Transcript When to START Antiretroviral Therapy? Dr. José R Arribas HIV Unit Life expectancy of individuals on combination antiretroviral therapy in high-income countries Non-IVDU IVDU Female Male Age 20

When to START Antiretroviral Therapy?
Dr. José R Arribas
HIV Unit
Life expectancy of individuals on combination
antiretroviral therapy in high-income countries
Non-IVDU
IVDU
Female
Male
Age 20 y
0
10
20
30
40
Life Expectancy (years; adjusted)
Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99
50
Survival from age 25 years (Non HCV)
Smoking?
Lifestyle?
Socioeconomic?
HIV?
Lohse N et al. Ann Intern Med. 2007;146:87-95.
SMR in 2435 HIV-infected adults, ANRS CO8
APROCO-COPILOTE, and ANRS CO3 AQUITAINE
cohorts, 1997 to 2005.
Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77
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SHOULD WE START HAART IN THIS PATIENT
NOW?
 32 year old male
 HIV negative: Sept/2000. HIV positive Dec/2000
 Nadir CD4 cell count: 453
 Current CD4 cell count: 479
 Current viral load: 16000
 No hepatitis coinfection.
 HIV negative couple
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WAITING AHEAD (NO TREATMENT)
 DEATH
 AIDS
32 y/o male
CD4 cell count: 479
Current viral load: 16000
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DEATH & AIDS. HAART and Survival Based
on Initial CD4+ Cell Count



Modeled data from ART Cohort
Cumulative Probability of AIDS/Death According
Collaborative
to CD4+ Cell Count at Initiation of HAART
10,855 patients included
0.14
101-200 cells/mm3
934 progressed to AIDS or died
201-350 cells/mm3
0.12
IDUs censored from model
351-500 cells/mm3
Initiating Rather than Deferring Haart0.10
at a CD4+ Count Between 351Progression and
Accordingis Associated with Improved Survival
500Death
Cells/mm3
0.08
to CD4+ Cell Count (cells/mm3)
(74% Lower risk)
< 200 vsKitahata
< 350
vs et al. ICAAC
0.06 2008. H-896b
MM
201-350
Hazard ratio for
AIDS or death
(95% CI)
2.93
(2.41-3.57)
351-500
1.26
(0.94-1.68)
Probability of AIDS or Death

0.04
0.02
0.00
0
1
2
3
4
5
Years Since Initiation of HAART
Sterne J, et al. CROI 2006. Abstract 525.
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AIDS. Hazard Ratio from initiation of HAART to
AIDS by CD4 cell count
Similar data: ARTC
Sterne J, et al. CROI 2006.
Abstract 525.
Jaen J, et al. JAIDS 2008;47:212–220
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PREDICTED 6-month risk of AIDS
The NNT (Number Needed to Treat) is 203
This means that about one in every 203
patients will benefit from the treatment.
BHIVA Guidelines 2008
32 y/o male
CD4 cell count: 479
Current viral load: 16000
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Panel
CD4+ Cell Count, cells/mm3
US DHHS
June 1998
< 500
February 2001
< 350
April 2005
< 200
January 2008
< 350
International AIDS Society-USA Panel
July 1998
Any
January 2000
< 500
July 2004
<200
August 2008
< 350
British HIV Association (BHIVA)
June 1998
< 350
July 2003
201-350
July 2005
< 200
September 2008
< 350
WAITING AHEAD (NO TREATMENT)
 DEATH
 AIDS
32 y/o male
CD4 cell count: 479
Current viral load: 16000
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NON-AIDS EVENTS. SMART STUDY
< 250
> 350
Of the 85 deaths that occurred in
SMART, only 7 (8%) were due to
opportunistic disease
Adapted from SMART Study Group. N Engl J Med 2006;355:2283-96.
WAITING AHEAD (NO TREATMENT)
 DEATH
 AIDS
32 y/o male
CD4 cell count: 479
Current viral load: 16000
 NON-AIDS EVENTS
– CARDIOVASCULAR DISEASE
– RENAL DISEASE
– LIVER DISEASE
– CANCER
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NON-AIDS EVENTS. CD4+ Cell Count and risk of death
1.6
1.2
0.8
Rate
/ 100
person
years
CASCADE
0.4
(ART-naïve)
0.0
Non-AIDS causes
All causes
1.6
95% CI
1.2
DAD
0.8
0.4
0.0
200 – 350 – > 500
349
499
200 – 350 – > 500
349
499
CD4 count (/mm3)
Weber et al, Arch Intern Med 2006
Marin et al 4th IAS [WEPEB019]
WAITING AHEAD (NO TREATMENT)
 DEATH
 AIDS
32 y/o male
CD4 cell count: 479
Current viral load: 16000
 NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER
 “IRREVERSIBLE” IMMUNODEFICIENCY
 HIV TRANSMISSION
 COST
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Mean CD4+ Count (cells/mm3)
“IRREVERSIBLE” IMMUNODEFICIENCY. CD4+
Count Response Based on Baseline CD4+ Count
Johns Hopkins HIV Clinical Cohort
ATHENA National Cohort
1000
1000
800
800
600
600
400
400
200
200
0
0
0
1
2
3
4
5
0
Years on HAART

48
96
144 192 240 288
Weeks From Starting HAART
336
Magnitude of CD4+ increase greatest if therapy started at low CD4+ counts, but greater
likelihood of CD4+ count normalization with earlier therapy
Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.
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“IRREVERSIBLE” IMMUNODEFICIENCY. Normalisation of
CD4 counts in patients with HIV-1 infection and maximum
virological suppression
Mocroft A, et al. Lancet 2007; 370: 407–13.
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HIV TRANSMISSION. HIV RNA level affects
probability of HIV transmission
5
Probability of Transmission/
1000 Coital Acts
4.5
GUD
No GUD
4
3.5
3
2.5
2
1.5
1
0.5
0
<1700
GUD = genital ulcer disease.
Gray R et al Lancet 2001;357:1149-1153
170012500Log Viral Load (c/mL)
38500+
GUD
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WAITING AHEAD (TREATMENT)
 TOXICITY
 RESISTANCE
32 y/o male
CD4 cell count: 479
Current viral load: 16000
– Transmitted resistance
 COST
 QOL

DEATH

AIDS

NON-AIDS EVENTS
–
CANCER
–
CARDIOVASCULAR
–
OTHER
–
HIV TRANSMISSION

“IRREVERSIBLE” IMMUNODEFICIENCY

HIV TRANSMISSION
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TOXICITY. A5142: Lipoatrophy (> 20% loss
Extremity Fat)
% Lipoatrophy (> 20% Loss)
40
EFV
LPV/r
LPV/r + EFV
P-values at Week 96
LPV/r+EFV vs LPV/r: 0.023
LPV/r+EFV vs EFV: <0.001
LPV/r vs EFV:
0.003
30
32%
20
21%
17%
10
10%
9%
7%
0
48
EFV
188
LPV/r
191
LPV/r + EFV
197
th
Haubrich R et al., 14 CROI, Los Angeles 2007, #38
Weeks on Study
96
171
166
173
ACTG A5142
MIs per 1000 PYFU (95%CI)
TOXICITY. HAART effect on CV risk driven by PIs
RR adjusted by year of PI: 1.15 [1.062–1.25]
RR adjusted by year of NNRTI: 0.94 [0.74–1.19]
876543210None
<1
1-2
2-3
3-4
4-5
5-6
>6
Years of Exposure to PI or NNRTI
Total
PIs MI
16
7
12
19
25
23
12
22
PYFU
11815
3108
3808
5144
6108
5199
3525
3306
16
6
3
3
3
2
11815
2585
2294
1980
1525
1425
NNRTIs MI
PYFU
136
42013
33
21623
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Friis-Møller N et al 13th CROI; 2006, #144
D:A:D

HIV infection itself affected endothelial
function
– Baseline FMD: 3.7%

FMD improved during HAART

No consistent correlations between
changes in FMD and changes in any
lipids or glycemic parameter

Improvement in FMD significantly
associated with decrease in HIV-1 RNA
at Week 24
– No relationship with baseline HIV-1 RNA
Torriani F, et al. Lipodystrophy Workshop 2007.
Abstract O-18. Torriani F, et al. IAS 2007. Abstract WEAB302.
Median Change in FMD From Baseline (%)
TOXICITY. A5152s: VL Decrease Associated
With Improved Endothelial Function
3.5
Week 4
Week 24
†
3.0
2.5
2.0
1.5
1.0
*
*
*
Overall
LPV/
NRTI
EFV/
NRTI
0.5
0
EFV/
LPV
*P < .01 compared with baseline.
†P < .01 compared with baseline and within group.
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RESISTANCE. Unadjusted and adjusted risk ratios
of virological failure by year of starting cART
Strategy A
Unadjusted
Adjusted 1
Adjusted 2
Risk ratio
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
1996
1997
1998
1999
2000
Year of starting CART
2001
2002
1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, preHAART VL and CD4, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd
drug count and nucleoside combination.
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Lampe et al, Arch Intern Med 2006;166:521-528
32 y/o male
CD4 cell count: 479
Current viral load: 16000
NO TREATMENT
TREATMENT
 DEATH
 TOXICITY
 AIDS
 RESISTANCE
– Transmitted resistance
 NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER
 “IRREVERSIBLE” IMMUNODEFICIENCY
 COST
 QOL

DEATH

AIDS

NON-AIDS EVENTS
 HIV TRANSMISSION

COST
–
CANCER
–
CARDIOVASCULAR
–
OTHER
–
HIV TRANSMISSION

“IRREVERSIBLE” IMMUNODEFICIENCY

HIV TRANSMISSION
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PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer,
Cardiovascular) & Toxicity & Transmission
32 y/o male
CD4 cell count: 479
Current viral load: 16000
Framingham risk: 8%
Hepatitis Coinfection: No
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PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer,
Cardiovascular, Other) & Toxicity & Transmission
NNT: ?
NNH: ?
32 y/o male
CD4 cell count: 479
Current viral load: 16000
Framingham risk: 8%
Hepatitis Coinfection: No
?
NNT (Prevent Transmission): ?
NNH (Transmitted resistance): ?
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SMART SUBSTUDY (NAÏVE/OFF-HAART, > 350)
Study halted early
Patients with CD4+ cell
count > 350 cells/mm³
who are antiretroviral naive
(n = 249) or have not
received ART
for ≥ 6 mos (n = 228)
(N = 477)
Virologic Suppression Strategy
Continuous therapy
(n = 249 not receiving ART at trial start)
Mean followup: 16
months
Treatment Interruption Strategy
Deferred therapy until CD4+ cell count
< 250 cells/mm³; discontinue therapy
when CD4+ cell count > 350 cells/mm³
(n = 228 not receiving ART at trial start)
CLINICAL OUTCOMES
Opportunistic disease (fatal and non-fatal)
Cum. Probability (X100)
Cum. Probability (X100)
Opportunistic disease and death
Hazard Ratio = 4·38 (95%CI: 1·45-13·.2) p=0·009
Deferred ART
Immediate ART
No. at Risk
No. at Risk
Months
Months
Def ART
Imm ART
Deferred ART
Immediate ART
No. at Risk
Composite endpoint
Hazard Ratio = 7·05 (95% CI: 1·58-31·5) p=0·01
Cum. Probability (X100)
Cum. Probability (X100)
Serious non-AIDS
Deferred ART
Immediate ART
Hazard Ratio = 4·40 (95%CI: 1·23-15·8) p=0·02
Months
No. at Risk
Def ART
Imm ART
SMART. The Journal of Infectious Diseases 2008; 197:1133– 44
Hazard Ratio = 5·08 (95% CI: 1·91-13·5)
p=0·001
Months
START: Design
HIV-infected participants with CD4+ cell
counts > 500 cells/mm3
Early ART Group
Deferred ART Group
Immediately initiate ART
Defer ART until CD4+ <350
cells/mm3 or symptoms develop
N=450 at 70 sites for pilot phase
N=2,000 (est.) for definitive study
N=450 at 70 sites for pilot phase
N=2,000 (est.) for definitive study
Composite Primary Endpoint
(Time to first event)
 AIDS*
– Clinical events included in 1993 CDC case definition, plus additional
conditions related to immunodeficiency (non-fatal esophageal candidiasis
and herpes simplex are excluded)
 Non-AIDS
– Cardiovascular disease: MI, angioplasty, CABG, stroke
– Chronic end-stage renal disease (ESRD): initiation of dialysis, renal
transplantation
– Decompensated cirrhosis
– Non-AIDS defining cancers (basal and squamous cell skin cancers are not
counted)
 Death from any cause
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Panel
CD4+ Cell Count, cells/mm3
US DHHS
June 1998
< 500
February 2001
< 350
April 2005
< 200
January 2008
< 350 (> 350 Individualized)
International AIDS Society-USA Panel
July 1998
Any
January 2000
< 500
July 2004
<200
August 2008
< 350 (> 350 Individualized)
British HIV Association (BHIVA)
June 1998
< 350
July 2003
201-350
July 2005
< 200
September 2008
< 350 (> 350 Individualized)
INDIVIDUALIZING FACTORS
> 55 y/o
↑ Cardiovascular Risk
Hepatitis Coinfection
High Viral Load
Rapid CD4 cell decline
When to start antiretroviral treatment?
 Current global consensus: < 350. This represents a prudent
decision given the available evidence.
 > 350?:
– Precise estimates of the risk of Death/AIDS are available
– Precise estimates of the risk non-AIDS (on/off HAART) events are
not available
– We do not know the exact individual risk/benefit ratio NNH/NNT.
– We do not know the exact population risk/benefit ratio NNH/NNT.
 A RCT might be a very important instrument but there are still
questions about feasibility (enrolment, duration, duration of
benefit, impact of toxicity, other)
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Dealing with uncertainty
“The practice of medicine is an art, based on
science. Medicine is a science of uncertainty
and an art of probability”
Sir William Osler
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