Maile A. Karris, MD, of the UC San Diego AntiViral Research Center, presents "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

10.  206 persons experienced SNA/death
 36% cancer 26% CVD 8% hepatic 3% renal 27% death/ot

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

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

33.  Switch to
Raltegravir was
accompanied by
significant decreases
in sCD14

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