HIV and Inflammation: A Paradigm Shift
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Transcript of HIV and Inflammation: A Paradigm Shift
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.