HIV 2012 : You are only as YOUNG as your Immune System..

1. HIV2012: You are only as YOUNG as your Immune System.. Daniel Nixon DO, PhD Associate Professor of Medicine Director – VCU HIV/AIDS Center (http://www.hivcenter.vcu.edu/) dnixon@mcvh-vcu.edu Office 804-828-4510

2. HIV…we now know where it came from and when(slide from Paul Sharp’s 2006 CROI lecture) When? Between ~ 1884 and 1924 Nature. Oct 2, 2008

3. “Rumble in the Jungle”

4. Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases

5. Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010

6. Guidelines 2012: When to Start ART Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents - www.aidsinfo.nih.gov 1initiate at any CD4 if Hep B or active TB

7. Conflicting Evidence from Observational Studies for Initiating ART with CD4 > 350 Comparison CD4+ count strata HR for death NA ACCORD <350 vs 350-500 1.7 (1.3 - 2.3) 350-500 vs > 500 1.9 (1.4 – 2.8) ART CC 251-350 vs 351-450 1.1 (0.8 - 1.6) 351-450 vs 451-550 0.9 (0.6 - 1.4) HIV-Causal 350 vs 500 1.0 (0.8-1.2) • Kitahata MM et al, N Engl J Med 2009 • When to Start Consortium, Lancet 2009 • HIV Causal Collaboration, Annals Int Med, 2011

8. CD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery • 1,378 Patients at 10 US Clinics followed From 1996-2007 • Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001) • Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD4 50-199 (HR=2.6) compared to 350 cells/mm3 • Lower baseline CD4 at initiation also associated with increased risk of death from non-AIDS-related causes Median CD4+ cell count Palella F, et al. 17th CROI, 2010

9. Evidence from Randomized Trials for Initiating Treatment at CD4 200-350 • CIPRA-HT001– a single center trial in Haiti • 2/3 of patients were clinical stage 2 or 3 and the median CD4+ count at initiation in the deferred ART group was 166 cells/mm3 (IQR: 130, 190). • SMART study - post-hoc analysis • Only involved 477 patients and of these only 249 were ART-naïve. • HPTN 052 • Deferral strategy was 200-250 cells; significant difference in extrapulmonary TB; not powered to address survival (10 versus 13 deaths).

10. Continuous ART at CD4> 350 associated with decreased serious non-AIDS Events in Subset of “relatively” Naïve to ART in SMART HR (DC/VS) Deferred vs. Early DC Group VS Group N Rate N Rate 95% CI P-value • OD or death 15 4.8 4 1.1 4.4 [1.5, 13.2] 0.009 • OD fatal or non-fatal 11 3.5 3 0.8 4.4 [1.2, 15.8] 0.02 • Serious non-AIDS 12 3.9 2 0.5 7.1 [1.6, 31.5] 0.01 • Composite21* 7.0 5 1.3 5.1 [1.9, 13.5] 0.001 Emery et al, JID, April 2008

11. HPTN 052:ART prevents HIV transmission • 1763 discordant couples (one HIV-infected partner) • Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, Zimbabwe (+ single US couple) • CD4 count at entry: 350 – 550 cells/mm䔡 • Index case randomized to IMMEDIATE ART vs DEFERRED ART • Deferral until CD4 count drops to < 250 cells/mm䔡or disease • RESULTS: • 1 new HIV infection in partners of those on ART • 27 new HIV infections in partners of those deferring ART • 96% efficacy of ART to prevent transmission in this population!!

12. START Study HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3 Early ART Group Initiate ART immediately following randomization N=2,000 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm3 or AIDS develops N=2,000

13. What to Start 2012: DHHS Initial ART Recs 1. EFV NOT to be used during the 1st trimester of pregnancy or in women who are not using effective and consistent contraception.

14. HIV drugs and especially protease inhibitors have many Interactions.. Statins Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. March 29, 2012. www.aidsinfo.nih.gov. FDA drug safety communication, March 1, 2012, www.fda.gov

15. Survival Trends in HIV-infected Patients Have Changed Since the Adoption of HAART Survival From Age 25 Years 1 0.75 Population Controls 0.5 Probability of Survival Late HAART (2000-2005) 0.25 Early HAART (1997-1999) Pre-HAART (1995-1996) 0 30 55 40 25 45 50 70 35 60 65 Age (years) Cumulative survival curve for HIV-infected persons (without hepatitis C coinfection) and persons from the general population. N=383,862 (HIV-infected patients, n=3990; General population controls, n=379,872) Lohse N, et al. Ann Int Med. 2007

16. HIV - the Good News & the Bad • Antiretroviral drugs have tripled average life expectancy over the last decade, by reducing opportunistic infections, however: • In ART era only ~10% deaths in HIV infected clinical trials subjects were due to AIDS defining illnesses. Non-AIDS malig ~ 21% CVD ~ 9% Liver Disease ~ 9% Non-AIDS Infection ~8%

17. In addition to reducing AIDS/Death, ART reduces serious Non-AIDS Outcomes Hazard Ratio (95% CI) No. of Patients with Events Rate Endpoints DC VS Major CVD, hepatic or renal disease 1041.81.1 1.7 CVD+ 79 1.30.8 1.6 Hepatic (Cirrhosis)17 0.30.2 1.4 Renal (ESRD) 11 0.20.1 4.5 Non-AIDS Malig++ 47 0.80.5 1.4 Other non-AIDS death 51 0.90.5 1.8 Any of the above 1863.22.0 1.6 + MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin Favors DC Favors VS The SMART Study Group. N Engl J Med 2006

18. INFLAMMATION??Inflammatory Biomakers are Elevated with HIV(SMART) compared to non-HIV (MESA) Neuhaus J et al. JID 2010

19. SMART Nested Case Control Biomarker Study (85 cases/170con) Conditional logistic used to estimate ORs for mortality (lowest quartile as reference) Adjusted OR consider covariates corresponding to: age, race, ART, HIV RNA, CD4+ count, BMI, total/HDL cholesterol, smoking, diabetes, Hep B/C co-infection, use of lipid and BP lowering medication

20. Baseline Biomarkers and All Cause Mortality Kuller L et al, PLoS Med 2008

21. DC Group VS Group D-dimer: Effect of ART Interruption (DC) for Participants on ART and with an HIV-RNA ≤ 400 copies/mL P<0.001 (27% increase in DC) Median (IQR) D-dimer (µg/mL) Baseline Month1 Kuller L et al, PLoS Med 2008

22. DC Group VS Group D-dimer: Effect of ART Initiation (VS) for Participants Not on ART at EntryStored plasma for 254 subjects (126 DC arm, 128 VS arm), naïve to ART or off ART >6 mo analyzed for IL-6, hs-CRP, & D-dimer (baseline, mo 2 & 6) P=0.002 P<0.001 (22% lower for VS) Baseline Month 2 Month 6 Baker JV et al. JAIDS 2010

23. Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals • While HAART partially reduces some biomarker levels, they still remain elevated compared with healthy non-HIV infected individuals

24. But where would the inflammation be coming from??Infection destroys gut-associated lymphoid tissue within 4 weeks of infection -> Recovery is impaired, even with ART.. Brenchley JM et al J Exp Med. 2004

25. HIV-induced gut CD4+ T-cell depletion leads to LPS/microbial translocation into the circulation -> CHRONIC IMMUNE ACTIVATION Brenchley, JM et al. Nature Medicine 2006

26. Excessive CD8+T-cell stimulation and activation predicts CD4+ depletion and AIDS • CD8+ T-cell activation is predictive of HIV disease progression, independent of HIV viral load (Giorgi JV et al. JID 1999 Calbone J et al. AIDS 2000) • Patients with HIV viremia fully suppressed by ART that have blunted CD4 recovery show continued CD8+ T-cell activation (Anthony KB et al. JAIDS. 2003, Hunt PW et al. JID 2003) • Elite controllers not on ART with undetectable HIV RNA & CD4 depletion have CD8+ T-cell activation (Hunt PW et al. JID 2008) • Note: that CD8 “activation” refers to expression of cell surface markers (e.g. CD38 and HLA-DR)..in REALITY, the CD4/CD8 cells are hypoactive/anergic functionally in setting of HIV infection

27. “Inflamm-aging” - Francesch C. et al.Ann NY Acad Sc 2000 De Martinis M et al. Exp and Mol Path 2006

28. HIV and “Inflamm-aging” • HIV infection shares numerous clinical similarities w/ aging • increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty

29. HIV and “Inflamm-aging” • HIV infection shares numerous clinical similarities w/ aging • increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty • HIV infection results in T-cell activation and Immunosenescence • In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers • Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people

30. HIV and “Inflamm-aging” • HIV infection shares numerous clinical similarities w/ aging • increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty • HIV infection results in T-cell activation and Immunosenescence • In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers • Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people • HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009)

31. HIV and “Inflamm-aging” • HIV infection shares numerous clinical similarities w/ aging • increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty • HIV infection results in T-cell activation and Immunosenescence • In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers • Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people • HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009) • As with increased CD8+ T-cell activation, increased senescence (reduced CD28 expression on CD8+ & CD4+ T cells) associated with more rapid HIV disease progression (Cao W et al. JAIDS 2009)

32. CMV and “Inflamm-aging” • CMV+ adults over ~ 65y/o have a much greater expansion of CD28- cells than age-matched CMV- controls • many of these cells reflect the oligoclonal expansion of CMV-specific T cellsHadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005

33. CMV and “Inflamm-aging” • CMV+ adults over ~ 65y/o have a much greater expansion of CD28- cells than age-matched CMV- controls • many of these cells reflect the oligoclonal expansion of CMV-specific T cellsHadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005 • Clinical significance of these findings is not clear, however, it has already been shown that: • CMV+ older persons are less likely to respond to vaccines than age-matched, CMV- personsTrzonkowski P et al. Vaccine 2003 • CMV-associated changes in the immune system are predictive of early mortality among older personsHadrup SR et al. J Immuno 2006, Wikby A et al. J Gerontol 2005

34. CMV & the Swedish OCTO and NONA studies • 231/240 individuals • mean age of ~ 90 years • followed longitudinally x 4+yrs • Grouped byImmune Risk Profile . Pawelec G et al. Immuno Reviews 2005

35. T-cells are not the only problem…HIV infection Associated w/ BOTH Adaptive and Innate Immune System Activation • Excess CD4 and CD8 T-cell activation observed in patients with HIV • Increased CD8 HLA-DR/CD38 expression associated with rapid CD4 loss, impaired CD4 recovery, poor immunologic responder on ART, & accelerated immune senescence • Excess B-cell activation observed in patients w/ HIV • Hypergammaglobulinemia, Autoantibodies • Excess Platelet activation observed in patients w/ HIV • Increased expression of TF, P-selectin, sCD40 • Excess Monocyte/Macrophage activation w/ HIV • Increased expression of TF, CD14/sCD14 • NOTE: CMV infection of monocytes  differentiation to proinflammatory “M1” macrophages (Chan G et al. J Immun 2008)

36. Macrophage Activation and HIV-Associated Vascular Disease Moore KJ Cell 2011 • HIV+ persons are at 2-fold  risk for CHD “risk equivalent” • Freiberg CROI 2011

37. CHD Risk Factors:Traditional and HIV-specific Family History Age Gender HIV Infection Smoking Antiretroviral Therapy CHD Risk Hypertension Lipids & Lipoproteins Endothelial Injury and Inflammation Metabolic Disease (hyperglycemia, insulin resistance, and obesity)

38. Biomarkers and Cardiovascular Disease:SMART: HDL, D-dimer, IL-6, CRP, & NT-pro-B BNP associated with CVD • BaselinehsCRP(p<0.0001), IL-6 (p<0.0001), & D-dimer(p=0.0008) elevated in CVD cases • Total HDL(p<0.0001) was reduced in CVD cases • HDL negatively associated with D-dimer and IL-6 (R= -0.25) • N-terminal pro-B-type Natriuretic Peptideelevated in CVD (OR highest vs. lowest quartile – adjusted = 2.3, P =0.02) Duprez D.A. et al. Atherosclerosis 2009 Duprez D.A. et al. 17th CROI 2010

39. Modulating Immune Activation:Aspirin *Levels declined after starting aspirin but did not reach significance for either dose (n=20/arm) Circulation 1999, Diab. Ob. Met 2008, JPP 2009, AJC 2003, AJC 2003

40. Relative Risk of MI by baseline CRP Stratified by Aspirin (325mg QOD) versus Placebo Ridker et. al. NEJM 1997 However, A 2009 Lancet Meta-analysis of RCTs found that: Aspirin is of uncertain net value as primary prevention of vascular disease

41. Modulating Immune Activation: ACTG A5275 - Atorvastatin • Why look at statins in (non-hyperlipidemic) HIV+ patients? • Blocking HMG-CoA reductase with a statin reduces activation of GTP-binding proteins RAS and Rho - “molecular switches” that regulate transcription of inflammatory response genes • Statins inhibit expression of IL-6 (hs- CRP), TF (d-dimer), sCD14, and TNF-a • Statins decrease CD8+ T-cell activation • Statins reduce these biomarkers in numerous settings (e.g. sepsis, pneumonia, influenza, COPD, hepatocellular CA, CVD) • JUPITER Study • Rosuvastatin decreased mortality and venous thrombotic disease in subjects with hsCRP>2 mg/L and “normal” LDL (<130 mg/dl) • Individuals achieving hsCRP < 2 mg/L (entry criteria >2) had 62% decrease in events • Ridker et al. NEJM 2008, Ridker et al. Lancet 2009

42. MI Rates by SBP & HIV Status in VACS Armah & Freiberg CROI 2012

43. Brusselle et al. Lancet 2011

44. Macrophage Activation and HIV-Associated Pulmonary Disease • Alveolar Macrophageexpression of Matrix MP from HIV+ smokers w/ early emphysema >> than in HIV- smokers w/ early emphysema • Kaner RJ et al. J. Leuk Bio 2009 • HIV and Matrix MP co-localize to areas of empysema at autopsy VA Cohort (n=100,000 matched) Crothers K et al. Am J Resp Crit Care Med 2011 Yearsly MM et al. Diag Mol Path 2005

45. Macrophage Activation and HIV-Associated Bone Density Loss • HIV infection associated with an increased risk (~3X higher that HIV neg) of osteopenia, fracture, and avascular necrosis of bone • Bone is an immunologically rich tissue & activated macrophages, T-cells, osteoclasts, & inflammatory cytokines play a central role in accelerated bone loss Mansky KC Clin Interventions in Aging 2010

46. HIV and Osteopenia – Some Issues • DXA Scanning if >50 y/o (McComskey et al. CID 2010) • Quit Smoking and Drinking (>3drinks/d)! • Treat Hypogonadism or Hypothyroidism • Weight Bearing Exercise • Safe Home • Vit D – treating low Vit D (<25 ng/dl) reasonable • Efavirenz is associated with reduction in 25-hydroxy vit D levels • Limited data on vitamin D supplementation in HIV-positive patients have shown transient, beneficial effects on PTH, but no effects on BMD. • Bisphosphonates effective (6 RCTs) • Treat witht-score ≤ 2.5 or -1.0-2.5 with FRAX 10 year fracture prob score >20 (NOF 2008) • Protease Inhibitors and Tenofovir as Risks? • Avoid starting protease inhibitors if possible with t-score ≤ 2.5

47. Macrophage Activation and HIV-Associated Mortality Only sCD14 levels* (a marker of monocyte/macrophage activation) are associated with mortality among microbial translocation biomarkers *after adjustment for other risk factors/biomarkers 1st/4th OR = 4.1 (p=0.02) Sandler N. et al J. Infect Dis. 2011

48. Model of HIV induced “Aging” Desai S and Landay A Curr HIV/AIDS Rep 2010

49. Model of VIRAL induced “Aging” HCV CMV CMV LPS HIV Bact 16sDNA Activated Macrophages and T-cells produce IL-6, MMP, etc. in brain, bone, lung, liver, vasculature ~ tissue level

50. Take Home Points • Chronic antigen (HIV, LPS, CMV, HCV, etc.) stimulation leads to excessive stimulation/activation of ALL arms of the immune system • Chronic immune activation leads to an immune system more likely to cause tissue inflammation & less likely to do its job! This has implications that extend well beyond HIV! • Premature aging – senescence and hypofunction of the immune system • Progression to AIDS • End organ damage • Inflammation correlates with many bad outcomes • Treating HIV helps & should be done but doesn’t entirely halt this problem • Numerous strategies to modulate immune activation/inflammation under study