Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division

Interventions to Reduce Inflammation

and Immune Activationin Treated HIV Infection

Peter W. Hunt, MD

Assistant Professor of Medicine

UCSF HIV/AIDS Division

Treating Immune Activation in HIV• What have we learned from recent

unsuccessful attempts?

• Mechanistic pathways of HIV pathogenesis inform therapeutic interventions.

• Highlight ongoing and recently reported studies of novel interventions.

– Importance of studying ART-suppressed patients

• A way forward

What have we learned from recent unsuccessful attempts to decrease immune activation?

IL-2 Increases CD4 Counts in Treated Patients

Abrams et al, NEJM, 2009

IL-2 also decreases HLA-DR and CD38 expression(Kovacs, NEJM, 1995)

However, IL-2 Had No Effect on AIDS/Death

Abrams et al, NEJM, 2009

P=0.47

P=0.55

Why Didn’t IL-2 Work?

IL-2

Preferential Expansion

of Tregs

Suppression of Healthy T Cell

Responses

Increased CD4 Count Good for

Health

Bad for Health

Maraviroc Intensification Increases CD8 Activation Compared to Placebo

Hunt, CROI, 2011, Abstract 153LB

>2-fold Increase in Plasma CCR5 Ligand Levels During Maraviroc Intensification

• Due to prevention of ligand-receptor complex internalization by CCR5+ cells (Lin/Corbeau, AIDS, 2007; Nakata, Antiviral Threrapy, 2010)

• RANTES/MIP-1a may activate monocytes/macrophages and neutrophils via CCR1

What Have We Learned?

• Immune system is complicated!

– Multiple parallel and competing pathways, feedback loops

• Primary effects assessed in vitro may fail to capture important competing secondary effects in vivo

• Need for carefully designed placebo-controlled trials, follow up studies to elucidate these mechanisms

• May need to improve more than surrogate inflammatory markers to advance to clinical endpoint trials (i.e., FMD, BMD, etc).

What specific mechanisms should we intervene upon?

Adapted from Appay V, et al. J Pathol. 2008;214:231-241.

HIV-1 Infection

ImmunodeficiencyBacterial

TranslocationViral Reactivation

(eg, CMV)

Innate Immune Activation (MØ/DC)

Increased Cell Turnover and Lymphoid Fibrosis

Immune Exhaustion

Malignancy, Infections

Cytokine Secretion(eg, IL-6, TNFL)

“Inflam-Aging”(eg, atherosclerosis,

osteoporosis)

HIV-Mediated Immune Activation and Aging

TLR 7,8Nef, gp120

Increased TF Expression and clotting

CAD/Stroke, Thrombosis


HIV-1 Infection



(eg, CMV)



Immune Exhaustion




osteoporosis)


TLR 7,8Nef, gp120




HIV-1 Infection



(eg, CMV)



Immune Exhaustion




osteoporosis)


TLR 7,8Nef, gp120



Anti-LPS antibodies have no effect on CD4 recovery: CORAL

HIV+On cART

CD4<350 cells/ul∆CD4<50 past 12 months

Raltegravir HIBC+

placebo HIBC+

Raltegravir placebo+

placebo placebo+

HIBC= hyperimmune bovine colostrumEnriched in anti-LPS antibodies

n=18

n=18

n=18

n=18RESULTSNo effect on CD4 recoveryNo effect on LPS, sCD14, T cell activation

Bykawaga et al, J Infect Dis 2011 (in press) Slide courtesy of Sharon Lewin

Microbial Translocation:Cause or Consequence of Immune Activation

in Treated HIV Infection?

• Observational studies linking MT to immune activation cannot prove causality– Causality can only be formally addressed in clinical trials

• DC/Macrophage activation can cause IDO induction, ↓Th17, and microbial translocation

• Ongoing/Planned studies assessing blocking microbial translocation directly– Rifaximin (ACTG)

– Sevalamer (ACTG)


HIV-1 Infection



(eg, CMV)



Immune Exhaustion




osteoporosis)


TLR 7,8Nef, gp120



Chloroquine Might Reduce CD8 Activationin Untreated HIV+ Patients

Chloroquine Placebo

Murray, JV, 2010

• No apparent effect on plasma HIV RNA Levels (though some missing data)• Possible early decrease in plasma LPS• Probable mechanism: TLR inhibition (3,4,7,8,9)

Hydroxychloroquine Did Not Reduce CD8 Activation in Untreated HIV+ Patients

%CD38+HLA-DR+ CD8s

Paton, IAS 2011, MOPE269

Why did viral load increase with HCQ?

And why didn’t CD8 activation increase with the increase in VL?

Viral Load

-.1

0

.1

.2

.3

.4

Me

an

(p

oin

twis

e 9

5%

CI)

0 12 24 36 48Weeks from randomisation

HCQ Placebo

Change in lrna from randomisation: by Arm

Pla

sma

HIV

RN

A L

evel

(lo

g10

co

pie

s/m

l)

-10

-5

0

5

Me

an (

poi

ntw

ise

95%

CI)

0 12 24 36 48Weeks from randomisation

HCQ Placebo

Change in cd8cd38DR_p from randomisation: by Arm

Impact of Innate Immune ResponseUntreated HIV Disease

The Bad:

Immune Activation ↑

The Good:

HIV replication ↓

Direct Antiviral Effects

Adjuvant to HIV-specific T cells

IL-6, TNFα↑

TF expression, D-dimer ↑

T cell turnover/exhaustion ↑

LN fibrosis ↑

Immune Activation ↓

Impact of Innate Immune ResponseDuring ART-mediated VL Suppression

The Good: None

VL already suppressed by

drugs

Antiviral Effects Irrelevant

The Bad

Immune Activation ↑

IL-6, TNFα↑

TF expression, D-dimer ↑

T cell turnover/exhaustion

LN fibrosis

HCQ Decreases Immune Activation in ART-suppressed Immunologic Non-responders

%CD38+ Memory CD8s

Piconi, Blood, 2011

%CD69+ CD14+ Monocytes


HIV-1 Infection



(eg, CMV)



Immune Exhaustion




osteoporosis)


TLR 7,8Nef, gp120



Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation

in HIV+ Patients with CD4<350 despite ART

-4.4%

HIV-Median

Hunt et al, JID, 2011

• Cytopenias may limit long-term usefulness.

• Need new, safer CMV agents!


HIV-1 Infection



(eg, CMV)



Immune Exhaustion




osteoporosis)


TLR 7,8Nef, gp120



Atorvostatin Decreases T Cell Activation in Untreated HIV Infection

Atorvostatin 80mg

Placebo

Ganesan, J Infect Dis, 2011

• 24 untreated patients, X-over design

• Significant reduction in HLA-DR on CD8s during atorvostatin Tx

• No effect on plasma HIV RNA levels

• Studies ongoing in ART-suppressed patients

COX-2 Inhibition Decreases T Cell Activation in Untreated HIV Infection

• 27 untreated patients, 12 weeks celecoxib vs. placebo.

• Significant reduction in CD38 on CD8s during celecoxib Tx

• No effect on plasma HIV RNA levels

• CAD toxicity a potential problem with celecoxib

• ASA? Mesalamine?

CD

38

Mo

lec

ule

s/c

ell

Pettersen, JV, 2011

CelecoxibPlacebo

Other Strategies to block Monocyte/Macrophage Activation?

• Combined CCR5/CCR2 blockade?– CCR5 inhibition increased immune activation, likely

indirectly through MØ activation

– CCR2 (MCP-1 receptor) blockade might overcome this effect?

• IDO inhibitors?– Prevent proliferative defects and allow for restoration

of Th17 cells

– Might interrupt vicious circle of microbial translocation and innate immune activation

Immunosuppressive Therapies

Suppression of Healthy Immune Reponses

DecreasedImmune Activation

The Good The Bad

TNFα inhibitors IL-6 inhibitors

CTLA-4 analogs IL-23/IL-12 inhibitors

Steroids Cyclosporine

Methotrexate

A Way Forward…• Target proximal causes of monocyte activation

• Small pilot trials to establish proof of principal– “Immunologic Non-Responders” have higher immune

activation and are at highest risk for disease

– Studying treated patients allows cleaner biologic inferences

– Need to thoroughly evaluate mechanistic pathways in vivo

• Advance promising agents to mid-range trials with surrogate markers of end-organ disease– Liver, renal, bone (BMD), cardiovascular (FMD)

• Advance promising/safe/scalable interventions to clinical endpoint trials

Documents

Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection Peter W. Hunt, MD Assistant Professor of Medicine UCSF HIV/AIDS Division