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Transcript of Www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Early ART, sexual behaviors and HIV-1...
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Early ART, sexual behaviors and HIV-1 transmission risk:
Estimates from the Temprano-ANRS 12136 Randomized Controlled Trial (Abidjan, Côte d’Ivoire)
K. Jean, D. Gabillard, R. Moh, C. Danel, R. Fassassi, A. Desgrées-du-Loû, S. Eholié, F. Lert, X. Anglaret, R. Dray-Spira
Inserm UMR-S 1018, Centre for Research in Epidemiology and Population Health, Villejuif, FRANCE
PAC-CI Program, CHU de Treichville, Abidjan, CÔTE D’IVOIRE
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Context - TasP 2
HPTN-052: among serodiscordant couples, early ART (350<CD4<550) decreases HIV transmission by 96%, as compared to initiation <250 CD4 (Cohen et al, NEJM 2011)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Context - TasP
Extrapolation to the population-level impact?
2
HPTN-052: among serodiscordant couples, early ART (350<CD4<550) decreases HIV transmission by 96%, as compared to initiation <250 CD4 (Cohen et al, NEJM 2011)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Context - TasP
Extrapolation to the population-level impact?
• Less than 1/3 of HIV transmission in sub-Saharan Af. occur among serodiscordant couples (Chemaitelly et al, AIDS 2013)
• Which preventive impact of early ART among a population with diverse sexual partnerships (stable/non-stable partners, serodiscordant/ concordant)?
2
HPTN-052: among serodiscordant couples, early ART (350<CD4<550) decreases HIV transmission by 96%, as compared to initiation <250 CD4 (Cohen et al, NEJM 2011)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Context - TasP
Extrapolation to the population-level impact?
• Less than 1/3 of HIV transmission in sub-Saharan Af. occur among serodiscordant couples (Chemaitelly et al, AIDS 2013)
• Which preventive impact of early ART among a population with diverse sexual partnerships (stable/non-stable partners, serodiscordant/ concordant)?
• Impact of early ART on sexual behaviors?• Observational studies documented decreased risky sexual behaviors after
ART initiated according to WHO guidelines (Venkatesh et al, AIDS 2011)• What effect among patients treated earlier, thus potentially healthier?
2
HPTN-052: among serodiscordant couples, early ART (350<CD4<550) decreases HIV transmission by 96%, as compared to initiation <250 CD4 (Cohen et al, NEJM 2011)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Objectives
1. To measure the impact of early antiretroviral therapy (ART) on sexual behaviors,
2. To estimate its protective effect against HIV transmission
among adults engaged in diverse heterosexual partnerships
in Abidjan, Côte d’Ivoire.
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Temprano-ANRS12136• Multicenter randomized open-label superiority trial
conducted in Côte d’Ivoire– To assess the clinical benefits and risks of early ART +/- INH prophylaxis– Main outcomes: mortality and morbidity– Results expected in 2015
• Inclusion criteria: >18y; HIV-1 or HIV 1+2; 350<CD4<800mm3 and no current WHO criteria for starting ART
« Early ART »ART initiation immediatly
after inclusion
« Standard ART »WHO recommendations
(CD4<350mm3)
Randomization
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Methods• Characteristics of last sex reported at M12• VL measured at M12Measures
• Risky sex: unprotected last sex in the past month with a partner of HIV-/unknown status
• Partner’s exposure to HIV: risky sex + VL>300 copies/mL• HIV transmission risk at last intercourse: sex. behaviors + VL +
per-coital HIV transmisson proba (Hughes et al, JID 2012)
Outcomes
• Sexual behaviors comparison between early vs. standard ART: Chi2 test
• For each ART group: estimated transmission rate at last intercourse
• Preventive effect of early ART: ratio of estimated transmission rates
• (CI95%: bootstrap, 10,000 replications)
Analysis
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Baseline characteristics
Standard ART Early ART Chi2/ t-test p-val
N=467 N=490CD4 (/mm3) Median [IQR] 488 [401-586] 472 [388-580] 0.49Sex Men 93 (19.9%) 94 (19.2%) 0.78
Women 374 (80.1%) 396 (80.8%)Age <30 118 (25.3%) 118 (24.1%) 0.30
30-40 217 (46.5%) 211 (43.1%)
>40 132 (28.2%) 161 (32.9%)Marital status Single 200 (42.8%) 203 (41.4%) 0.52
Living in couple 218 (46.7%) 224 (45.7%)
Widowed/Separated 49 (10.5%) 63 (12.9%)
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Viral Load
Wilcoxon rank-sum test
• p=0.51
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Viral Load
Wilcoxon rank-sum test
• p=0.51 • p<0.001
Standart ART: 70 (15%) initiated ART(Median time until ART: 9.5 months)
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Estimated HIV transmission rates at last sexual intercourse in the past month
9
Among all participants
Exp
ecte
d H
IV-tr
ansm
issi
on ra
te /1
0,00
0
0.0
0.5
1.0
1.5
2.0
2.5
Standard armEarly arm
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Among all participants
Exp
ecte
d H
IV-tr
ansm
issi
on ra
te /1
0,00
0
0.0
0.5
1.0
1.5
2.0
2.5
Standard armEarly arm
Estimated HIV transmission rates at last sexual intercourse in the past month
90%[81%-95%]
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Discussion
• Sexual behaviors M12 after early ART initiationo No difference as compared to standard ART (large sample size)o Levels of sexual behaviors consistent with previous studies
conducted in Côte d’Ivoire (Moatti et al, 2003; Diabate et al, 2008; Protopopescu et al, 2010)
• Protective effect of early ART: 90%
o Estimated among a population closer to the general HIV+ population (as compared to previous studies)
o Through biological effect of ART on HIV replicationo Estimated… not measuredo Consistent with previous results (Cohen et al, NEJM 2011; Baggaley et al,
Epidemiology 2013)
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Perspectives on TasP
Our results, obtained among a population with diverse sexual partnerships suggest a strong protective effect of early ART on HIV transmission without
any effect on sexual behaviors
• For now: early ART is recommended only for patients in serodiscordant couples
• Acceptability /equity of prioritizing access to early ART to this population? (Delva et al, Plos Med 2012)
• Targeting solely these couples may have a limited impact (Chemaitelly et al, AIDS 2013, Bellan et al, Lancet 2013)
Results providing evidence for the public health significance of early ART among a wider segment of the HIV-infected population
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www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Thank you for your attention!
contact: [email protected]
Any question?
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Immediate ART+ 6-months IPT
Ra
ndo
miz
atio
n
Immediate ART
ART according to WHO criteria
Temprano trial: design
6-months IPT ART according to WHO criteria
2009 WHO criteria for ART initiation: <350 CD4 or WHO clinical stage 3 or 4
IPT: Isoniazid Prophylaxis against Tuberculosis
« standard ART » group
« early ART » group
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Methods: Estimate of preventive effect
Characteristics of the last intercourse (condom use, serodiscordant/concordant
partner)
Viral Load (measured at the time of last
intercourse)
Ref: Hughes et al, JID 2012
Then: • If VL<300 copies/mL: r =0 (sensitivity analysis)
• If partner is HIV+: r =0• If partner is HIV?: considered as HIV- (sensitivity analysis)
• If condom reported: r =0.22*p• If patient is women, then partner considered as circumcised man: r =0.53*p
(Additional sensitivity analysis)
r : HIV transmission risk at last intercourse
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Methods: Estimate of preventive effect
Characteristics of the last intercourse (condom use, serodiscordant/concordant
partner)
Viral Load (measured at the time of last
intercourse)
r : HIV transmission risk at last intercourse
Ref: Hughes et al, JID 2012
For both ART group: Estimated
transmission rate at last intercoursemean (r) = Î
Estimated protective effect:
- First: among those sexually active in the past month- Then: in the whole population (r = 0 if sexualy inactive)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Sensitivity analysisStudied
population
VL-specific HIV transmission
probabilities of reference
Specific assomption
Expected HIV-transmission events at last sexual intercourse in the past month, for 10,000 persons
[95%CI]
Protective effect [95%CI]
Standard arm Early arm
Total sample Hughes et al, JID 2012 Main analysis 1.87 [1.39-2.39] 0.20 [0.09-0.33] 89% [84-92%]
Baseline CD4 count>350 Hughes et al, JID 2012 Same as in the main
analysis 2.03 [1.47-2.66] 0.20 [0.08-0.36] 90% [81-96%]
Total sample Hughes et al, JID 2012
Considering a VL equal to the detectability threshold (=300
copies/mL) for patients with an undetectable VL
1.88 [1.40-2.40] 0.30 [0.19-0.43] 84% [75-90%]
Total sample Gray et al, Lancet 2001 Same as in the main analysis 1.72 [1.36-2.11] 0.25 [0.14-0.4] 85% [75-92%]
Total sample Hughes et al, JID 2012
Considering a probability of 0.4 to be HIV-positive for a sexual partner with
unknown serostatus
1.34 [1.01-1.70] 0.13 [0.07-0.22] 90% [82-95%]
Total sample Hughes et al, JID 2012
Considering all participants as having had a last unprotected intercourse with a HIV-
negative partner
18.4 [16.6-20.3] 2.1 [1.4-2.9] 89% [84-92%]
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Preventive effect among sub-sample
Criteria defining the subpopulation
Parameters taked into account Standard arm transmission rate (last intercourse,
/10,000 pers)
Early arm transmission rate(last intercourse,
/10,000 pers)
Transmission reduction
Women (Standard arm=374; Early arm=396)
Sexual intercourse, partner serostatus, condom, circumcision 1.83 [1.3-2.44] 0.11 [0.05-0.19] 0.94 [0.88-0.97]
Men (Standard arm=93 ; Early arm=94) idem 2 [0.98-3.28] 0.54 [0.12-1.17] 0.73 [0.23-0.94]
Last intercourse with a stable HIV-negative partner (Standard arm=72 ; Early arm=68)
idem 3.1 [2.07-4.24] 0.3 [0.12-0.52] 0.90 [0.81-0.96]
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Representativity of the population?
• Results obtained in a selected pop. (long-term trial)– Virological failure rate (≈ 20%): comparable to what is
routinely observed (Barth et al, Lancet Inf Dis 2010)
– 80% of women: may reflect sex-specific prevalence + testing landscape in Côte d’Ivoire (Jean et al, Plos One 2012)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Probability of ART initiation in the standard group
• Median time until ART initiation: ≈24 months
• (1st quartile: ≈ 13 months)
• % under ART at the end of follow-up (30-months): ≈ 60%
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Characteristics at M12Standard ART Early ART Chi2 p-val
n=467 n=490Perceived health 0.19
NA 24 ( .%) 15 ( .%)Excellente/very good 126 (28.4%) 139 (29.3%)
Good 278 (62.8%) 309 (65.0%)Poor/bad 39 (8.8%) 27 (5.7%)
Sexual problems 0.37NA 24 ( .%) 13 ( .%)
No or not disturbed 422 (95.3%) 460 (96.4%)Not disturbed 21 (4.7%) 17 (3.6%)
Sexual activity in the past 12 months 0.51Yes 335 (71.7%) 342 (69.8%)
Multipartnership in the past 12 months 0.11Yes 29 (6.2%) 44 (9.0%)
Last partner was: 0.87
NA 132 ( .%) 148 ( .%)Cohabiting 197 (58.8%) 199 (58.2%)
Not cohabiting 138 (41.2%) 143 (41.8%)Last partner’s serostatus 0.47
Unknown 147 (43.9%) 163 (47.7%)HIV- 89 (26.6%) 78 (22.8%)
HIV+ 99 (29.5%) 101 (29.5%)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Sexual behaviors at M12, by genderMen Women
Standard ART Early ART Chi2 p
Standard ART Early ART Chi2 p
n=93 n=94 n=374 n=396 Sexual activity (past year) 0.17 0.22
Oui 73 (78.49%) 81 (86.17%) 262 (70.05%) 261 (65.91%)
Sexual activity (past month) 0.21 0.026
Oui 48 (51.61%) 57 (60.64%) 178 (47.59%) 157 (39.65%)
Risky sex 0.31 0.051
Oui 6 ( 6.45%) 10 (10.64%) 54 (14.44%) 39 ( 9.85%)
Partner's exposure to HIV 0.74 <.0001
Oui 6 ( 6.45%) 5 ( 5.32%) 44 (11.96%) 7 ( 1.77%)