Coagulation and Morbidity in Treated HIV Infection Michael M. Lederman, MD Scott R. Inkley Professor of Medicine Case Western Reserve University
Although survival has improved, predicted life expectancy still seems shorter in the HIV+ population 1 Survival from Age 25 Years N= 3,990 Probability of Survival 0.75 0.5 0.25 Population controls Late HAART (2000 2005) Early HAART (1997 1999) 0 25 30 35 40 45 50 55 60 65 70 Age, years Pre-HAART (1995 1996) Adapted from Lohse N, et al. Ann Intern Med 2007;146:87 95
Many Age-associated Diseases Are More Common in Treated HIV Disease Than In Age-matched Uninfected Persons Cardiovascular disease Cancer (non-aids) Bone fractures/osteopenia Left ventricular dysfunction Lung Disease Liver failure Kidney failure Cognitive decline Frailty Multiple factors likely explain this increased risk, including co-morbid conditions, other exposures, ARV drug toxicity S. Deeks
Inflammation/coagulation predicts morbidity/mortality in HIV infection Interleukin-6 D-dimers C-reactive protein in SMART Kuller et al PLOS Medicine 08
NWCS 329 Nested case control study within the ACTG ALLRT cohort Cases (n=143): Virologically suppressed (VL < 400 copies/ml) ARTtreated subjects with: Non-accidental death Non-AIDS morbidity Myocardial infarction Stroke Malignancy Serious bacterial infections Controls: 2 virologically suppressed subjects matched for: Age Gender and sex Baseline CD4+ T-cells (within 50 cells/mm3) ART regimen at week 48 (PI- or ABC-containing or not) Parent study
NWCS 329 in treated HIV Infection, pre-event Soluble Markers relate to Outcome Pre-event Marker IL6 Unadjusted 2.58 (1.91-3.48) <.001** Adjusted* 2.48 (1.83-3.35) <.001** IP-10 Unadjusted 1.49 (1.16-1.91) 0.002** Adjusted* 1.42 (1.10-1.84) 0.007** stnfr-i stnfr-ii Unadjusted 1.99 (1.49-2.66) <.001** Adjusted* 1.94 (1.45-2.60) <.001** Unadjusted 1.88 (1.44-2.46) <.001** Adjusted* 1.81 (1.38-2.38) <.001** Soluble CD14 D-Dimer Unadjusted 1.74 (1.29-2.35) <.001** Adjusted* 1.67 (1.23-2.27) <.001** Unadjusted 2.41 (1.78-3.27) <.001** Adjusted* 2.38 (1.75-3.25) <.001** CD8+ %DR+38+ Odds Ratio per 1 IQR increase Unadjusted 1.06 (0.88-1.28) 0.516 Adjusted* 0.98 (0.80-1.20) 0.863 *Adjusted by CD4 count 0.50 1.00 4.00 Similar findings by Hunt et al JID 14 P Value OR for: Death CA MI/Stroke 20.9** 3.1** 2.2** 19.9** 2.9** 2.1** 1.9 1.7* 1.7* 1.8 1.5 1.7* 3.3** 2.3** 2.1** 3.3* 2.2** 2.1** 2.6** 2.1** 1.9** 2.9** 1.9* 2* 2.7* 1.5 1.7 2.8* 1.4 1.7 8.4** 3.2** 2.6** 8.1** 3.1** 2.6** 1.4 1 1 0.8 0.9 0.9 Tenorio J Inf Dis 14
Arteries are inflamed in treated HIV infection Subramanian et al JAMA 12
Monocyte subsets can be identified by expression of CD14 and CD16 Inflammatory Monocytes SSC FSC HIV- migg1 migg2b Traditional Monocytes HIV+ Patrolling Monocytes CD16 CD14 Funderburg et al Blood 2012
Proportions of inflammatory and patrolling monocytes are increased in HIV disease Traditional Inflammatory Patrolling Funderburg et al Blood 2012
Monocytes elaborate inflammatory mediators (IL-6, TNF, IL-18, IL-1b, IL-10) in response to microbial elements Medium alone Pam3CSK4 LPS IL-8 IL-1B IL-6 IL-10 TNF-a Nick Funderburg
Tissue Factor a cell surface protein that activates the Extrinsic Coagulation Pathway Cell surface Goodsell The Oncologist 2006
Microbial Products may drive coagulation via induction of the procoagulant Tissue Factor on Monocytes No Stim LPS 20ng Flagellin 1ug 10.1 57.7 78.1 Tissue Factor TF MFI 331 1194 2336 Funderburg et al Blood 10
Inflammatory and Patrolling monocytes are enriched for the procoagulant Tissue Factor in HIV infection and in uninfected persons with Acute Coronary Syndromes %TF+ HIV- HIV+ <400c/mL HIV+ >400c/mL Cardio CTRLs ACS Patients Traditional Inflammatory Patrolling Funderburg et al Blood 2012
Like LPS, oxidized LDL (but not LDL) alters inflammatory profiles of blood monocytes No Stim LPS LDL oxldl CD16 CD14 David Zidar, Nick Funderburg, unpublished
Like LPS, oxidized LDL (but not LDL) increases Tissue factor expression on blood monocytes *** % Tissue Factor *** * *** *** *** No Stim LPS LDL oxldl No Stim LPS LDL oxldl No Stim LPS LDL oxldl Classical (CD14+CD16-) Inflammatory (CD14+CD16+) Patrolling (CD14dimCD16+) David Zidar, Nick Funderburg
Plasma levels of oxldl are increased in HIV infection oxldl (u/ml) HIV- HIV+ <400c/mL HIV+ >400c/mL Cardio CTRLs ACS Patients Zidar, Funderbug et al Ox LDL - correlated to scd14, TF levels on patrolling monocytes and Framingham Risk
CD8 T cell homeostasis in HIV infection CD8 T cell expansion is characteristic of untreated HIV infection -and often persists after ART These are matured effector cells, often senescent and exhausted yet capable of robust inflammatory cytokine expression In setting of ART, expanded CD8 T cells are not HIVreactive Drivers of persistent CD8 T cell expansion in this setting are not defined CD8 T cell expansion and resultant low CD4/CD8 ratios predict morbid outcomes in treated HIV infection (Serrano-Villar et al PLOS One 13, Lee et al JID 14, Serrano-Villar PLOS Pathogens 14)
Even with complete virologic control and CD4 T cell restoration, CD8 T lymphocytosis persists for many years Mann-Whitney p=<0.0001 Carey Shive,, JC Mudd unpublished
Do CD8 T cells contribute to the development of atherosclerotic plaque? Activated CD8+ T cell numbers in blood linked to atherosclerotic plaque in treated HIV infection (Kaplan 11, Longenecker 12) And are found within them (Grivel 11)
Circulating CD8 T cells exclusively express CX3CR1 or CCR7 CX3CR1 CD3 JC Mudd, unpublished
CD8 T cells expressing CX3CR1 are relatively (and absolutely) expanded in treated HIV infection Healthy control CX3CR1 Treated HIV+ Healthy control Treated HIV+ CCR7 JC Mudd, unpublished
CX3CR1+ CD8 T cells are enriched for protease activated receptor (PAR-1) expression and PAR-1+ cells are increased in treated HIV-infection CD3+CD8+CCR7+ CX3CR1 16.6% CD3+CD8+CX3CR1+ HIV- Treated HIV+ 52.0% Par-1 CCR7+ CX3CR1+ PAR-1 is cleaved and activated by Thrombin
Coagulation driven by activated monocytes may recruit and activate CX3CR1+ PAR-1+ CD8 T cells at endothelial surfaces
Summary Persons with HIV infection are at increased risk for cardiovascular and other morbidities of aging: this risk is predicted by indices of coagulation and inflammation Monocyte subsets are inflammatory and procoagulant in HIV infection; this phenotype may be driven by microbial products translocated from the damaged gut and by inflammatory lipids Mature CD8 T cell numbers are expanded in HIV infection, home to endovascular sites and are linked to ART-era cardiovascular morbidities. Coagulation and inflammation collaborate to drive increased CVD risk in treated HIV infection.
Dramatis Personae: CWRU: Nick Funderburg Scott Sieg Benigno Rodriguez Carey Shive JC Mudd Marie Ebner Souheil Younes Clifford Harding Chris Longenecker Grace McComsey David Zidar Brian Clagett Ben Kyi Janet Robinson The NWCS 329 Team: Allan Tenorio Benigno Rodriguez Steven Deeks Alan Landay Ron Bosch Peter Hunt Evelyn Zheng Supriya Krishnan Arjun Seth The AIDS Clinical Trials Group AI 076174 The Fasenmyer Foundation
The Bad Boys of Cleveland E.Haddad G. Hardy A. Levine B. Rodriguez J. Estes R. Bosch S. Sieg J Tilton J. Brenchley S. Deeks A. Tenorio Not shown: I. Sereti N. Sandler M. Carrington N. Klatt W. Jiang T. Schacker C. Harding M. Lederman L. Margolis M. Paiardini D. Douek Z. Grossman G. Silvestri R. Kalayjian N. Funderburg R. Sekaly A. Landay P. Hunt