Kuala Lumpur, Malaysia, 30 June - 3 July 2013 At the Heart of Longevity Cardiovascular Health A good head and a good heart are always a formidable combination Nelson Mandela Founder of The Elders ( Peter Reiss Director HIV Monitoring Foundation Professor of Medicine Department of Global Health &Division of Infectious Diseases Amsterdam Institute for Global Health and Development Academic Medical Center, University of Amsterdam

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Disclosures Unrestricted scientific grant support to my insitution for investigator-initiated research fromGilead Sciences, ViiV, Janssen Pharmaceutica, Merck and Bristol Myers Squibb Honoraria paid to my institution for DSMB participation and scientific advisory board participation from Janssen Pharmaceutica and Gilead Sciences

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Case 52 year old man known with HIV for > 15 years. HIV well controlled with cART for 10+ years; CD4 450/mm 3 ART: history of long-term d4T use; currently on TDF+3TC+EFV BMI 27 kg/m 2 ; BP 150/100 mmHg; creatinine clearance 55 ml/min Presents with increasingly frequent episodes of chest pain Evaluation: D x : angina pectoris as result of coronary artery disease

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 What may be contributing to this mans coronary artery disease? 1.Being overweight 2.His HIV infection 3.His hypertension 4.His prior d4T use 5.His reduced renal function 6.Each of the above

Age-related chronic diseases rise exponentially with age Age INCIDENCE Age is the largest single risk factor

Chronic liver disease Neurocognitive decline Non-Aids cancers Chronic kidney disease Osteoporosis & Fragility fractures Cardiovascular disease Frailty Diabetes mellitus Chronic obstructive pulmonary disease

Comorbidity in relation to age

Comorbidity distribution *

Increased age-related complications on ART Frieberg et al., JAMA Internal Med 2013 Increased risk of AMI in HIV compared to HIV uninfected HR = 1.48 (CI = 1.27 – 1.72) Further increase HR if CD4 500 Mean AMI events per 1000 person years N=82,459; Veterans Ageing Cohort Study Virtual Cohort

More Co-morbidity related to worse QoL

Proportion reporting to be 100% unfit-to-work by age category among working age cohort participants I. Stolte et. al. NCHIV 2012; Poster 46 HIV-positivity, older age and experiencing 3 age-associated non-communicable co-morbidities, each were independently associated with higher levels of non-participation in paid work

13 HIV Infection is an Independent Risk Factor for Atherosclerosis Similar in Magnitude to Traditional Cardiovascular Disease Risk Factors Carl Grunfeld, J.A.C. Delaney, Christine Wanke, Judith Currier, Rebecca Scherzer, Mary Lou Biggs, Stephen Sidney, Joseph Polak, Daniel O'Leary, and Richard Kronmal for the FRAM Investigators Funding from the NHLBI, NIH and Department of Veterans Affairs O-114

14 Multivariable Analysis of Associated Factors Estimated Effect in mm Internal CarotidCommon Carotid HIV infection0.15 mm**0.033 mm * Male 0.13 mm***0.054 mm*** Current smoker0.17 mm***0.020 mm** Past smoker0.09 mm***0.020 mm*** Diabetes0.12 mm***0.026 mm*** Age (per 10 years) 0.16 mm***0.073 mm*** Systolic BP (per 10 mmHg) 0.05 mm***0.025 mm*** Diastolic BP (per 10 mmHg) mm*** mm*** Total Chol (per 10 mg/dl) mm***0.004 mm*** HDL (per 10 mg/dl) mm*** mm*** *p<0.01, **p<.001, ***p<.0001; There was a significant gender interaction

Increased risk of cardiovascular disease (CVD) with age in men: a comparison of D:A:D with HIV negative CVD risk equations K. Petoumenos, W. El-Sadr, A dArminio Monforte, C. Sabin, P. Reiss, L. Ryom, S. De Wit, M. Rickenbach, JD Lundgren and M G Law for the D:A:D Study group

Relative risk of CHD from age 40 years

Chronic disease drivers, known and suspected Many chronic diseases of ageing are more common in those with HIV, even after adjustment for ART use and lifestyle factors ART Toxicity Lifestyle (smoking etc.) Clinical Chronic Co-morbidity Persistent Inflammation in treated HIV disease Deeks SG, et al. BMJ 2009; 338:a3172

Control HIV Axial Image Coronal Image F Representative 18 F- FDG PET Images S.Subramanian et al JAMA 2012;308: and S. Grinspoon CROI 2012

Proportion of deaths attributed to AIDS fell over time Largely explained by increases in CD4+ cell counts Proportion of deaths attributed to non- AIDS causes increased over time non-AIDS ̶ defining malignancies now the leading cause in this category Rate of death attributed to cardiovascular or liver disease declined over time possibly suggesting improved management and care Rate of death attributed to non-AIDS malignancy remained stable over time D:A:D: Changes in Causes of Death Over Time (N = 255) (N = 548) Weber R, C. Smith et al. IAC2012. Abstract THAB % 16% 10% 8% 32% AIDS relatedLiver related CVD relatedNADM Other/unknown 22% 9% 10% 20% 39% AIDS relatedLiver-related CVD relatedNADM Other/unknown

Kuala Lumpur, Malaysia, 30 June - 3 July 2013 What advice would you give to our patient? 1.Loose weight and exercise regularly 2.Stop smoking 3.Discontinue cART 4.Change current cART treatment 5.1. and 2 of the above

Age h IV Study Team Academic Medical Center P. Reiss (PI) F.W. Wit M. van der Valk J. Schouten K. Kooij B.C. Elsenga A. Henderiks Public Health Service Amsterdam M. Prins (co-PI) I.G. Stolte M. Martens J. Berkel S. Moll A. van Roosmalen G.R. Visser HIV Monitoring Foundation F. de Wolf S. Zaheri Y.M. Ruijs L. Gras A. Kesselring Amsterdam Institute of Global Health and Development M. Heidenrijk R. Meester F. Janssen Financial support: The Netherlands Organisation for Health Research and Development (ZonMW) grant nr & Stichting AIDS Fonds grant nr Additional unconditional grants from: Gilead Sciences ViiV Healthcare Janssen Pharmaceuticals Merck & Co Bristol Myers Squibb