when to start antiretroviral therapy?
DESCRIPTION
When to START Antiretroviral Therapy?. Dr. José R Arribas HIV Unit. Non-IVDU. IVDU. Female. Male. Life expectancy of individuals on combination antiretroviral therapy in high-income countries. Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99. - PowerPoint PPT PresentationTRANSCRIPT
When to START Antiretroviral Therapy?
Dr. José R Arribas
HIV Unit
0 10 20 30 40 50
Age 20 y
Life Expectancy (years; adjusted)
Life expectancy of individuals on combination antiretroviral therapy in high-income countries
Non-IVDU
IVDU
Female
Male
Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99
Survival from age 25 years (Non HCV)
Lohse N et al. Ann Intern Med. 2007;146:87-95.
Smoking?Lifestyle?Socioeconomic?HIV?
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SMR in 2435 HIV-infected adults, ANRS CO8APROCO-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 maleCD4 cell count: 479Current viral load: 16000
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101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
DEATH & AIDS. HAART and Survival Based on Initial CD4+ Cell Count
Modeled data from ART Cohort Collaborative
10,855 patients included 934 progressed to AIDS or died IDUs censored from model
Sterne J, et al. CROI 2006. Abstract 525.
Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART
Years Since Initiation of HAART
0 1 2 3 4 50.00
0.02
0.04
0.06
0.08
0.10
0.12
Pro
ba
bil
ity
of
AID
S o
r D
ea
th
0.14
Progression and Death According to CD4+ Cell Count (cells/mm3)
< 200 vs 201-350
< 350 vs 351-500
Hazard ratio for AIDS or death (95% CI)
2.93 (2.41-3.57)
1.26(0.94-1.68)
Initiating Rather than Deferring Haart at a CD4+ Count Between 351-500 Cells/mm3 is Associated with Improved Survival
(74% Lower risk)Kitahata MM et al. ICAAC 2008. H-896b
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AIDS. Hazard Ratio from initiation of HAART to AIDS by CD4 cell count
Jaen J, et al. JAIDS 2008;47:212–220
Similar data: ARTCSterne J, et al. CROI 2006. Abstract 525.
clinicaloptions.com/hivBHIVA Guidelines 2008
PREDICTED 6-month risk of AIDS
32 y/o maleCD4 cell count: 479Current viral load: 16000
The NNT (Number Needed to Treat) is 203 This means that about one in every 203 patients will benefit from the treatment.
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
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WAITING AHEAD (NO TREATMENT)
DEATH
AIDS
32 y/o maleCD4 cell count: 479Current viral load: 16000
Adapted from SMART Study Group. N Engl J Med 2006;355:2283-96.
NON-AIDS EVENTS. SMART STUDY
< 250 > 350
Of the 85 deaths that occurred in SMART, only 7 (8%) were due to
opportunistic disease
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WAITING AHEAD (NO TREATMENT)
DEATH
AIDS
NON-AIDS EVENTS
– CARDIOVASCULAR DISEASE
– RENAL DISEASE
– LIVER DISEASE
– CANCER
32 y/o maleCD4 cell count: 479Current viral load: 16000
200 – 350 – > 500 349 499
CD4 count (/mm3)
Rate
/ 100 personyears
95% CI
Non-AIDS causes All causes0.0
0.4
0.8
1.2
1.6
0.0
0.4
0.8
1.2
1.6
200 – 350 – > 500 349 499
DAD
CASCADE(ART-naïve)
Weber et al, Arch Intern Med 2006 Marin et al 4th IAS [WEPEB019]
NON-AIDS EVENTS. CD4+ Cell Count and risk of death
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WAITING AHEAD (NO TREATMENT)
DEATH
AIDS
NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER
“IRREVERSIBLE” IMMUNODEFICIENCY
HIV TRANSMISSION
COST
32 y/o maleCD4 cell count: 479Current viral load: 16000
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“IRREVERSIBLE” IMMUNODEFICIENCY. CD4+ Count Response Based on Baseline CD4+ Count
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.
Johns Hopkins HIV Clinical Cohort
Mea
n C
D4+
Co
un
t (c
ells
/mm
3 )
1000
800
600
400
200
00 48 96 144 192 240 288 336
ATHENA National Cohort
0 1 2 3 4 5
200
400
600
800
0
1000
Years on HAART Weeks From Starting HAART
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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
GUD = genital ulcer disease.
Gray R et al Lancet 2001;357:1149-1153
GUD No GUD
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
<1700 1700- 12500- 38500+
Log Viral Load (c/mL)
Pro
bab
ility
of
Tra
nsm
issi
on
/10
00 C
oit
al A
cts
GUD
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WAITING AHEAD (TREATMENT)
TOXICITY RESISTANCE
– Transmitted resistance
COST QOL DEATH AIDS NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER
– HIV TRANSMISSION “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION
32 y/o maleCD4 cell count: 479Current viral load: 16000
0
10
20
30
40
48 96Weeks on Study
% L
ipo
atro
ph
y (>
20%
Lo
ss) EFV LPV/r LPV/r + EFV
TOXICITY. A5142: Lipoatrophy (> 20% loss Extremity Fat)
P-values at Week 96 LPV/r+EFV vs LPV/r: 0.023LPV/r+EFV vs EFV: <0.001LPV/r vs EFV: 0.003
9%
17%
32%
7%10%
21%
EFV 188 171LPV/r 191 166LPV/r + EFV 197 173
Haubrich R et al., 14th CROI, Los Angeles 2007, #38 ACTG A5142
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RR adjusted by year of PI: 1.15 [1.062–1.25]RR adjusted by year of NNRTI: 0.94 [0.74–1.19]
None <1 1-2 2-3 3-4 4-5 5-6 >60 -1 -
2 -
3 -
4 -
5 -
6 -
7 -
8 -M
Is p
er
10
00
PY
FU
(9
5%
CI)
Years of Exposure to PI or NNRTI Total
PIs MI 16 7 12 19 25 23 12 22 136
PYFU 11815 3108 3808 5144 6108 5199 3525 3306 42013
NNRTIs MI 16 6 3 3 3 2 33
PYFU 11815 2585 2294 1980 1525 1425 21623
Friis-Møller N et al 13th CROI; 2006, #144 D:A:D
TOXICITY. HAART effect on CV risk driven by PIs
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TOXICITY. A5152s: VL Decrease Associated With Improved Endothelial Function
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 Med
ian
Ch
ang
e in
FM
D F
rom
Bas
elin
e (%
)LPV/NRTI
EFV/NRTI
EFV/LPV
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Overall
Week 4 Week 24
* * *
†
*P < .01 compared with baseline.†P < .01 compared with baseline and within group.
Torriani F, et al. Lipodystrophy Workshop 2007. Abstract O-18. Torriani F, et al. IAS 2007. Abstract WEAB302.
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RESISTANCE. Unadjusted and adjusted risk ratios
of virological failure by year of starting cART
1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, pre-HAART VL and CD4, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd drug count and nucleoside combination.
Lampe et al, Arch Intern Med 2006;166:521-528
0.5
1.0
1.5
2.0
2.5
3.03.54.0
Ris
k ra
tio
Strategy A
1996 19981997 1999 2000 2001 2002Year of starting CART
UnadjustedAdjusted 1Adjusted 2
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DEATH AIDS NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION COST
32 y/o maleCD4 cell count: 479Current viral load: 16000
TOXICITY RESISTANCE
– Transmitted resistance COST QOL DEATH AIDS NON-AIDS EVENTS
– CANCER
– CARDIOVASCULAR
– OTHER
– HIV TRANSMISSION “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION
NO TREATMENT TREATMENT
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PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular) & Toxicity & Transmission
32 y/o maleCD4 cell count: 479Current viral load: 16000Framingham risk: 8%Hepatitis Coinfection: No
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PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular, Other) & Toxicity & Transmission
32 y/o maleCD4 cell count: 479Current viral load: 16000Framingham risk: 8%Hepatitis Coinfection: No
?
NNT: ?
NNH: ?
NNT (Prevent Transmission): ?
NNH (Transmitted resistance): ?
SMART SUBSTUDY (NAÏVE/OFF-HAART, > 350)
Virologic Suppression StrategyContinuous therapy
(n = 249 not receiving ART at trial start)
Treatment Interruption StrategyDeferred 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)
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)
Mean follow-up: 16 months
Study halted early
SMART. The Journal of Infectious Diseases 2008; 197:1133– 44
No. at RiskNo. at Risk
Opportunistic disease and death
Months
Cum. Probability (X100)
Immediate ARTDeferred ART
Deferred ARTImmediate ART
Hazard Ratio = 4·38 (95%CI: 1·45-13·.2) p=0·009
Opportunistic disease (fatal and non-fatal)
Months
Cum. Probability (X100)
Hazard Ratio = 4·40 (95%CI: 1·23-15·8) p=0·02
Serious non-AIDS
Months
Cum. Probability (X100)
No. at Risk
Hazard Ratio = 7·05 (95% CI: 1·58-31·5) p=0·01
Composite endpoint
Months
Cum. Probability (X100)
No. at Risk
Hazard Ratio = 5·08 (95% CI: 1·91-13·5) p=0·001
Imm ARTDef ART
Imm ART
Def ART
Immediate ARTDeferred ART
CLINICAL OUTCOMES
START: Design
HIV-infected participants with CD4+ cell counts > 500 cells/mm3
Early ART Group
Immediately initiate ART
N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study
Deferred ART Group
Defer ART until CD4+ <350 cells/mm3 or symptoms develop
N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study
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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
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 RiskHepatitis CoinfectionHigh Viral LoadRapid CD4 cell decline
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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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“The practice of medicine is an art, based on science. Medicine is a science of uncertainty and an art of probability”
Sir William Osler
Dealing with uncertainty