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