HIV and Inflammation:A Paradigm Shift

Wafaa El-Sadr, MD, MPH

Columbia University & Harlem Hospital

New York

Effect of Protease Inhibitor-Containing Regimens on Mortality in Patients with <100 CD4+ cells

Adapted from Palella F, et al. N Engl J Med, 1998.

1994 1995 1996 1997

Antiretroviral Therapy

Deaths

0

10

20

30

40

0

20

40

60

80

100

Therapy with a Protease Inhibitor

(% of patient-days)

Dea

ths

per 1

00 P

erso

n-Ye

ars

Survival from Seroconversion Compared to Pre 1996

Adapted from Ewings et al, 2008.

Haz

ard

Ratio

of D

eath

1 0.63 0.24 0.14 0.08 0.03

Change in Mortality over Time

Adapted from Lau et al, JAIDS 2007

HAART

AIDS

Non-AIDS

Mor

talit

y (p

er 1

000

pers

on-y

ears

)

Calendar Year

Perc

ent R

ecei

ving

The

rapyAll cause

Causes of Death in HIV: France 2005

Adapted from Lewden et al, CROI 2007

0 5 10 15 20 25 30 35 40

AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown

Percent

N = 937 deaths

Optimization of Use of Antiretroviral Therapy

RisksBenefits

SMART Study

Drug Conservation (DC)

Defer use of ART until CD4+ < 250; episodic ART based on CD4+ cell

count to increase counts to > 350

Viral Suppression (VS)

Continuous use of ART to maintain viral load as low as

possible

CD4+ cell count >350 cells/mm3 N= 5,472

n = 2,752 n = 2,720

Primary Endpoint: Opportunistic Disease or Death

Increased Risk Opportunistic Disease or Death with DC versus VS Strategy

Logrank = 31.1 p < 0.0001

DC 2720 1170 589 322 VS 2752 1167 625 334

Months from randomization

DC Group

VS Group

Perc

ent w

ith E

vent

0 4 8 12 16 20 24 28 32 36 40 440

5

10

15

20

Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events

No. of Patients with EventsEndpoint

Serious AIDS 59 1.3 0.4

Favors VS ►►Favors DC

Hazard Ratio (DC/VS) (95% CI)

Rate**DC VS

3.6

1.9

Serious non-AIDS* 186 3.2 2.01.6

•Cardiovascular, renal, hepatic, non-AIDS malignancy, others** Per 100 person-years

Serious AIDS or 239 4.4 2.4non-AIDS

Adapted from Curr Opin HIV AIDS 2008;3:112-17.

0.1 1 10

Unifying FrameworkHIV-Associated Immune Activation

• HIV replication• T cell apoptosis immunosuppression• Coagulation cascade• Inflammation

– Atherosclerosis - Liver disease– Osteoporosis - Neurocognitive decline– Renal disease

Michael Ross Russell Ross, NEJM 1999

Inflammatory and Coagulation Markers in SMART

• Inflammatory– hs C-reactive protein (hs-CRP)– IL-6– Serum amyloid A– Serum amyloid P

• Coagulation– D-dimer– Prothrombin fragment 1+2 (F1.2)

Baseline Biomarker Levels Associated with All Cause Mortality – SMART Study

BiomarkerBaseline Level

DC arm OR (95% CI) P value

VS Arm OR (95%CI) P value

Hs CRP (Ug/ml) 2.3 (1.2-4.4) 0.01 2.7 (0.9-7.9) 0.08

IL-6 (Ug/ml) 3.8 (2.1-7.2) 0.0002 2.4 (1.1-5.2) 0.03

Amyloid A (mg/l) 1.6 (0.9-2.8) 0.11 1.5 (0.6-3.8) 0.40

Amyloid P (Ug/ml 0.8 (0.5-1.3) 0.40 0.7 (0.3-1.6) 0.46

D-dimer (ug/ml) 5.9 (1.9-18.7) 0.002 7.1 (0.8-63.2) 0.08

F1.2 (pmol/l) 0.8 (0.4-1.5) 0.47 0.7 (0.2-2.2) 0.55

Adapted from Kuller et al. Plos Medicine 2008.

Association of C Reactive Protein and HIV with Myocardial Infarction

Marker CRP High vs Not High OR (95%CI) P value

HIV vs no HIVOR (95%CI) P value

CRP 2.5 (2.4-2.8)

<0.0001

HIV 2.1 (1.3-3.1)

0.0009

CRP, HIV 2.5 (2.3-2.8)

<0.0001 1.74 (1.1-2.6)

0.01

CRP, HIV, age, sex, race, HPN, diabetes, dyslipidemia

2.1 (1.9-2.4)

<0.0001 1.9 (1.2-2.9)

0.0035

Adapted from Triant et al, J Acquir Immune Defiic Syndr, 2009.

C-Reactive Protein Level is Associated with AIDS-Free Survival

Adapted from Lau et al, Arch Intern Med 2006.

Prop

ortio

n A

IDS

Free

Time from Baseline, years

C Reactive Protein Level is Associated with AIDS – Free Survival

Variable Relative Time(95% CI)

P Value

CRP, mg/L <1.2 1.3-2.3 >2.3

1.00.86 (0.68-1.09)0.63 (0.51-0.79)

0.21<0.001

CD4+ cell count 1.12 (1.08-1.16) <0.001

HIV RNA (log10) 0.34 (0.29-0.39) <0.001

Hemoglobin (g/dL) 1.14 (1.06-1.23) <0.001

Adapted from Lau et al, Arch Intern Med 2006.

C Reactive Protein Levels Increase over Time prior to AIDS Diagnosis

C re

activ

e pr

otei

n, g

eom

etric

mea

n ug

/L

Months from AIDS DiagnosisAdapted from Lau et al, Arch Intern Med 2006.

AIDS

The Natural History of HIV Infection Clinical Latency?

Adapted from Pantaleo G, et al. N Engl J Med 1993.

Opportunistic Infections Occur at Higher CD4+ Cell Count Strata

0.01

0.1

1

10

100

<100

100-

199

200-

299

300-

399

400-

499

>=50

0<1

00

100-

199

200-

299

300-

399

400-

499

>=50

0<1

00

100-

199

200-

299

300-

399

400-

499

>=50

0

Latest CD4 count

Inci

denc

e pe

r 100

0 PY

FU (9

5%CI

)

CMV / MAC / TOXO PCP /EC TB

N events 134 45 13 9 2 2 89 55 61 35 13 16 12 9 10 11 11 14

Adapted from Podlekareva et al. J Infect Dis 2006.

Non-AIDS-Related Deaths Occur at Higher CD4+ Cell Counts

CASCADE

DAD

CD4+ Cell Count

Rate

per

100

per

son/

yrs

Adapted from Phillips et al, AIDS 2008.

Deaths due to Non-AIDS Exceed AIDS Causes in Patients enrolled with CD4+ Count >200 cell/mL—Post 1999

CD4<200 CD4+ 201-350 CD4+ 351-500 CD4+>500

Adapted from Lau et al, JAIDS 2007.

AIDS

AIDS AIDS AIDSNon-AIDS

Non-AIDS

Non-AIDS Non-AIDS

0

0.4

0.8

Cum

ulati

ve m

orta

lity

A New Paradigm

Time in YearsInfection

CD4+

cel

ls C

ount

1000

800

600

400

200

0

Opportunistic Diseases

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Ongoing Morbidity from HIV

Timing of Initiation of ART

Adapted from Sterne et al, Lancet 2009.

Haz

ard

Ratio

for A

IDS

or D

eath

CD4+ cell count threshold

Earlier Initiation of ART and Risk of Death

Variable CD4+ count 351-500 cells/ml

CD4+ count >500 cells/ml

Relative Risk P Value

Relative Risk P Value

ART deferral 1.6 (1.2-2.2)

0.002 1.9 (1.2-2.9)

0.006

Female sex 1.9 (1.7-2.1)

0.04 1.4 (0.9-2.1)

0.20

Older age (10yr) 1.9 (1.7-2.1

<0.001 1.8 (1.6-2.1)

<0.001

Baseline CD4+ (100 cell increment)

0.7 (0.6-1.0)

0.06 1.0 (0.4-1.0)

0.45

Baseline HIV RNA (log 10 increment)

1.1 (1.0-1.3)

0.15 1.1 (1.0-1.3)

0.14

Adapted from Kitahata et al, New Eng J Med 2009 .

Effect of ART on C Reactive Protein

Adapted from Henry et al, AIDS 2004.

C Re

activ

e Pr

otei

n Le

vel

Effect of ART Interruption on Biomarkers

Marker DC Group VS Group

NMedian M1-bl

(IQR) NMedian M1-bl

(IQR)P-

value1

IL-6 247 0.60(-0.17-1.87)

249 0.12(-0.88-0.97)

<.0001

D-dimer 248 0.05(-0.07-0.18)

248 0.00(-0.13-0.08)

<.0001

1 Wilcoxon 2-sided test comparing DC and VS from baseline to month 1

Change from Baseline to Month 1 SMART Study

START Study

HIV-infected, ART-naïve CD4+ count > 500 cells/mm3

Early ART GroupInitiate ART immediately

Deferred ART GroupDefer ART until CD4+ count < 350 cells/mm3 or AIDS

Primary OutcomeSerious AIDS, Serious non-AIDS Events or Death

Measurement of biomarkers

Effect of Rosuvastatin on CVD in General Population with High CRP & Low LDL-Jupiter Study

Adapted from Ridker et al, N Engl J Med 2008.

Cum

ulati

ve In

cide

nce

Years

Atorvastatin

Placebo Atorvastatin

Placebo

Week 0 20 48

Arm A

Arm B

28

A5275 – Pilot Study of Effects of Atorvastatin on Biomarkers in HIV

WASHOUT

Biomarkers of Inflammation, Coagulopathy, Angiogenesis, and T-lymphocyte Activation

• HIV infected

• On boosted-PI regimen with HIV RNA <50 copies/ml

• LDL < 130 mg/dl • D-dimer >0.34

Mortality in HIV-infected Persons after Seroconversion Compared to General Population

Adapted from Bhaskaran et al, Lancet 2008.

Cum

ulati

ve M

orta

lity,

Pro

porti

on

Time from Seroconversion, Years Time from Seroconversion, Years

Age <45 yrs at seroconversion Age >45 yrs at seroconversion

Cum

ulati

ve M

orta

lity,

Pro

porti

on

HIV Pre -1996

HIV 2004-2006

HIV Pre -1996

HIV 2004-2006

General 2004-2006 General 2004-2006

Dramatic Increase in Access to ART;Low & Middle Income Countries

Effect on HIV-related Deaths inResource-limited Countries

Adapted from Bendavid et al, Ann Int Med 2009.

Dea

ths

from

HIV

, Tho

usan

ds

Dea

ths

from

HIV

, Tho

usan

ds

Year Year

PEPFAR Focus Countries (12) Control Countries (29)

High Mortality Pre-ART

Adapted from Lawn et al, AIDS 2005.

Surv

ival

Pro

babi

lity

Days after Enrollment

High Risk of Early Mortality after ART Initiation:Resource Poor/Resource Settings

HR unadjusted HR adjusted for cohort, age, sex, baseline CD4, ART-regimen, disease stage

Haz

ard

Ratio

(95%

CI)

Months from Starting HAART

Summary

• Remarkable progress achieved with use of ART • The spectrum of HIV-related complications evolved with a

predominance of non-AIDS related events, particularly in patients with higher CD4+ cell counts

• Inflammatory and coagulation markers associated with serious complications, AIDS and death

• A survival gap exists:– for those with HIV versus general population in resource-rich

settings – and an even more pronounced gap in outcomes in HIV infected

individuals in resource –rich versus limited settings

Conclusions

• A re-conceptualization of the pathogenesis of HIV disease is necessary-- clinical latency is a misperception;

• Inflammation and coagulopathy are important causes of end-organ damage, disease progression and death;

• Role of ART and of other interventions in averting and suppressing these processes and their consequences needs urgent definition.