1. Currier, JS. IAC Mexico City, 8/06/08 HIV-related complications: The contributions of virus, host and ART Judith S. Currier, M.D. University of California, Los Angeles USA

2. Currier, JS. IAC Mexico City, 8/06/08 HIV Related Complications

3. Currier, JS. IAC Mexico City, 8/06/08 HIV Associated Complications HOST VIRUS ART Understand the pathogenesis of these events and the relative contributions of these factors will help us develop strategies for prevention and treatment

4. Currier, JS. IAC Mexico City, 8/06/08 Spectrum of HIV-Related Clinical Events  The SMART examined a strategy of limiting time on ART with the hopes of reducing the rates of ART associated complications.  CD4 > 350, 5472 pts randomized to DC or VS groups Event #Rate DCRate VS HR OD/Death1693.41.32.6 CVD/Renal1041.81.11.7 Liver This study brought into focus the importance of serious non- AIDS Events among patients interrupting ART El-Sadr WM, Lundgren JD et al NEJM 2006; 355:2283–2296

5. Currier, JS. IAC Mexico City, 8/06/08 Spectrum of HIV-Related Clinical Events  The SMART was designed to examine a strategy of limiting time on ART with the hopes of reducing the rates of ART associated complications.  CD4 > 350, 5472 pts randomized to DC or VS groups Event #Rate DCRate VS HR OD/Death1693.41.32.6 CVD/Renal1041.81.11.7 Liver The study brought into focus the importance of serious non AIDS Events among patients interrupting ART El-Sadr WM, Lundgren JD et al NEJM 2006; 355:2283–2296

6. Clinical Outcomes Better for Immediate vs Delayed ART in Patients with CD4 >350: Subset of SMART Study not on ART at Entry JID 2008;197 (April15) 1133-44 =Immediate =Defer  Untreated HIV was associated development of these Non-AIDS events

7. Currier, JS. IAC Mexico City, 8/06/08 Focus of this talk  Role of host, virus and ART Clinical Events/Complications –Using atherosclerosis as an example

8. Currier, JS. IAC Mexico City, 8/06/08 Focus of this talk  Role of host, virus and ART in Non AIDS Defining Events –Atherosclerosis –Renal Disease –Hepatic Events –Lipodystrophy

9. Currier, JS. IAC Mexico City, 8/06/08 Role of Other Host Factors  Smoking  Family History CHD  Diabetes  Hypertension

10. Currier, JS. IAC Mexico City, 8/06/08 Are Contributions from Traditional Risk Factors the Same in HIV? Adapted from, Currier JS, Lundgren JD et al. Circulation 2008;118:198-210. Sabin CA, Worm S. Curr Opin HIV AIDS 2008;2:214-219 Risk FactorUnitIloeje, HIV Med 2005 Friis-Moller N et al. DAD NEJM 2003 HIV – Studies (# studies) AgeYr inc9%6%6-9% (7) SexM vs FNA110%110-160% (2) DiabetesY vs N260%90%140-252% (3) SmokingY vs N140%290%70-290% (3) HTNY vs N30%80%80-90% (3)

11. Currier, JS. IAC Mexico City, 8/06/08 Genetic Factors and CHD Risk  Genetic predisposition to CHD and genetic predisposition to HIV acquisition/progression- could they be linked?  Monocyte Chemoattractant Protein (MCP-1) and CCR2 axis  MCP-1 involved in migration of monocytes into intima during atherosclerosis plaque formation  MCP-1 Alleles linked to atherosclerosis in HIV- and HIV + populations (Alonso-Villaverde C, 2004)  CCR-2 is receptor for MCP-1  Polymorphisms in CCR-2 gene examined for role in atherosclerosis and also in HIV transmission, no clear link

12. Currier, JS. IAC Mexico City, 8/06/08 How HIV infection per se may contribute to atherosclerosis  HIV demonstrated to infect smooth muscle cells in vitro and in vivo and increase secretion of monocyte chemoattractant (CCL-2 ) Eugenin EA et al Am J Pathol 2008;172:1100-11  Macrophages are host for HIV and these cells play a pivotal role in atherosclerosis –HIV impairs ABCA-1 in macrophages, important for reverse cholesterol transport; this in turn may lead to conversion into foam cells and initiate placque formation in the vessel wall. Mujawar, Z, et al PLoS Biol 2006;4:@365

13. Currier, JS. IAC Mexico City, 8/06/08 How HIV infection per se may contribute to atherosclerosis (2)  HIV may also directly impair HDL metabolism- enhancing transfer of HDL to apoB lipoproteins (Rose,H, et al Atherosclerosis 2008;199:79-86).  HIV TAT may promote secretion of MCP-1 (Park IW, Blood, 2001)  Collectively these findings suggest that untreated HIV could contribute to development of atherosclerosis; magnitude of the effect is unclear

14. Currier, JS. IAC Mexico City, 8/06/08 Inflammation and HIV  CRP is an acute phase reactant that independently predicts risk of CV events in adults  CRP predicts HIV disease progression and mortality in untreated women (adj for RNA and CD4) ( Feldman 2003; Drain 2007)  Uncontrolled HIV infection is associated with elevated levels of markers of inflammation (CRP), levels decline with treatment but not to normal (Henry, 2002) –Less is known about how different ART agents impact CRP during successful treatment of HIV, data on abacavir and TDF presented at this conference  In SMART Study IL-6 and d-dimer rose after treatment interruption and baseline levels were associated with all cause mortality. (Kuller, CROI 2008)

15. Currier, JS. IAC Mexico City, 8/06/08 Inflammation, HIV and Markers of Atherosclerosis  Higher levels of hsCRP not strongly associated with IMT in several small studies (Ross CROI 2008; Currier 2007; Hsue 2006)  Hsue reported CMV specific T cells responses, but not hsCRP or immune activation (CD38+ CD4 and CD8) associated with IMT (AIDS 2006;20:2275-83)  Endothelial function improved during 24 weeks of ART with no significant change in hsCRP (ACTG 5152s; JACC 2008 in press)  Pilot study of TNF inhibitor, pentoxifylline 400 mg TID, showed improvements in endothelial activation marker, VCAM-1, and in brachial FMD (2% to 8%) over 8 weeks ( Gupta S,CROI 2008)

16. Currier, JS. IAC Mexico City, 8/06/08 Effects of ART  Lipids effects of ART  Clinical Event Data

17. Currier, JS. IAC Mexico City, 8/06/08 ART and Lipids in Naïve Patients (Adapted From Eckhardt and Glesby Curr Opin HIV/AIDS 2008) DrugNRTIT cholLDLHDLTGTC: HDL ATV/rTDF/FTC LPVABC/3TC LPVTDF/FTC FAPV/rABC/3TC FAPV/rTDF/FTCNA DRV/rTDF/FTC EFVZDV/3TCNA EFVTDF/FTCNA MVCZDV/3TCNA RTGTDF/FTCNo chg

18. Currier, JS. IAC Mexico City, 8/06/08 Association between ART and CVD  Types of Studies –Randomized Trials –Prospective Observational Cohorts –Retrospective Reviews –Administrative Databases  Challenges –different endpoints –variable assessment of and control for risk factors –Limited follow-up in some studies

19. Currier, JS. IAC Mexico City, 8/06/08 Study# Events Type of Event PI effectType of Study Coplan,200319MINoRCT Phillips, 200831CVDYRCT Holmberg, 200221CVDYP Cohort Iloeje, 2005127CVDYP Cohort DAD I, 2007345MIYP Cohort Mary Krause, 200366MIYRetro Rickerts, 200029MIART effectRetro Klein, 2007162CAD admYAdm Data Bozette, 20031207CAD admNoAdm Data Currier, 20031360CAD admARTAdm Adapted from Currier J, Lundgren JD et al. Circulation, July 2008

20. Currier, JS. IAC Mexico City, 8/06/08 Study# Events Type of Event PI effectType of Study Coplan,200319MINoRCT Phillips, 200831CVDYRCT Holmberg, 200221CVDYP Cohort Iloeje, 2005127CVDYP Cohort DAD I, 2007345MIYP Cohort Mary Krause, 200366MIYRetro Rickerts, 200029MIART effectRetro Klein, 2007162CAD admYAdm Data Bozette, 20031207CAD admNoAdm Data Currier, 20031360CAD admARTAdm Adapted from Currier J, Lundgren JD et al. Circulation 2008 PI effect appears to be cumulative, and partially mediated by lipid changes

21. Currier, JS. IAC Mexico City, 8/06/08 NRTIs and MI Risk  Hypothesis- thymidine analogues associated with more lipid changes and expected to see contribution to MI risk  DAD Study (Lancet, 2008 371:1417-28) –No association between ZDV or d4T and MI risk, incomplete data on tenofovir to date –Increased risk associated with recent exposure to ABC (HR 1.9), less so with ddI (HR 1.49) –Excess risk magnified in those with underlying RF –Risk decreased after cessation –Contrasts with PI Risk which is cumulative, mechanism unknown, possible link to inflammation ?  GSK Meta-analysis, RCT- no association  SMART study- see Late Breaker THAB0305,

22. Currier, JS. IAC Mexico City, 8/06/08 Smoking Hypertension DiabetesGenetics Endothelial Function Altered Lipid Effects Inflammation Immune Activation HIV Replication ART Effects Macrophage recruitment Insulin Resistance HIV Summary of HIV, Host and ART Effects

23. Currier, JS. IAC Mexico City, 8/06/08 Where Does this Leave Us?  ART treatment benefits outweighs risk, delaying therapy not the answer, impact of earlier treatment under study  Understanding differences between ART agents is critical when we are considering treatment over decades  Addressing CVD risk factors and tailoring ART regimens for individual patients pending further data  Important to understand mechanism of ART risk, and the contributions of HIV –Prospective assessment of inflammatory markers in cohorts and controlled trials with patients at comparable stages of disease is a start

24. Currier, JS. IAC Mexico City, 8/06/08 Future Directions Continue efforts to enhance screening and reduce modifiable risk factors for CVD, renal and hepatic disease Examine the role of earlier treatment on non-AIDS events and morbidity in controlled trials and cohorts Examine differences between treatment regimens on markers of inflammation and atherosclerosis, renal and hepatic disease Continue to investigate direct effects of HIV on CV, renal and hepatic events

25. Currier, JS. IAC Mexico City, 8/06/08 Acknowledgements AHA State of the Science Conference : Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living with HIV, Proceedings Circulation published online June, 2008 Jens D. Lundgren, James Stein, Andrew Carr