Tas P et prvention combine Gilles PIALOUX Tenon

Tas. P et prévention combinée Gilles PIALOUX Tenon APHP COREVIH Idf Centre Vice Président SFLS www. vih. org ASSISES de la SFLS 2011

• Déclaration de conflits d’intérêts , Gilles Pialoux : Membre de board, d’un conseil scientifique, ou intervenant dans un symposium d’un laboratoire pharmaceutique : Abbott, Boehringer-Ingelheim, BMS, GSK, Gilead, MSD, Pfizer, Roche, Schering-Plough, Nephrotec, Tibotec, Vii. VHealthcare Parts sociales ou actions dans un laboratoire pharmaceutique : Aucune

Tas. P 2000 -2011* * elle fut longue la route …

2000 RAKAI

L’étude « Rakai » Quinn et al. N Engl J Med 2000; 342: 921 -9 Rakai

Tous Homme-Femme-Homme Pas de transmission si CV « indétectable » Etude « Rakai » : Risque de transmission en fonction de la charge virale 415 couples séro-discordants héterosexuels VIH-1 – 30 mois (fin des années 90); 21. 7% transmission VIH ! Quinn et al. N Engl J Med 2000; 342: 921 -9

2011 HPTN 052

CONFIDENTIAL – NOT FOR EXTERNAL USE HPTN 052 Study Design The scaling up in Tas. P 8 Stable, healthy, serodiscordant couples, sexually active CD 4 count: 350 to 550 cells/mm 3 HPTN 052 Immediate ART CD 4 350 -550 Randomization Delayed ART CD 4 <250 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 9 HPTN 052 Enrollment 10, 838 Individuals Screened Major reasons for exclusion: 3058 HIV+ but CD 4 count out of range 2565 HIV- but HIV+ partner ineligible 308 Seroconcordant couples 155 Ineligible due to sexual history 1763 Couples (3526 Individuals) Randomized Immediate Arm 886 Couples Delayed Arm 877 Couples Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 10 HPTN 052 Enrollment (Total Enrollment: 1763 couples) U. S. Thailand Americas 278 India Kenya Malawi Brazil Zimbabwe Botswana South Africa 954 Asia 531 Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 11 HPTN 052 Enrollment Region Americas (278) Asia (531) Africa (954) Site Couples Porto Alegre, Brazil 90 Rio de Janeiro, Brazil 186 Boston, United States 2 Chennai, India 250 Pune, India 175 Chiang Mai, Thailand 106 Gaborone, Botswana 77 Kisumu, Kenya 60 Blantyre, Malawi 230 Lilongwe, Malawi 251 Johannesburg, South Africa 46 Soweto, South Africa 50 Harare, Zimbabwe 240 Total 1763 Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 12 HPTN 052: Baseline Characteristics Index Partner Immediate Delayed N = 886 N = 877 N = 893 N = 882 Female 49% 50% 49% 47% Age (median) 33 32 32 32 Married 94% 95% 93% 94% Any unprotected sex 6% 8% 8% 8% 442 428 [373 -522] [357 -522] --- 4. 4 [3. 8 -4. 9] [3. 9 -4. 9] --- CD 4 (median [IQR]) HIV RNA log 10 (median [IQR]) Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 13 HPTN 052: Baseline Characteristics Index Partner Immediate Delayed N = 886 N = 877 N = 893 N = 882 Female 49% 50% 49% 47% Age (median) 33 32 32 32 Married 94% 95% 93% 94% Any unprotected sex 6% 8% 8% 8% 442 428 [373 -522] [357 -522] --- 4. 4 [3. 8 -4. 9] [3. 9 -4. 9] --- CD 4 (median [IQR]) HIV RNA log 10 (median [IQR]) Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE DSMB Recommendation 14 April 28, 2011 “The Board recommends that the results of the trial be announced as soon as possible” HPTN 052 continues to follow couples, but all HIVinfected participants are being offered ART Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 15 HPTN 052: HIV-1 Transmission Total HIV-1 Transmission Events: 39 Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 • 18/28 (64%) transmissions from infected participants with CD 4 >350 cells/mm 3 Immediate Arm: 1 Delayed Arm: 27 • 23/28 (82%) transmissions in sub-Saharan Africa • 18/28 (64%) transmissions from female to male partners !? p < 0. 001 Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 16 Multivariate Analysis – Linked Transmission Variable Hazard Ratio 95% Confidence Interval Treatment (immediate vs. delayed) 0. 04 [0. 01 - 0. 28] Baseline CD 4 (per 100 CD 4 Increment) 1. 24 [1. 00 - 1. 54] Baseline VL (per unit log increment) Baseline condom use (100% vs. <100%) Gender (HIV +) (male vs. female) 96 % de réduction 2. 84 du risque de transmission hétérosexuelle si 0. 33 traitement anti-VIH 0. 73 VIH+ du partenaire [1. 51 - 5. 41] [0. 12 - 0. 91] [0. 33 - 1. 65] Cohen, M et al. 6 th IAS Conf. MOAX 0102.

CONFIDENTIAL – NOT FOR EXTERNAL USE 17 All Primary Clinical Events (N = 129) 17 subjects experienced >1 primary clinical event Immediate Delayed Total (N=129) 53 76 Tuberculosis 17 33 Severe bacterial infection 16 11 Death 10 13 Chronic herpes simplex Bacterial pneumonia (recurrent) Oesophageal candidiasis Cervical carcinoma Kaposi’s sarcoma … 3 et en plus 2 le traitement 2 précoce diminue 0 la 1 morbidité 7 2 2 2 1 Wasting syndrome 0 lymphoma, PCP, septicemia 2 * Extrapulmonary crypto, HIV-related encephalopathy, (recurrent) Grinsztejn, B et al. 6 th IAS Conf. MOAX 0105.

Prévention combinée « Sida : 12 millions d’infections « évitables avec une prévention combinée » (AFP 6/8/2008)

Efficacité des outils de Prevention vih Essais randomisés - Study Effect Size, % (95% CI) 0 Abdool Karim SS, et al. Lancet. 2011 96 (73 -99) 80 % [35, 4 - 94, 2%] 73 (49 -85) 63 (21 -84) 54 (38 -66) 44 (15 -63) 42 (21 -58) 39 (6 -60) 31 (1 -51) 20 40 60 Efficacy (%) 80 100 préservatif ART for prevention; HPTN 052, Africa, Asia, Americas Pr. EP for discordant couples; Partners Pr. EP, Uganda, Kenya Pr. EP for heterosexual men and women; TDF 2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu Pr. EP for MSMs; i. Pr. EX, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV 144, Thailand

Qu’est ce que la prévention combinée ? 1 4 2 3 Coates et al. , Lancet 2008

Pathway to reversing the epidemic Seeing prevention research/funding as a continuum Circumcision Treatment as prevention ARV Pr. EP (oral, microbicide) Partially effective vaccine HIV incidence highly effective vaccine Behavioral and structural interventions Robin Shattock IAS Roma 2011 et Science. 2011; 333: 42 -3