1 / 36

HIV and Inflammation: A Paradigm Shift

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

ayanna
Download Presentation

HIV and Inflammation: A Paradigm Shift

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. 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 Adapted from Palella F, et al. N Engl J Med, 1998.

  3. Survival from Seroconversion Compared to Pre 1996 Hazard Ratio of Death 0.24 1 0.63 0.14 0.08 0.03 Adapted from Ewings et al, 2008.

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

  5. 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 Adapted from Lewden et al, CROI 2007 Percent

  6. Optimization of Use of Antiretroviral Therapy Risks Benefits

  7. 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

  8. 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

  9. 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 Adapted from Curr Opin HIV AIDS 2008;3:112-17.

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

  11. 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)

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

  13. Association of C Reactive Protein and HIV with Myocardial Infarction Adapted from Triant et al, J Acquir Immune Defiic Syndr, 2009.

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

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

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

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

  18. 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 Adapted from Podlekareva et al. J Infect Dis 2006.

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

  20. 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 from Lau et al, JAIDS 2007.

  21. 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

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

  23. Earlier Initiation of ART and Risk of Death Adapted from Kitahata et al, New Eng J Med 2009 .

  24. Effect of ART on C Reactive Protein C Reactive Protein Level Adapted from Henry et al, AIDS 2004.

  25. Effect of ART Interruption on Biomarkers Change from Baseline to Month 1 SMART Study

  26. 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

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

  28. A5275 – Pilot Study of Effects of Atorvastatin on 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

  29. 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 Adapted from Bhaskaran et al, Lancet 2008.

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

  31. 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 Adapted from Bendavid et al, Ann Int Med 2009.

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

  33. 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

  34. 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

  35. 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.

More Related