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HIV 2012: You are only as YOUNG as your Immune System.. Daniel Nixon DO, PhD Associate Professor of Medicine Director – VCU HIV/AIDS Center Director –

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Presentation on theme: "HIV 2012: You are only as YOUNG as your Immune System.. Daniel Nixon DO, PhD Associate Professor of Medicine Director – VCU HIV/AIDS Center Director –"— Presentation transcript:

1 HIV 2012: You are only as YOUNG as your Immune System.. Daniel Nixon DO, PhD Associate Professor of Medicine Director – VCU HIV/AIDS Center Director – VCU HIV/AIDS Center (http://www.hivcenter.vcu.edu/) Office

2 HIV…we now know where it came from and when (slide from Paul Sharps 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, > 500 VL>5KVL>10K VL>5K <200 CD

6 Guidelines 2012: When to Start ART Guideline HIV with symptoms or Hep B/C Asymptomatic/No Hepatitis – CD4 < DHHS Mar2012 Yes Yes (mod Rec) IAS- USA Yes BHIVA Feb2012 Yes Defer EACS Oct2011 Yes Concider WHOYes 1 Yes No 1 initiate at any CD4 if Hep B or active TB Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents -

7 Conflicting Evidence from Observational Studies for Initiating ART with CD4 > 350 Comparison CD4+ count strata HR for death NA ACCORD <350 vs ( ) vs > (1.4 – 2.8) ART CC vs ( ) vs ( ) HIV-Causal350 vs ( ) 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 Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001) Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD (HR=2.6) compared to 350 cells/mm 3 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 CD 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/mm 3 (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 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 DC GroupVS Group HR (DC/VS) Deferred vs. Early P-valueNRate 95% CI OD or death [1.5, 13.2]0.009 OD fatal or non-fatal [1.2, 15.8]0.02 Serious non-AIDS [1.6, 31.5]0.01 Composite 21* [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 Index case randomized to IMMEDIATE ART vs DEFERRED ART –Deferral until CD4 count drops to < 250 cells/mmor 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/mm 3 Early ART Group Initiate ART immediately following randomization N=2,000 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,000

13 What to Start 2012: DHHS Initial ART Recs NNRTI based Efavirenz 1 + Tenofovir/Emtricitibine (TDF/FTC) daily Protease-Inhibitor based Atazanvir or Darunavir with low dose Ritonavir boosting agent+ TDF/FTC daily Integrase Inhibitor based Raltegravir bid + TDF/FTC daily Pregnant Women Lopinavir/Ritonavir bid + AZT and Lamiviudine bid 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.. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. March 29, FDA drug safety communication, March 1, 2012, StatinsInteracting Protease Inhibitor Prescribing recommendation AtorvastatinTipranavir/r Lopinavir/r Darunavir/r Fosamprenavir Fosamprenavir/r Saquinavir/r Nelfinavir Avoid concurrent administration Use with caution and lowest dose Do not exceed 20 mg atorvastatin Do not exceed 40 mg atorvastatin FluvastatinNo data available Lovastatin/SimvastatinContraindicated PitavastatinAtazanavir/r Darunavir/r Lopinavir/r No dose limitations PravastatinDarunavir/r Lopinavir/r No dose limitions RosuvastatinAtazanavir/r Lopinavir/r Do not exceed 10mg Statins

15 Survival Trends in HIV-infected Patients Have Changed Since the Adoption of HAART Lohse N, et al. Ann Int Med 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) Survival From Age 25 Years Age (years) Probability of Survival Population Controls Late HAART ( ) Early HAART ( ) Pre-HAART ( )

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 No. of Patients with Events Endpoints Major CVD, hepatic or renal disease CVD Hazard Ratio (95% CI) Rate DCVS Renal (ESRD) Hepatic (Cirrhosis) Non-AIDS Malig Favors DCFavors VS Other non-AIDS death Any of the above MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin 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 Un-adjusted Adjusted MarkerOR (4 th /1 st )P-valueOR (4 th /1 st )P-value hs-CRP Amyloid A Amyloid P IL-68.3< < D-dimer12.4< < F Kuller L et al, PLoS Med 2008

21 D-dimer: Effect of ART Interruption (DC) for Participants on ART and with an HIV-RNA 400 copies/mL DC Group VS Group Baseline Month 1 Median (IQR) D-dimer (µg/mL) P<0.001 (27% increase in DC) Kuller L et al, PLoS Med 2008

22 D-dimer: Effect of ART Initiation (VS) for Participants Not on ART at Entry Stored 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) BaselineMonth 6Month 2 P<0.001P=0.002 DC Group VS Group Baker JV et al. JAIDS 2010 (22% lower for VS)

23 Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals BiomarkerOdds ratios*: 1 st vs 4 th Quartile Effect of HAARTOther HIV disease Associations D-dimer12.4 (SMART), 2.4 (FIRST) 2.6 (Phidisa) DecreasesCVD hs-CRP2.0 (SMART), 2.1 (FIRST), 3.6 (Phidisa) No decreaseCVD, OD IL-68.3 (SMART), 1.8 (FIRST), 3.8 (Phidisa), 1.5** (ACTG 384 and 5015 ) May decreaseCVD, OD sCD146.0 (SMART) UnknownMicrobial translocation 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?? I nfection 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 cells Hadrup 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 cells Hadrup 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- persons Trzonkowski P et al. Vaccine 2003 –CMV-associated changes in the immune system are predictive of early mortality among older persons Hadrup 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 by Immune 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 CHD Risk HIV Infection Antiretroviral Therapy Lipids & Lipoproteins Endothelial Injury and Inflammation Hypertension Smoking Metabolic Disease (hyperglycemia, insulin resistance, and obesity) Age Gender Family History

38 Biomarkers and Cardiovascular Disease: SMART: HDL, D-dimer, IL-6, CRP, & NT-pro-B BNP associated with CVD Baseline hsCRP (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 Peptide elevated 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. 17 th CROI 2010

39 Modulating Immune Activation: Aspirin PopulationASA dose DesignCRPIL-6TNF-α Chronic stable angina300mgPlacebo controlled -- Metabolic syndrome300mgPlacebo controlled Metabolic syndrome100mgPlacebo controlled NS Post-myocardial infarction 160mgvs. warfarin -- Diabetes (Type 2)*300/100m g Dose comparison NS* -- Healthy volunteers325mgCross-overNS Circulation 1999, Diab. Ob. Met 2008, JPP 2009, AJC 2003, AJC 2003 *Levels declined after starting aspirin but did not reach significance for either dose (n=20/arm)

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 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 A 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- –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) 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 SBP Category (mmHg): < <140 (on Rx)140 aHR for HIV uninfectedref aHR for HIV infectedref * Adjusted for age, race/ethnicity, diabetes cholesterol, smoking, HCV, BMI, renal disease, and cocain/EtOH

43 Brusselle et al. Lancet 2011

44 Macrophage Activation and HIV-Associated Pulmonary Disease Alveolar Macrophage expression 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 Crothers K et al Crothers K et al. Am J Resp Crit Care Med 2011 VA Cohort (n=100,000 matched) 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 with t-score 2.5 or 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 BiomarkerDC-armVS-armp-value for Interacti on OR (95% CI) a p-valueOR (95% CI) p- value sCD14 (x10 6 pg/ml)3.5 (1.5,8.3) (0.8,5.4) LPS (pg/ml)1.0 (0.6,1.7) (0.3,1.7) I-FABP (pg/ml)0.9 (0.4,2.1) (0.6,8.8) S rDNA (copies/ l) 0.9 (0.3,2.2) (0.2,1.4) EndoCAb (MMU/ml)1.1 (0.8,1.6) (0.5,1.4) 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 1 st /4 th 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 Activated Macrophages and T-cells produce IL-6, MMP, etc. in brain, bone, lung, liver, vasculature ~ tissue level in brain, bone, lung, liver, vasculature ~ tissue level HCV CMV Bact 16sDNA LPS CMV HIV

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 doesnt entirely halt this problem –Numerous strategies to modulate immune activation/inflammation under study

51 Take Home Points Inflammation also increased by: –Smoking: e.g. a study found that HIV - women who stopped smoking showed decreased levels of CRP, IL-6, TNF-alpha within weeks after quitting –Diet / Obesity: adipocytes are cytokine factories –Other common disease processes like diabetes Role of PCP: Managing these sources of inflammation, CVD risk reduction (e.g. BP, ASA, Statin), alcohol cessation, expanded cancer and bone density screening, helping with adherence, watch drug-drug interactions, & STD risk reduction Dont forget routine OPT-OUT HIV testing.. Inpatient, outpatient, ED

52 THANK YOU for your ATTENTION!


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