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CROI Update: What's New with HIV Associated Immune Activation
1. 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
2. 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
3. What we will cover today
HIV Immune Activation
Why does it matter?
Can we do anything about it?
What about ART choices?
4. 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
5. 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
6. The main contributor to this observed increase risk
of non-AIDS events is thought to be persistent
immune activation
7. Soluble Markers of Inflammation & Coagulation,
but not T-Cell Activation, Predict Non-AIDS-
Defining Events During Suppressive ART
TenorioA, Zheng E, Bosch R, Deeks S, Rodriguez B, Krishnan S, Hunt P,Wilson C, Leerman M,
LandayA andACTG
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 ofART
+ Maintained HIV RNA < 400 c/mL
143 Cases and 315 Controls
Evaluated multiple markers of IA
T cell, and soluble markers 790
8. 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 despiteART
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
9. 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
12. 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
13. 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
ImmunophenotypedT cells and monocytes
SESSION 10 ORAL ABSTRACTS #66LB
14. Short time progression in Coronary atherosclerosis was
predicted by higher frequence of CD16+ monocytes
No associations present between CD4 or CD8T ell
phenotypes or immune depletion (total CD4T cell count)
Suggest ongoing innate IA may be a proximal mechanism and
subsequently possible therapeutic target in the pathogenesis
of HIV-related CAD
15.
16. 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, LuqueA, Deeks S, Bosh R.
Evaluate the impact of age, CD4 and CD8T-cell
activation on AIDS and NAE during
suppressive ART
1025ART naïve who were had HIV RNA < 200 cp/mL at
1 yr ofART
CD8+T cell activation (% CD38+HLA-DR+), CD4
counts, and age as predictors of NAE or AIDS 2-5 years
fromART
793
17. 94 subjects had events in years 2-5
12AIDS defining 82 nonAIDS defining = 13% probability
18. Older HIV infected persons are at significantly icnreased
risk of clinical events compared to younger subjects
19. 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 infectedT cells
Replication induced by
- HIV
- Immunosuppression
- Cytokines
-Loss of GALT CD4T cells
-Local cytokine release damages gut epithelials
-Collagen deposition
20. 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)
21. 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 haveAE
22. The Effect of Statins on Immune Activation and
Inflammation in HIV-Infected Subjects on ART
McComsey G, JiangY, 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
StableART 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
23. Changes in the proportion of CD14dim16+TF+ and in levels of sCD14
and lipoprotein associated phospholipase A2
CD14dimcd16+TF+
sCD14+
Lp-PLA2
24. 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
25. 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
26. 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?
27. 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, LeonA, Gatell J, SorianoV, 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
withTDF/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
28. 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
29. Early Changes in Adhesion Molecules Expression
and Endothelial Function in Patients Initiating
ART with Atazanavir or Lopinavir
BanderaA,Trabattoni D, Squillace N, MuscatelloA, Calascibetta F, MaolbertiA, Giannattasio C,
MarcandalliV, 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
30. No difference between study arms was observed for
Changes in proportions ofT cell subsets
Decreases in cell surface activation markers onT
cells and monocytes
Did observe that persons on atazanavir demonstrated a
“particularly strong” increase in the expression of
CD11a on CD4+T-cells
31. 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
32. 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, HulganT,Wanke C, MangiliA,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 HIVVL < 50 copies/mL
On NNTRI or PI based regimen
Evaluated sCD14, sCD164,TNFRII, I-FABP,TNF-a
34. Other changes observed include significant increases in
expression ofTNF-alpha andTNFRII
35. 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
36. 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
37. Conclusions on HIV IA
What aboutART choices?
ART choices may impact IA, but more
extensive studies are necessary
38. 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 andThreats toART Success
WEDNESDAY
-Themed Discussion 49: Inflammatory Biomarkers,
Microparticles and Clinical Outcomes