Why is inflammation elevated in treated HIV infection and why does it matter?

Why is inflammation elevated in treated HIV infection and

why does it matter?

Steven G. DeeksProfessor of Medicine

University of California, San Francisco

Many Age-associated Diseases Are More Common in Treated HIV Disease Than In Age-

matched Uninfected Persons

• Cardiovascular disease• Cancer (non-AIDS)• Bone fractures/osteopenia• Left ventricular dysfunction• Liver failure• Kidney failure• Cognitive decline• Frailty• Immune system

Multiple factors likely explain this increased risk, including co-morbid conditions and antiretroviral drug toxicity

Schouten J AIDS 2012

Co-morbid conditions common in HIV-infected adultsHIV-infected adults age 50-55 similar to uninfected adults > 65

Inflammatory Biomarkers Predict Risk for All-Cause Mortality among Treated Adults

Cohort Design T cell acti-

vation

CRP IL-6 K/T IDO

Cysta-atin C

sCD-14

D-dimer

Fibrin-ogen

Hyalu-ronic Acid

SMARTESPRIT

Case-control ✔ ✔ ✔ ✔ ✔

FRAM Cohort ✔ ✔ ✔SOCA/SCOPE Cohort ✔ ✔ ✔ ✔ ✔ ✔

UARTO Cohort ✔ ✔VACS Cohort ✔ ✔FIRST (Pre-ART)

Case-control ✔ ✔ ✔ ✔

Pfidisas(Pre-ART)

Case-control ✔ ✔ ✔

T cells

Innate

Microbes

Coagulation

Fibrosis

“Over the past decade, it has become widely accepted that inflammation is a driving force behind chronic diseases that will kill nearly all of us . . .”

Science , 2010

Chronic inflammation is also harmful in non-HIV-infected adults

Courtesy of Peter Reiss

Is there something unique about

inflammation in HIV disease?

T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal”

Hunt et al JID 2003, PLoS ONE 2011 and unpublished

% C

D38

+HLA

DR

+C

D8+

T C

ells

0

20

40

60

80

HIVNegative(n=82)

Non-Controller

(n=65)

HAART(n=132)

P < 0.001

P < 0.001

HIV –(n=132)

HIV +ART

(n=65)

HIV +Untreated

(n=82)

0

25

50

75

100

125

150

175

200

IL-6 D-dimer Cystatin-C

UnadjustedAdjusted for age, gender, raceFully adjusted

UnadjustedAdjusted for age, gender, raceFully adjusted

hsCRP

% D

iff.

from

Gen

eral

Pop

ula

tion

(M

ESA

)

Neuhaus et al JID 2010

• Among those with undetectable viral load (<400 copies/mL), hsCRP was 40% higher, IL-6 was 60% higher, and D-dimer was 49% higher, compared with controls from MESA

Many common plasma biomarkers of inflammation are also higher in treated HIV disease than “normal”

Among treated adults, D-dimers (and perhaps other biomarkers) are stable over years

Courtesy of Jens Lundgren

Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE)

Hunt et al CROI 12

A single measurement of D-dimers predicts mortality through 8 years of observation, whereas effect wanes in 2-3

years in general population (SMART/ESPRIT; n=3227)

There were only 5 deaths over 8 years among those in the lowest quartile (as compared to 45 deaths in highest quartile)

Lane et al; CROI 2011

Are all of the biomarkers describing the same mechanistic

pathway?

Biomarkers covering apparently unique pathways (inflammation and coagulation) provided

independent prognostic capacity in FRAM

Associations for CRP and Fibrinogen

persist when CD4 >500

Tien et. al. JAIDS 2010;55(3):316-322

Among adults with durable viral suppression, a low CD4+ T cell count is associated with significant T cell abnormalities

Hatano CROI 2011

P = 0.0001 P < 0.0001

P < 0.0001 P = 0.05

After controlling for CD4+ T cell count, inflammatory biomarkers have stronger prognostic effect that T cell

activationtreated infection

Hunt et al CROI 12

Early ART Also Appears to Reduce Residual T Cell Activation during ART

Jain et al, CROI 2011

What causes HIV-associated

inflammation?

Inflammation↑ Endothelium adhesion↑ Monocyte activation

DyslipidemiaHypercoagulation/thrombotic events

Endothelial dysfunction

Microbial translocation

HIV-associated fatMetabolic syndrome

HIV productionHIV replication

CMVExcess pathogens

HIV-mediated loss of regulatory cells (Tregs)

Conclusions• Inflammation during treated HIV disease is unique

• Higher than expected• Stable over time• Stronger prognostic significance

• Multiple mechanisms cause activation• Residual HIV production (or replication)• Microbial translocation• CMV and other co-pathogens• Loss of immunoregulatory responses• Lymphoid fibrosis• Metabolic syndrome, abdominal obesity• Treatment toxicity (e.g., telomerase inhibition)

AcknowledgementsUCSFPeter HuntHiroyu HatanoPriscilla HsueJeff MartinBecky HohMa SomsoukVivek JainElizabeth SinclairMike BuschSteve YuklJoe WongMike McCune

INSIGHTJason BakerCliff LaneAndrew PhillipsJim NeatonJens Lundgren

ElsewhereNetanya SandlerDanny DouekMike Lederman (CLIC)Peter ReissRafick SekalyTim Schacker