HIV and Inflammation:A Paradigm Shift

Wafaa El-Sadr, MD, MPHColumbia University & Harlem Hospital

New York

XI International Conference on AIDSVancouver 1996

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

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 SeroconversionCompared to Pre 1996

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

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

Lewden et al, CROI 20070 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

8

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

Curr Opin HIV AIDS 2008;3:112-117

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

Ross, NEJM 1999

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

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

Triant et al, J Acquir Immune Defiic Syndr, 2009 (adapted)

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

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

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 DiagnosisLau et al, Arch Intern Med 2006

AIDS

The Natural History of HIV InfectionClinical Latency?

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

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

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, 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

Sterne et al, Lancet 2009

Haz

ard

Ratio

for A

IDS

or D

eath

CD4+ cell count threshold

Earlier Initiation of ART andRisk 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

Kitahata et al, New Eng J Med 2009 (adapted)

Effect of ART on C Reactive Protein

Henry et al, AIDS, 2004

C Re

activ

e Pr

otei

n Le

vel

Effect of ART Interruption on Biomarkers Change from Baseline to Month 1 Change from Baseline to Month 1

SMART StudySMART Study

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

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

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

A5275A5275 – – Pilot Study of Effects of Pilot Study of Effects of Atorvastatin on Biomarkers in HIVAtorvastatin on Biomarkers in HIV

WASHOUT

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

• HIV infected

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

• LDL < 130 mg/dl • D-dimer >0.34

A World Apart?

Mortality in HIV-infected Persons after Seroconversion Compared to

General Population

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

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

Lawn et al, AIDS 2005.

Surv

ival

Pro

babi

lity

Days after Enrollment

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

One World-One Hope