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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 (http://www.hivcenter.vcu.edu/) [email protected] Office 804-828-4510 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 “Rumble in the Jungle” Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010 > 500 VL>5K VL>10K 350-500 VL>5K VL>5K 200-350 <200 CD4 1996 1998 2000 2002 2004 2006 2008 2010 Guidelines 2012: When to Start ART Guideline HIV with symptoms or Hep B/C Asymptomatic/No Hepatitis – CD4 <200 200-350 350-500 DHHS Yes Yes Yes Yes (mod Rec) IAS-USA Yes Yes Yes Yes BHIVA Yes Yes Yes Defer EACS Yes Yes Yes Concider WHO Yes1 Yes Yes No Mar2012 Feb2012 Oct2011 1initiate at any CD4 if Hep B or active TB Guidelines for the Use of Antiretroviral Agents in HIV-1Infected Adults and Adolescents - www.aidsinfo.nih.gov Conflicting Evidence from Observational Studies for Initiating ART with CD4 > 350 Comparison CD4+ count strata HR for death NA ACCORD <350 vs 350-500 350-500 vs > 500 1.7 (1.3 - 2.3) 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) 350 vs 500 1.0 (0.8-1.2) HIV-Causal • Kitahata MM et al, N Engl J Med 2009 • When to Start Consortium, Lancet 2009 • HIV Causal Collaboration, Annals Int Med, 2011 CD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery • 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-AIDSrelated causes Median CD4+ cell count • 1,378 Patients at 10 US Clinics followed From 1996-2007 Palella F, et al. 17th CROI, 2010 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). Continuous ART at CD4> 350 associated with decreased serious nonAIDS Events in Subset of “relatively” Naïve to ART in SMART N Rate HR (DC/VS) VS Group Deferred vs. Early N Rate 95% CI P-value 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 • Composite 21* 7.0 5 1.3 5.1 [1.9, 13.5] 0.001 DC Group • OD or death Emery et al, JID, April 2008 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!! START Study HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3 Early ART Group Deferred ART Group Initiate ART immediately following randomization Defer ART until the CD4+ count declines to < 350 cells/mm3 or AIDS develops N=2,000 N=2,000 What to Start 2012: DHHS Initial ART Recs NNRTI based Protease-Inhibitor based Integrase Inhibitor based Pregnant Women • Efavirenz1 + Tenofovir/Emtricitibine (TDF/FTC) daily • Atazanvir or Darunavir with low dose Ritonavir “boosting agent”+ TDF/FTC daily • Raltegravir bid + TDF/FTC daily • 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. HIV drugs and especially protease inhibitors have many Interactions.. Statins Interacting Protease Inhibitor Prescribing recommendation Atorvastatin Tipranavir/r Avoid concurrent administration Lopinavir/r Use with caution and lowest dose Darunavir/r Fosamprenavir Fosamprenavir/r Saquinavir/r Do not exceed 20 mg atorvastatin Statins Nelfinavir Do not exceed 40 mg atorvastatin Fluvastatin No data available Lovastatin/Simvastatin Contraindicated Pitavastatin Atazanavir/r Darunavir/r Lopinavir/r No dose limitations Pravastatin Darunavir/r Lopinavir/r No dose limitions Rosuvastatin Atazanavir/r Lopinavir/r Do not exceed 10mg 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 Patients Have Changed Since the Adoption of HAART Survival From Age 25 Years Probability of Survival 1 0.75 Population Controls 0.5 Late HAART (2000-2005) 0.25 Early HAART (1997-1999) Pre-HAART (1995-1996) 0 25 30 35 40 45 50 55 60 65 70 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 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% In addition to reducing AIDS/Death, ART reduces serious Non-AIDS Outcomes No. of Patients Rate with Events DC VS Endpoints Hazard Ratio (95% CI) Major CVD, hepatic or renal disease CVD+ 104 1.8 1.1 1.7 79 1.3 0.8 1.6 Hepatic (Cirrhosis) 17 0.3 0.2 Renal (ESRD) 11 0.2 0.1 Non-AIDS Malig++ 47 0.8 0.5 Other non-AIDS death 51 0.9 0.5 186 3.2 2.0 Any of the above + MI (clinical or silent), stroke, surgery for CAD ++ Except non-melanoma skin 0.1 1.4 4.5 1.4 1.8 1.6 1 10 Favors DC Favors VS The SMART Study Group. N Engl J Med 2006 INFLAMMATION?? Inflammatory Biomakers are Elevated with HIV (SMART) compared to non-HIV (MESA) Neuhaus J et al. JID 2010 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 Baseline Biomarkers and All Cause Mortality Adjusted Un-adjusted OR (4th/1st) P-value OR (4th/1st) P-value hs-CRP 2.0 0.05 3.1 0.02 Amyloid A 2.2 0.07 3.1 0.05 Amyloid P 0.7 0.39 1.1 0.78 IL-6 8.3 <0.0001 12.4 <0.0001 D-dimer 12.4 <0.0001 41.2 <0.0001 F1.2 1.0 0.92 1.3 0.64 Marker Kuller L et al, PLoS Med 2008 D-dimer: Effect of ART Interruption (DC) for Participants on ART and with an HIV-RNA ≤ 400 copies/mL 0.8 DC Group Median (IQR) D-dimer (µg/mL) VS Group P<0.001 (27% increase in DC) 0.6 0.4 0.2 0 Baseline Month 1 Kuller L et al, PLoS Med 2008 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) DC Group Median (IQR)D-dimer (µg/mL) 1 VS Group P=0.002 P<0.001 0.5 (22% lower for VS) 0 Baseline Month 2 Baker JV et al. JAIDS 2010 Month 6 Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals Biomarker Odds ratios*: 1st vs 4th Quartile Effect of HAART Other HIV disease Associations D-dimer 12.4 (SMART), 2.4 (FIRST) 2.6 (Phidisa) Decreases CVD hs-CRP 2.0 (SMART), 2.1 (FIRST), 3.6 (Phidisa) No decrease CVD, OD IL-6 8.3 (SMART), 1.8 (FIRST), 3.8 (Phidisa), 1.5** (ACTG 384 and 5015 ) May decrease CVD, OD sCD14 6.0 (SMART) Unknown Microbial translocation • While HAART partially reduces some biomarker levels, they still remain elevated compared with healthy non-HIV infected individuals 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 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 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 “Inflamm-aging” - Francesch C. et al. Ann NY Acad Sc 2000 De Martinis M et al. Exp and Mol Path 2006 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 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 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) 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) 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 CMVspecific T cells Hadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005 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 CMVspecific 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 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 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) 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 CHD Risk Factors: Traditional and HIV-specific Age Gender HIV Infection Antiretroviral Therapy Family History Smoking CHD Risk Hypertension Lipids & Lipoproteins Metabolic Disease (hyperglycemia, insulin resistance, and obesity) Endothelial Injury and Inflammation 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 Ddimer 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. 17th CROI 2010 Modulating Immune Activation: Aspirin Population ASA dose Design CRP IL-6 TNF-α Chronic stable angina 300mg Placebo controlled -- Metabolic syndrome 300mg Placebo controlled Metabolic syndrome 100mg Placebo controlled NS NS Post-myocardial infarction 160mg vs. warfarin -- Diabetes (Type 2)* 300/100m Dose g comparison NS* NS* -- Healthy volunteers 325mg NS NS NS Cross-over *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 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 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 GTPbinding 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 AMI rate per 10,000 p-y MI Rates by SBP & HIV Status in VACS 1000 HIV(-) HIV(+) 800 600 400 200 0 <120 120-124 125-129 130-134 135-139 140-144 145-149 150-154 155-159 >160 . Systolic BP (mmHg) <120 120-139 <140 (on Rx) ≥140 aHR for HIV uninfected ref 1.1 1.2 1.4 aHR for HIV infected ref 1.7 2.8 2.8 SBP Category (mmHg): * Adjusted for age, race/ethnicity, diabetes cholesterol, smoking, HCV, BMI, renal disease, and cocain/EtOH Armah & Freiberg CROI 2012 Brusselle et al. Lancet 2011 Macrophage Activation and HIV-Associated Pulmonary Disease VA Cohort (n=100,000 matched) • 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 • Crothers K et al. Am J Resp Crit Care Med 2011 HIV and Matrix MP co-localize to areas of empysema at autopsy Yearsly MM et al. Diag Mol Path 2005 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 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 -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 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) Biomarker DC-arm VS-arm p-value for Interacti on OR (95% CI)a p-value OR (95% CI) pvalue sCD14 (x106 pg/ml) 3.5 (1.5,8.3) 0.004 2.0 (0.8,5.4) 0.15 0.43 LPS (pg/ml) 1.0 (0.6,1.7) 0.96 0.7 (0.3,1.7) 0.40 0.63 I-FABP (pg/ml) 0.9 (0.4,2.1) 0.84 2.3 (0.6,8.8) 0.19 0.58 16S rDNA (copies/l) 0.9 (0.3,2.2) 0.90 0.5 (0.2,1.4) 0.21 0.26 EndoCAb (MMU/ml) 1.1 (0.8,1.6) 0.49 0.9 (0.5,1.4) 0.66 0.57 Sandler N. et al J. Infect Dis. 2011 Model of HIV induced “Aging” Desai S and Landay A Curr HIV/AIDS Rep 2010 Model of VIRAL induced “Aging” CMV HCV CMV LPS HIV Bact 16sDNA Activated Macrophages and T-cells produce IL-6, MMP, etc. in brain, bone, lung, liver, vasculature ~ tissue level 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 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 • Don’t forget routine OPT-OUT HIV testing.. Inpatient, outpatient, ED THANK YOU for your ATTENTION!