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

2. 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)

3. 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)

4. 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)

5. 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)

6. 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. 3

7. 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 4

8. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Methods Characteristics of last sex reported at M12 VL measured at M12 Measures 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

9. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Baseline characteristics Standard ARTEarly ART Chi2/ t-test p-val N=467N=490 CD4 (/mm3) Median [IQR]488 [401-586]472 [388-580] 0.49 Sex Men93 (19.9%)94 (19.2%) 0.78 Women374 (80.1%)396 (80.8%) Age <30118 (25.3%)118 (24.1%) 0.30 30-40217 (46.5%)211 (43.1%) >40132 (28.2%)161 (32.9%) Marital status Single200 (42.8%)203 (41.4%) 0.52 Living in couple218 (46.7%)224 (45.7%) Widowed/Separated 49 (10.5%)63 (12.9%) 6

10. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Viral Load Wilcoxon rank-sum test p=0.51 7

11. 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) 7

12. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Last sexual partnership at M12 8

13. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 8 Last sexual partnership at M12

14. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Last sexual partnership at M12 8

15. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Estimated HIV transmission rates at last sexual intercourse in the past month 9

16. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Estimated HIV transmission rates at last sexual intercourse in the past month 90% [81%-95%] 9

17. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Discussion Sexual behaviors M12 after early ART initiation o 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 replication o Estimated… not measured o Consistent with previous results (Cohen et al, NEJM 2011; Baggaley et al, Epidemiology 2013) 10

18. 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 11

19. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Thank you for your attention! contact: kevin.jean@inserm.fr Any question?

20. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Immediate ART + 6-months IPT Randomization 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

21. 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 r : HIV transmission risk at last intercourse

22. 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 intercourse mean (r) = Î -First: among those sexually active in the past month -Then: in the whole population ( r = 0 if sexualy inactive)

23. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Sensitivity analysis Studied 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 armEarly arm Total sampleHughes et al, JID 2012Main analysis1.87 [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 sampleHughes 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 sampleGray 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 sampleHughes 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 sampleHughes 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%]

24. 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) idem2 [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]

25. 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)

26. 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%

27. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Characteristics at M12 Standard ARTEarly ARTChi2 p-val n=467n=490 Perceived health0.19 NA24 (.%)15 (.%) Excellente/very good126 (28.4%)139 (29.3%) Good278 (62.8%)309 (65.0%) Poor/bad39 (8.8%)27 (5.7%) Sexual problems0.37 NA24 (.%)13 (.%) No or not disturbed422 (95.3%)460 (96.4%) Not disturbed21 (4.7%)17 (3.6%) Sexual activity in the past 12 months0.51 Yes335 (71.7%)342 (69.8%) Multipartnership in the past 12 months0.11 Yes29 (6.2%)44 (9.0%) Last partner was:0.87 NA132 (.%)148 (.%) Cohabiting197 (58.8%)199 (58.2%) Not cohabiting138 (41.2%)143 (41.8%) Last partner’s serostatus0.47 Unknown147 (43.9%)163 (47.7%) HIV-89 (26.6%)78 (22.8%) HIV+99 (29.5%)101 (29.5%)

28. www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Sexual behaviors at M12, by gender MenWomen Standard ARTEarly ARTChi2 p Standard ARTEarly ARTChi2 p n=93n=94 n=374n=396 Sexual activity (past year)0.170.22 Oui73 (78.49%)81 (86.17%)262 (70.05%)261 (65.91%) Sexual activity (past month)0.210.026 Oui48 (51.61%)57 (60.64%)178 (47.59%)157 (39.65%) Risky sex0.310.051 Oui6 ( 6.45%)10 (10.64%)54 (14.44%)39 ( 9.85%) Partner's exposure to HIV0.74<.0001 Oui6 ( 6.45%)5 ( 5.32%)44 (11.96%)7 ( 1.77%)