 1. Women 2. Patients with intermediate CHD risk FRAMINGHAM CALCIUM SCORE >400 Tot <10% % >20% Tot CAC measurement in asymptomatic patients with intermediate CHD risk (between 10% and 20%) demonstrates incremental risk prediction information in comparison to low CVD risk. In these patients management might be modified. It is reasonable to consider use of CAC measurement in asymptomatic patients with intermediate CHD risk (between 10% and 20%) because of incremental risk prediction information in this patient group. This conclusion is based on the possibility that such patients might be reclassified to a higher risk status based on high CAC score, and subsequent patient management may be modified. 51

Coronary ageing in HIV-infected patients Background The objectives of this study were to assess the coronary age (CA) of a cohort of HIV-infected patients based on the extent of coronary artery

25 Coronary ageing in HIV-infected patients Background The objectives of this study were to assess the coronary age (CA) of a cohort of HIV-infected patients based on the extent of coronary artery calcium (CAC) and to identify the variables associated with it. Methods Observational cross-sectional study of 400 HIV patients receiving HAART. All patients underwent screening using computed tomography and individuals CA was calculated based on CAC score tables generated by the Multi-Ethnic Study of Atherosclerosis (MESA). Prevalence of CAC in the whole cohort and vascular age group distribution in the subpopulation with CAC>0. Increased CA was observed in 162 patients (40.5%) with an average increase of 15 (range 1-43) years compared to their chronological age. 52

regression analysis of increased vascular age and

26 Multivariable linear regression in the group with increased vascular age Univariate linear regression analysis of increased vascular age and CD4+ cell count in the group with increased vascular age 53

27 Hypothesis of the association between vascular damage and CD4 VASCULITIS ATHEROMA INFLAMMATION CD4 Low Cd4 Immune disregulation High Cd4 Immune activation Interpretation Increased CA was highly prevalent in our cohort, and the current CD4+ cell count was the sole independent predictor of it. This is a hypothesis generating observation suggesting that CA may be a surrogate of premature biological ageing in HIV infected patients and that the increase in CD4+ count due to HAART may promote atherosclerosis development. 54

28 Research questions: 1. Does endothelial function tests identify people vulnerable to CVD? 2. Does endothelial function tests identify antiretroviral-induced CVD toxicity? Clinical data suggest a (sub)acute reversible pathogenic mechanism, rather than a gradual progressive one CAD risk Only 1st year of ABC exposure? (FHDB data) Some PI: progressive risk with cumulative exposure Start ABC Stop ABC Reiss, P. CROI 2009 #

ACTG 5152s: rapid improvement of endothelial function in treatmentnaive HIV+ individuals on LPV, EFV, and/or AZT + 3TC Endothelial cell function measured by brachial artery flow-mediated dilation

29 ACTG 5152s: rapid improvement of endothelial function in treatmentnaive HIV+ individuals on LPV, EFV, and/or AZT + 3TC Endothelial cell function measured by brachial artery flow-mediated dilation (FMD) in 82 patients receiving: PI-sparing (EFV + NRTI), NNRTI-sparing (LPV/r + NRTI), and NRTI-sparing (LPV/r + EFV) regimens Conclusions: Pre-ART FMD was impaired (4.0% vs normal > 7%) After 4 and 24 weeks of ART, FMD increased by 1.1% (p = 0.003) and 1.9% (p < 0.001) Benefits similar for all 3 regimens, at 4 weeks and 24 weeks (p > 0.5) Change in FMD over time FMD (%) EFV LPV/r LPV/r/EFV All Week 0 p = 0.82 Torriani FJ et al. 4 th IAS 2007, Abs WeAB 302 Week 4 p = 0.61 NRTI = 3TC + d4t or AZT Week 24 p = 0.78 Impairment of functional integrity of the vasculature during structured treatment interruption 17 cases: patients undertaking voluntary STI. 46 matched controls 56

FMD change in cases and controls stratified by plasma HIV RNA (VL) changes over time Group SEBAR Study Endothelial lunction, lipoproteins, and cardiovascular Iimatory markers in

subjects who continued their PI regimen, those who switched to ATV had : Stable CD4 and plasma HIV RNA Significant reductions in total cholesterol, triglycerides, and non-hdl

30 FMD change in cases and controls stratified by plasma HIV RNA (VL) changes over time Group SEBAR Study Endothelial lunction, lipoproteins, and cardiovascular Iimatory markers in treated HIV-infected patients with Hyperlipidemia who were switched to an atazanavir-containing regimen or continued on other protease inhibitor-based based therapy Compared to subjects who continued their PI regimen, those who switched to ATV had : Stable CD4 and plasma HIV RNA Significant reductions in total cholesterol, triglycerides, and non-hdl cholesterol levels Significantly higher bilirubin level No significant changes in endothelial function and cardiovascular inflammatory markers Murphy R, Guaraldi G, CROI 2009 #

31 Independant predictors of FMD<10% Cross sectional study (858 observations) Multivariable logistic regression analysis OR 95% CI p-value Male sex ; Age ; Hypertension ; MDRD, per 10 ml/min ; HDL cholesterol ; PIs exposure, per year ; Association between cumulative and current exposure to ARV drug classes and FMD Logistic regression analysis restricted in people with HIV-VL<40 c/ml (532 observations). 58

32 Independant predictors of FMD change prospective study (339 observations) No differences in FMD change was found between gender (p = 0.43) First obs. Second obs. p-value FMD (%) beta 95% CI p-value Male sex ; < First FMD value ; < Age ; Other covariates included in the analysis: current CD4 cell count, MDRD, hypertension, years of NRTIs, NNRTIs and Pis exposure, current NNRTIs and Pis exposure. Research questions: 1. Does endothelial function tests identify people vulnerable to CVD? 2. Does endothelial function tests identify antiretroviral induced CVD toxicity? 59

33 Research questions: 1. Does endothelial function tests identify people vulnerable to CVD? Probably yes 2. Does endothelial function tests identify antiretroviral-induced CVD toxicity? Probably no Conclusion Given the complex pathophysiology of cardiovascular disease, no single biomarker will likely prove to be an adequate stand-alone surrogate for the presence of clinically significant disease, i.e. one for which changes in values measured can independently predict clinical benefit, increased risk, or no effect among all individuals tested, regardless of drugs received. For now, the mainstays of cardiovascular disease prevention for HIV-infected persons at high risk include judicious selection of HAART agents, appropriate lifestyle changes, and use of lipid-lowering and antiaggregants medications 60

34 Thanks to the Metabolic Clinic Team: HIV phisicians Gabriella Orlando Federica Carli Sara Ciaffi Cardiologists Rosario Rossi Annachiara Nuzzo Endocrinologist Vincenzo Rochira Giovanni Caffagni Sonographer Antonella Lattanzi Statisticians Stefano Zona Alessandro Cozzi Lepri Plastic Surgeons Antonio Pedone Antonio Spaggiari Alessio Baccarani Physical trainer Costantino Bertucelli Dietician Barbara Pellati My Boss Prof. R. Esposito 15 th Annual Conference of the British HIV Association (BHIVA) 1-3 April 2009, Arena and Convention Centre Liverpool 1-3 April 2009, Arena and Convention Centre Liverpool 61

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