Context - TasP

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


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)


Context - TasP

Extrapolation to the population-level impact?

2



Context - TasP


• 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



Context - TasP


• 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



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.

3


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

4


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

5


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%)

6


Viral Load

Wilcoxon rank-sum test

• p=0.51

7


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)

7


Last sexual partnership at M12 8


8Last sexual partnership at M12


Last sexual partnership at M12 8


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


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%]

9


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)

10


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

11


Thank you for your attention!

contact: [email protected]

Any question?


Immediate ART+ 6-months IPT

Ran

dom

izat

ion

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


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


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)


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%]


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%]


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%]


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]


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)


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%


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%)


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%)

Documents

Context - TasP