1. The role of treatment versus disease in causing premature non-AIDS morbidity Judith S. Currier, MD University of California, Los Angeles

2. Serious Non AIDS Events Growing cause of morbidity and mortality but still relatively rare – More common than AIDS events among treated cohorts J Neuhaus et al AIDS 2010 – Related to immunodeficiency Heterogeneous group of diseases, some common etiologies

3. HOST/ LIFESTYLE VIRUS/IMMUNE SYSTEM ART Understanding the relative contributions of each of these factors to the pathogenesis of complications in HIV will help to inform the development of strategies for prevention and treatment Factors Associated with NCD in HIV

4. Serious Non-AIDS Events Cardiovascular Disease Renal Disease Hepatic Disease Malignancy

5. Serious Non-AIDS Events Cardiovascular Disease Renal Disease Hepatic Disease Malignancy

6. Smoking Hypertension Genetics Endothelial Function Altered Lipids Inflammation Immune Activation HIV Replication ART Effects Macrophage recruitment Insulin Resistance HIV (nef) Summary of HIV, Host and ART Effects Microbial translocation

7. HOST/ LIFESTYLE IMMUNE SYSTEM ART Cardiovascular Disease Age, Genetics, lifestyle, environment may overshadow contributions of ART and immune activation/inflammation In high risk- predisposed individual- contributions of ART may be Magnified

8. Risk Factors for MI in D:A:D DAD Study Group. N Engl J Med 2007; 356:1723. Adjusted Model 1Adjusted Model 2 Relative Rate (95% CI) P Value Relative Rate (95% CI) P Value Exposure to PIs (per year)1.16 (1.10-1.23)<0.0011.10 (1.04-1.18)0.002 Age (per 5 yr)1.39 (1.31-1.46)<0.0011.32 (1.23-1.41)<0.001 Male sex1.91 (1.28-2.86)0.0022.13 (1.29-3.52)0.003 BMI > 30 kg/m 2 1.70 (1.08-2.69)0.021.34 (0.77-2.34)0.31 Family history of CHD1.56 (1.10-2.23)0.011.40 (0.96-2.05)0.08 Smoking status Current2.83 (2.04-3.93)<0.0012.92 (2.04-4.18)<0.001 Former1.65 (1.12-2.42)0.011.63 (1.07-2.48)0.02 Previous cardiovascular event 4.30 (3.06-6.03)<0.0014.64 (3.22-6.69)<0.001 Diabetes mellitus--1.86 (1.31-2.65)<0.001 Hypertension--1.30 (0.99-1.72)0.06 Total cholesterol (per mmol/liter increase) --1.26 (1.19-1.35)<0.001 HDL cholesterol (per mmol/liter increase) --0.72 (0.52-0.99)0.05

9. HIV and CRP both predict MI risk MarkerCRP High vs Not High OR (95%CI) P value HIV vs no HIV OR (95%CI) P value CRP2.5 (2.4-2.8) <0.0001 HIV2.1 (1.3-3.1) 0.0009 CRP, HIV2.5 (2.3-2.8) <0.00011.74 (1.1-2.6) 0.01 CRP, HIV, age, sex, race, HPN, diabetes, dyslipidemia 2.1 (1.9-2.4) <0.00011.9 (1.2-2.9) 0.0035 Triant et al, J Acquir Immune Defiic Syndr, 2009 (adapted)

10. Low HDL contributes to CVD Risk Estimates in HIV Cotter AG et al AIDS 2011 Mar 27;25(6):867-9

11. Way Forward Role of ART – Does treatment at higher CD4 prevent non-AIDS events? – Ongoing RCTs of treatment at CD4 > 500 – RCTs can also compare contribution of different ART regimens Role of immune activation/inflammation – Studies to dampen immune activation and inflammation can probe whether surrogates of non- AIDS events are improved, ultimately will need clinical endpoint studies

12. Current Approach Manage known traditional risk factors for serious non-AIDS events – Smoking – Hypertension – Obesity, excess visceral fat – Diabetes

13. Associations between markers of microbial translocation and End Organ Diseases sCD14 and all cause mortality sCD14 and mild neurocognitive impairment(Lyons, JAIDS 2011) LPS (but not sCD14) negatively correlated with FMD in ART treated but not naïve subjects (Dube, Lipo workshop,2011) * Nef may also increase CD14 expression and release (Creery D, 2002)