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Maile A. Karris, MD, of the UC San Diego AntiViral Research Center, presents "CROI Update: What's New with HIV Associated Immune Activation"
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The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
Maile Karris, MD
Check out Sharon Lewin’s CROI 2013 webcast “ART and Inflammation: Implications for the Approach to Care in 2013”
Original presentation: Tuesday March 5
Update from CROI 2013: HIV and Immune Activation
What we will cover today
HIV Immune Activation Why does it matter? Can we do anything about it? What about ART choices?
HIV Immune Activation?
HIV is characterized not only by immunodeficiency but also by generalized persistent immune activation
Adaptive immunity (T cells, B cells) Innate immunity (APCs, NKs) Coagulation cascade
Why does it matter? HIV infected persons experience more non-AIDS
associated events than HIV negative peers Even after adjustments for age, ART exposure and traditional
risk factors
The main contributor to this observed increase risk of non-AIDS events is thought to be persistent immune activation
Soluble Markers of Inflammation & Coagulation, but not T-Cell Activation, Predict Non-AIDS-Defining Events During Suppressive ART
Tenorio A, Zheng E, Bosch R, Deeks S, Rodriguez B, Krishnan S, Hunt P, Wilson C, Leerman M, Landay A and ACTG
Define the associations between IA with NAE - accounting for ART and traditional RF Case-control study of ALLRT cohort ART naïve + HIV-1 RNA < 400 c/mL at week 48 of ART
+ Maintained HIV RNA < 400 c/mL 143 Cases and 315 Controls
Evaluated multiple markers of IA T cell, and soluble markers 790
Higher IL-6, sCD14, sTNFr-I, sRNFR-II, and D-dimer were associated with non-AIDS related morbidity or death Associations were present prior to ART and persisted despite ART Independent of traditional risk factors
Controls had higher median CD4+ T cell change one year on ART than cases
A greater CD4+ T cell change at one year was associated with decreased risk for non-AIDS related outcome
Association of biomarkers and odds of SNAE BASELINE ONE-YEAR PRE-EVENT
Combined Effect of IL-6 and D-dimer on the risk of Serious Non-AIDS Conditions
Grund B, Baker J, Deeks S, Wolfson J, Wentworth D, Cozzi-Lepri A, Cohen C, Phillips A, Lundgren J, Neaton J
Estimate the joint associations of IL-6 and D-dimer with the risk of composite outcome of SNA/death in treated suppressed pts
The predictive utility of using IL-6 and/or D-dimer as a markers for future candidate drugs
Data from ESPRIT, SILCAAT, SMART
SESSION 10 ORAL ABSTRACTS #60
206 persons experienced SNA/death 36% cancer 26% CVD 8% hepatic 3% renal 27% death/ot
The IL-6 & d-dimer score could be used to compare drugs with different mechanisms of action (targeting IL-6, d-dimer, or both) for their potential to reduce SNA/death
Monocyte Activation but not T cell Activation Predicts Progession of Coronary Artery Calcium
in a Contemporary HIV Cohort (SUN) Baker J
Identify cellular phenotypes reflecting IA that predict accelerated coronary atherosclerosis
SUN study – prospective observational cohort Naïve to ART or solely exposed to combination ART
Measured changes in CAC scores Immunophenotyped T cells and monocytes
SESSION 10 ORAL ABSTRACTS #66LB
Short time progression in Coronary atherosclerosis was predicted by higher frequence of CD16+ monocytes
No associations present between CD4 or CD8 T ell phenotypes or immune depletion (total CD4 T cell count)
Suggest ongoing innate IA may be a proximal mechanism and subsequently possible therapeutic target in the pathogenesis of HIV-related CAD
The Impact of Age on the Prognostic Capacity of CD8+ T-cell Activation during Suppressive ART
Lok J, Hunt P, Collier A, Benson C, Witt M, Luque A, Deeks S, Bosh R.
Evaluate the impact of age, CD4 and CD8 T-cell activation on AIDS and NAE during suppressive ART
1025 ART naïve who were had HIV RNA < 200 cp/mL at 1 yr of ART
CD8+ T cell activation (% CD38+HLA-DR+), CD4 counts, and age as predictors of NAE or AIDS 2-5 years from ART
793
94 subjects had events in years 2-5 12 AIDS defining 82 non AIDS defining = 13% probability
Older HIV infected persons are at significantly icnreased risk of clinical events compared to younger subjects
What Causes HIV IA?
Immune Activation
Low level HIV
replication
Microbial Translocation
Co-infection with other viruses
- Incomplete drug penetration into compartments - Suboptimal HAART - Intermittent activation of latently infected T cells
Replication induced by - HIV - Immunosuppression - Cytokines
-Loss of GALT CD4 T cells -Local cytokine release damages gut epithelials -Collagen deposition
What can we do about it? Treating immune activation Immunosuppressive drugs Ongoing HIV Replication - treatment
intensification Co-infections – treatment of co-infections Microbial translocation
Drugs that specifically impact known biomarkers
associated with NAE (d-dimer, IL-6, sCD14 etc)
Statin Use in HIV Known to reduce CV and plaque regression Decreased inflammation (CRP) Decreased pro-inflammatory monocyte subsets in
animal models Significantly beneficial survival ratio in persons
on statins with HIV (longitudinal cohort study)
But statins have AE
The Effect of Statins on Immune Activation and Inflammation in HIV-Infected Subjects on ART McComsey G, Jiang Y, Debanne S, Clagett B, Robinson J, Labbato D, Storer N, Lederman M,
Funderburg N.
To assess the effect of 24 weeks of statin on systemic and vascular inflammation and in monocyte and lymphocyte IA in HIV + on ART
146 participants enrolled in a RCCT of rosuvastatin Stable ART with HIV-1 RNA < 1,000 copies/mL CD8+CD38+HLA-DR+ > 19% or hsCRP > 2 mg/L LDL < 130 mg/dL
Measured soluble IA markers, vascular inflammation, monocyte and lymphocyte activation markers 186LB
Changes in the proportion of CD14dim16+TF+ and in levels of sCD14 and lipoprotein associated phospholipase A2
CD
14 d
im c
d16+
TF
+
sC
D14
+
Lp-
PLA
2
Impact of Statin Exposure on Mortality and Non-AIDS Complications in HIV Patients on HAART
Drechsler H, Zhang S, Maalouf N, Cutrell J, Tebas P, Bedimo R.
Evaluate the impact of cumulative exposure of statins on death or NAE in a clinical cohort
VA Clinical Case Registry to find persons on HAART < 14 days (1995-2009) Analyzed all persons on HAART (n = 25,884) and those
who were suppressed within 18 weeks (n = 15,936)
Looked at occurrence of death, CVA, MI, malignancy, fragility fractures 765
Cumulative exposure to statins was associated with a signficant reduction in all-cause mortality in virologically suppressed persons
The effect size was larger with exposure to atorvastatin and rosuvastatin
Does ART matter? ART regimens historically evaluated on their
ability to suppress viremia and CD4+ T-cell recovery
ART regimens are also evaluated by their toxicities
So are certain ART regimens “better” at decreasing HIV associated IA?
cART-Induced Immunological Function Restoration is Independent of the cART Regimen and is not
Correlated with the Extent of CD4 Gains Rallon N, Torres B, Diaz Al, Alos L, Martinez E, Leon A, Gatell J, Soriano V, Garcia F, Benito J.
Assess the impact of LPV/r vs EFV on parameters of immune function in a RCCT
50 naïve participants randomized to LPV/r or EFV with TDF/FTC , 22 underwent evaluation of immune parameters
Evaluated persons at baseline and week 48 for CD4 and CD8 subsets, activation, recent thymic emigration, senescence, exhaustion and apoptosis
310
The use of either LPV/r or EFV did not alter levels of cellular IA
It is unclear if the differential changes that were observed are of clinical significance
Early Changes in Adhesion Molecules Expression and Endothelial Function in Patients Initiating
ART with Atazanavir or Lopinavir Bandera A, Trabattoni D, Squillace N, Muscatello A, Calascibetta F, Maolberti A, Giannattasio C,
Marcandalli V, Clerici M, Gori A.
Does treatment with ATZ versus KAL differentially impact immune or metabolic parameters
Prospective randomized study of 30 naïve participants 200 < CD4 < 500/uL No CVD,OI or tx with immunomodulant agents
Evaluated clinical, lipid, and immune parameters and indices of endothelial structure, function and arterial stiffness
752
No difference between study arms was observed for Changes in proportions of T cell subsets Decreases in cell surface activation markers on T
cells and monocytes Did observe that persons on atazanavir demonstrated a
“particularly strong” increase in the expression of CD11a on CD4+ T-cells
ART with either atazanavir or lopinavir did not impact intima mediat thickness, or pulse wave velocity by week 24
However there was a trend to decreased arterial diameter in the atazanavir arm compared to lopinavir
Soluble CD14 Declines in Virologically Suppressed Women Switching from PI or NNRTI to Raltegravir: The Women, Integrase and Fat Accumulation Trial
794
Lake J, McComsey G, Hulgan T, Wanke C, Mangili A, Walmsley S, Boger M, Stramotas S, Currier J.
Describe changes in markers of microbial translocation and monocyte activation during ART regimen switches
48 week study HIV women who switch to RAL at week 0 or week 24 with central adiposity HIV VL < 50 copies/mL On NNTRI or PI based regimen
Evaluated sCD14, sCD164, TNFRII, I-FABP, TNF-a
Switch to Raltegravir was accompanied by significant decreases in sCD14
Other changes observed include significant increases in expression of TNF-alpha and TNFRII
Conclusions on HIV IA Why does it matter? SNAE are associated with abnormalities in innate
immune markers Steps are being made to attempt to come up with a
marker or score that in the future may assist clinicians in identifying which of their patients are at most risk for SNAE
As our patients are living longer, we need to be more vigilant about prevention of known risk factors for SNAE
Conclusions on HIV IA Can we do anything about it? Support is growing for the use of statins in our
population but the recommendation is not there yet Stay tuned for CROI 2014 and beyond
Conclusions on HIV IA What about ART choices? ART choices may impact IA, but more
extensive studies are necessary
CROI 2013 PODCASTS MONDAY - Themed Discussion 16: Statin Use and HIV: How Sweet Is It? - Oral Abstracts Session 19: CVD and other Non-AIDS Events
Epidemiology and Pathogenesis TUESDAY - Symposia: Opportunities and Threats to ART Success WEDNESDAY - Themed Discussion 49: Inflammatory Biomarkers,
Microparticles and Clinical Outcomes
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