HIV and Inflammation: A Paradigm Shift

1. HIV and Inflammation:A Paradigm Shift Wafaa El-Sadr, MD, MPH Columbia University & Harlem Hospital New York

2. XI International Conference on AIDSVancouver 1996

3. Effect of Protease Inhibitor-Containing Regimens on Mortality in Patients with <100 CD4+ cells 40 100 Deaths 80 30 60 Deaths per 100 Person-Years Therapy with a Protease Inhibitor (% of patient-days) 20 40 Antiretroviral Therapy 10 20 0 0 1994 1995 1996 1997 Palella F, et al.N Engl J Med, 1998.

4. Survival from SeroconversionCompared to Pre 1996 Hazard Ratio of Death 0.24 1 0.63 0.14 0.08 0.03 Ewings et al, 2008

5. Change in Mortality over Time All cause AIDS HAART Mortality (per 1000 person-years) Percent Receiving Therapy Non-AIDS Calendar Year Lau et al, JAIDS 2007

6. Causes of Death in HIV: France 2005 AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown N = 937 deaths Percent Lewden et al, CROI 2007

8. Optimization of Use of Antiretroviral Therapy Risks Benefits

9. SMART Study CD4+ cell count >350 cells/mm3 N= 5,472 n = 2,720 n = 2,752 Drug Conservation (DC) Defer use of ART until CD4+ < 250; episodic ART based on CD4+ cell count to increase counts to > 350 Viral Suppression (VS) Continuous use of ART to maintain viral load as low as possible Primary Endpoint: Opportunistic Disease or Death

10. Increased Risk Opportunistic Disease or Death with DC versus VS Strategy 20 Logrank = 31.1 p < 0.0001 15 DC Group Percent with Event 10 VS Group 5 0 0 4 8 12 16 20 24 28 32 36 40 44 Months from randomization DC 2720 1170 589 322 VS 2752 1167 625 334

11. Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events Hazard Ratio (DC/VS) (95% CI) No. of Patients with Events Rate** Endpoint DC VS 3.6 Serious AIDS 59 1.30.4 1.6 Serious non-AIDS* 186 3.22.0 1.9 Serious AIDS or 239 4.42.4non-AIDS 0.1 1 10 Favors VS ► Favors DC ► • Cardiovascular, renal, hepatic, non-AIDS malignancy, others • ** Per 100 person-years Curr Opin HIV AIDS 2008;3:112-117

12. Unifying FrameworkHIV-Associated Immune Activation Ross, NEJM 1999 • HIV replication • T cell apoptosis immunosuppression • Coagulation cascade • Inflammation • Atherosclerosis - Liver disease • Osteoporosis - Neurocognitive decline • Renal disease Michael Ross Russell Ross, NEJM 1999

13. Inflammatory and Coagulation Markers in SMART • Inflammatory • hs C-reactive protein (hs-CRP) • IL-6 • Serum amyloid A • Serum amyloid P • Coagulation • D-dimer • Prothrombin fragment 1+2 (F1.2)

14. Baseline Biomarker Levels Associated with All Cause Mortality – SMART Study Kuller et al. Plos Medicine 2008

15. Association of C Reactive Protein and HIV with Myocardial Infarction Triant et al, J Acquir Immune Defiic Syndr, 2009 (adapted)

16. C-Reactive Protein Level is Associated with AIDS-Free Survival Proportion AIDS Free Time from Baseline, years Lau et al, Arch Intern Med 2006

17. C Reactive Protein Level is Associated with AIDS –Free Survival Lau et al, Arch Intern Med 2006

18. C Reactive Protein Levels Increase over Time prior to AIDS Diagnosis AIDS C reactive protein, geometric mean ug/L Months from AIDS Diagnosis Lau et al, Arch Intern Med 2006

19. The Natural History of HIV Infection Clinical Latency? Pantaleo G, et al. N Engl J Med 1993

20. Opportunistic Infections Occur at Higher CD4+ Cell Count Strata CMV / MAC / TOXO PCP /EC TB Incidence per 1000 PYFU (95%CI) Latest CD4 count N events 134 45 13 9 2 2 89 55 61 35 13 16 12 9 10 11 11 14 Podlekareva et al. J Infect Dis 2006

21. Non-AIDS-Related Deaths Occur at Higher CD4+ Cell Counts CASCADE Rate per 100 person/yrs DAD CD4+ Cell Count Phillips et al, AIDS 2008

22. Deaths due to Non-AIDS Exceed AIDS Causes in Patients enrolled with CD4+ Count >200 cell/mL—Post 1999 0.8 AIDS Non-AIDS 0.4 Cumulative mortality Non-AIDS Non-AIDS Non-AIDS AIDS AIDS AIDS 0 CD4<200 CD4+ 201-350 CD4+ 351-500 CD4+>500 Adapted, Lau et al, JAIDS 2007

23. A New Paradigm Ongoing Morbidity from HIV 1000 800 600 400 200 0 Opportunistic Diseases CD4+ cells Count 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time in Years Infection

24. Timing of Initiation of ART Hazard Ratio for AIDS or Death CD4+ cell count threshold Sterne et al, Lancet 2009

25. Earlier Initiation of ART andRisk of Death Kitahata et al, New Eng J Med 2009 (adapted)

26. Effect of ART on C Reactive Protein C Reactive Protein Level Henry et al, AIDS, 2004

27. Effect of ART Interruption on BiomarkersChange from Baseline to Month 1 SMART Study

28. START Study HIV-infected, ART-naïve CD4+ count > 500 cells/mm3 Early ART Group Initiate ART immediately Deferred ART Group Defer ART until CD4+ count < 350 cells/mm3 or AIDS Primary Outcome Serious AIDS, Serious non-AIDS Events or Death Measurement of biomarkers

29. Effect of Rosuvastatin on CVD in General Population with High CRP & Low LDL-Jupiter Study Cumulative Incidence Years Ridker et al, N Engl J Med 2008

30. A5275– Pilot Study of Effects of Atorvastatinon Biomarkers in HIV Arm A Atorvastatin Placebo • HIV infected • On boosted-PI regimen with HIV RNA <50 copies/ml • LDL < 130 mg/dl • D-dimer >0.34 WASHOUT Week0 20 28 48 Atorvastatin Placebo Arm B Biomarkers of Inflammation, Coagulopathy, Angiogenesis, and T-lymphocyte Activation

31. A World Apart?

32. Mortality in HIV-infected Persons after Seroconversion Compared to General Population Age <45 yrs at seroconversion Age >45 yrs at seroconversion HIV Pre -1996 HIV Pre -1996 Cumulative Mortality, Proportion Cumulative Mortality, Proportion HIV 2004-2006 HIV 2004-2006 General 2004-2006 General 2004-2006 Time from Seroconversion, Years Time from Seroconversion, Years Bhaskaran et al, Lancet 2008

33. Dramatic Increase in Access to ART;Low & Middle Income Countries

34. Effect on HIV-related Deaths inResource-limited Countries PEPFAR Focus Countries (12) Control Countries (29) Deaths from HIV, Thousands Deaths from HIV, Thousands Year Year Bendavid et al, Ann Int Med 2009

35. High Mortality Pre-ART Survival Probability Days after Enrollment Lawn et al, AIDS 2005.

36. High Risk of Early Mortality after ART Initiation:Resource Poor/Resource Settings  HR unadjusted  HR adjusted for cohort, age, sex, baseline CD4, ART-regimen, disease stage Hazard Ratio (95% CI) Months from Starting HAART

37. Summary • Remarkable progress achieved with use of ART • The spectrum of HIV-related complications evolved with a predominance of non-AIDS related events, particularly in patients with higher CD4+ cell counts • Inflammatory and coagulation markers associated with serious complications, AIDS and death • A survival gap exists: • for those with HIV versus general population in resource-rich settings • and an even more pronounced gap in outcomes in HIV infected individuals in resource –rich versus limited settings

38. Conclusions • A re-conceptualization of the pathogenesis of HIV disease is necessary-- clinical latency is a misperception • Inflammation and coagulopathy are important causes of end-organ damage, disease progression and death • Role of ART and of other interventions in averting and suppressing these processes and their consequences needs urgent definition

39. One World-One Hope