How to best manage HIV patient ? 1 2 Treatment Failure Treatment success HIV therapy = a long life therapy

Why do we want to change a suppressive ART ? Reservoir Side effect Reduce drug burden Prevention Comorbidities How to modify ART? Simplification

Lipodystrophy increases inflammation and metabolic disorders

Concepts in Induction Maintenance ART Maintenance strategy Nb drugs required Depending on - HIV - RNA - CD4 - HIV DNA Which antiviral potency do we need - to maintain viral suppression - CD4 above 500 /mm3 - without enlarging reservoir ? Viral load 2–5 log drop Which markers can we use ? Viral DNA ? Activation markers ? Time

Drugs with relatively low potency and genetic barrier to resistance Simplication with drug burden reduction Monotherapy ? Newer efficacious and well tolerated ARVs with higher potency and genetic barrier to resistance Dual Therapy Dual Therapy Drugs with relatively low potency and genetic barrier to resistance ? Triple Therapy Triple therapy needed to ensure efficacy and limited emergence of resistance1 1. Perez-Valero I, et al. J Antimicrob Chemother. 2011;66:1954–62.

Switching therapy Objective : maintain viral suppression Decrease drug burden Decrease/ prevent toxicity Simple regimen Robust regimen Reconstitutes ART and resistance history The switched regimen has to include potent and robust drugs Do not let a drug in a position of functionnal monotherapy Do not keep resistant drugs that cumulates toxicity and cost

Modern dual-therapy studies : 48-week results 100 HIV-1 RNA <200 copies/mL HIV-1 RNA <50 copies/mL 80 % of patients 60 EFV + 2 NRTI (n=250) EFV + LPV/r (n=250) LPV/r BID + FTC/TDF (n=105) LPV/r BID + RAL BID (n=101) ATV/r QD + FTC/TDF (n=61) 40 LPV/r + 2 NRTI (n=253) ATV/r QD + FTC/TDF (n=30) ATV/r QD + MVC QD (n=60) DRV/r QD + RAL BID (n=112) ATV BID + RAL BID (n=63) 20 ACTG 5142* SPARTAN PROGRESS ACTG 5262 Study 1078** Created from 1. Portsmouth S, et al. AIDS 2011, Rome, Italy. Oral presentation TUAB0103; 2. Riddler SA, et al. NEJM 2008;358:2095–106; 3. Kozal MJ, et al. HIV Clin Trials 2012;13:119–30; 4. Reynes J, et al AIDS Res Hum Retro. 2012 Aug 3. [Epub ahead of print]. DOI: 10.1089/aid.2011.0275; 5. Taiwo B, et al. AIDS 2011;25:2113–22; 6. Mills A, et al. AIDS 2012, Washington, USA. Oral Presentation TUAB0102.

Dual therapy VF and resistance development1 Trial Arm VFs with genotypic data (%) Resistance detected at VF (%) *ACTG51422 (N=753) EFV + 2 NRTI (n=250) 46 (18) 22 (48) EFV + LPV/r (n=250) 56 (22) 39 (70) LPV/r + 2 NRTI (n=253) 78 (31) 16 (21) SPARTAN3 (N=93 [2:1]) ATV/r QD + FTC/TDF (n=30) 8 (27) 0 (0) ATV BID + RAL BID (n=63) 11 (17) 4 (36) PROGRESS4 (N=206) LPV/r BID + FTC/TDF (n=105) 3 (3) 1 (33) LPV/r BID + RAL BID (n=101) 4 (4) 1 (25) ACTG52625 (N=112) DRV/r + RAL BID (n=112) 28 (25) 5 (18) Study 10786 (N=121) ATV/r QD + FTC/TDF (n=61) 1 (2) ATV/r QD + MVC QD (n=60) 4 (7)

Dual therapy Summary of safety outcomes in studies of dual-therapies in ARV-naïve patients* Study Regimen Follow up Lipids Renal Bone Other ACTG 51421 LPV/r + EFV 96 weeks Elevated Not reported - PROGRESS2 LPV/r + RAL Improved CPK ↑ SPARTAN3 ATV† + RAL Neutral Bilirubin ↑ ACTG 52624 DRV/r + RAL 48 weeks Study 10785,6 ATV/r + MVC

Monotherapy with LPV/r*1 Induction/Maintenance PI/r monotherapy Monotherapy with LPV/r*1 MONARK Initial therapy M03-613 Induction/Maintenance OK04 Simplification 100 80 60 Patients (%) 40 SUPPRESSED (SHORT†) SUPPRESSED (LONG‡) NAÏVE 20 16 32 48 16 32 48 64 80 96 12 24 36 48 Week Wk Discontinued On study, HIV-1 RNA 50–400 copies/mL On study, HIV-1 RNA >400 copies/mL On study, HIV-1 RNA <50 copies/mL *Boosted PI monotherapy is an off-label approach. †Short-term suppression: ≤24 weeks;2 ‡Long-term suppression: >6 months.3 Adapted from 1. Arribas JR, EACS 2009, Cologne, Germany. Oral Presentation; 2. Cameron WD, et al. J Infect Dis. 2008;198:2234–40; 3. Arribas JR, et al. JAIDS 2005;40:280–7.

MONET: Primary Efficacy Analysis: HIV RNA <50 copies/mL at Week 48 Per Protocol analysis (PP) Intent to Treat analysis (ITT) Primary analysis 1.6%; lower limit 95%CI: -10.1% 1%; lower limit 95%CI: -9.9% 100 87.8% 90 86.2% 85.3% 84.3% 80 HIV RNA <50 by Week 48 (%) 70 60 50 40 30 20 10 DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT) N=123 N=123 N=129 N=127 Table EFF 4-5 J. Arribas et al, AIDS 2010

MONOI Primary Endpoint W48 DRV/r DRV/r + NRTIs Who are the patients with VL< 50 cp/ml in DRV/r ? Patients with low VL and low DNA Now coming to the RESULTS and the PRIMARY END POINT AT W48 - Considering the per protocol population , the rate of virologic success of DRV monotherapy was 94.1% compared to 99% in the triple therapy group; the difference was 4.9% with a lower limit of CI of -9% under the 10% limit allowing therefore to assess the non-inferiority in the efficacy of monotherapy Considering then the intent to treat population , - the rate of success was 92% in the triple therapy arm and 87.5%in the monotherapy; - While the difference between the 2 arms is very consistent with a 4.5% difference, here the lower limit of CI is 11% which does not allow to assess non inferiority of the monotherapy arm.

ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART Randomized, double-blind, placebo-controlled, noninferiority phase III trial Part of ongoing effort to identify ARVs effective at lower doses (and cost) No significant difference in SAEs between treatment arms More pts with AEs for EFV 600 mg vs EFV 400 mg (47.2% vs 36.8%; P = .008) More pts discontinued EFV 600 mg due to AE vs EFV 400 mg (1.9% vs 5.8%; P = .010) HIV-1 RNA < 200 c/mL at Wk 48, % NC = F 90.0 85.8 Stratified by clinical site and HIV-1 RNA at screening (< 100,000 or ≥ 100,000 copies/mL) Wk 48 EFV* 400 mg + placebo + TDF/FTC 300/200 mg (n = 324) ART-naive pts, CD4+ 50-500 cells/mm3, HIV-1 RNA > 1000 copies/mL (N = 636) EFV* 600 mg + TDF/FTC 300/200 mg (n = 312) AE, adverse events; ITT, intention-to-treat analysis; NC = F, noncompleters = failure analysis; PP, per-protocol analysis; SAE, serious adverse events For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%2 0Data/Capsules/WELBB01.aspx Puls R, et al. IAS 2013. Abstract WELBB01. *EFV administered as 200-mg tablets. ©2012 Clinical Care Options, LLC. All rights reserved 13

Is HIV cure achievable ?

Drug free remission : Functional cure Drug burden decrease: Reduce ARV Decrease plasma HIV RNA to lowest replication Decrease reservoir Drug free remission : Functional cure Drug burden decrease: Reduce ARV Eradicate reservoir Sterilizing cure

Is Cure achievable ? Mississipi baby Visconti patients Elite controllers Never treated Special phenotype: HLA /Strong CD4 and CD8 response/High level cytokine towards HIV/Preserved central memory cells/Low immune activation Berlin patient : CCR5 defective stem cell graft Mississipi baby Visconti patients Treated at early stage of infection Chronic long term patients ? Salto

Guérison fonctionnelle chez un nouveau-né Le bébé du Mississipi (1) 36 Suivi de la charge virale Enfant né à 35 semaines de gestation par voie naturelle Test rapide VIH mère et CV réalisé au cours du travail positif (CV = 2 423 cp/ml) Pas d’ARV pendant la grossesse, ni travail Enfant : ARN et ADN VIH positifs (infection confirmée à J2, J7, J12 et J20) Début des ARV : ZDV/3TC/NVP à la 31e heure jusqu’à 7 jours puis ZDV/3TC/LPV/r de 7 jours à 18 mois 10 100 1 000 10 000 100 000 19 812 c/ml 2 617 c/ml 516 c/ml 265 c/ml < 48 c/ml ZDV/3TC/LPV/r J7-M18 ZDV/3TC/NVP H31-J7 20 40 60 80 A noter la faible CV de la mère, aucun dosage d’ARV réalisé et aucune notion sur les antécédents. De même, la faible CV du nouveau-né peut évoquer une contamination récente dans les dernières semaines de grossesse. Enfin, il manque aussi la quantification de l’ADN VIH. En effet, seul un résultat qualitatif est disponible. Persaud D, CROI 2013, Abs. 48LB

Mississipi baby 37 Born 35 weeks gestation ;mother tested at delivery low VL 2423 cp/ml ART started at H31 . 13 000 cp/ml up M18 then lost to FU M24 : functionnal cure 100 000 5 10 15 20 25 30 10 000 1 000 100 Mois HIV RNA : undetectable CV plasmatique indétectable ELISA negative HIV DNA: undetectable Viral load evolution (c/ml) Arrêt ARV Régime ARV 1 : ZDV/3TC/NVP (31 heures - 7 jours) Régime ARV 2 : ZDV/3TC/LPV/r (7 jours - 18 mois) Arrêt des ARV Batterie d’analyses virologiques ultra-sensibles Persaud D, CROI 2013, Abs. 48LB

Recul encore limité : 8 mois après arrêt des ARV Le Bébé du Mississipi 38 Mesure Echantillon Age au moment du test Quantité (pour 1 x 106 cellules) Nb cellules testées par puits (nombre de tests positifs) ADN VIH total PBMC 24 mois < 2,7 (0) 122 000 (0/2) 26 mois 4,2# (0) 113 000 (1/6) Cellules CD4 latentes < 3,5 (0) 96 500 (0/3) < 2,5 (0) 134 000 (0/6) Enrichies avec des cellules CD4 activées < 2,2 (0) 154 000 (0/6) < 2,6 (0) 130 000 (0/6) Cellules monocytaires 37,6* (0) 14 300 (1/3) < 11,5 (0) 29 000 (0/6) Virémie résiduelle Plasma 1- c/ml ND < 2 c/ml Virus infectieux < 1 pour 22 x 106 IUPM (aucune détection) IUPM : unité infectieuse par million de cellules. # Seuil de détection = 2,9 c/106 cellules ; * Seuil de détection = 23,3 c/106 cellules Pas de virus infectieux détecté dans le réservoir  le « Bébé du Mississipi » ? Recul encore limité : 8 mois après arrêt des ARV Persaud D, CROI 2013, Abs. 48LB

Post ART controllers After > 6 years OFF ART Visconti Patients Post ART controllers 12 patients treated at PHI ART Duration (med ): 35mths Duration Off ART : 5 years CD4 count - pre ART 489 ( 371-955) - at ART stop: 931 (354-1639 -last value : 837( 388-1598 HIV RNA - preART : 5.0 log ( 3 - 7.3) - last value : 1.7 log ( 1.7 -2.4) After > 6 years OFF ART Median RNA= <20 copies/mL Median DNA = 83 copies/M PBMC Very limited CD8 activation A. Saez-Cirion et al., # F-126 – CROI 2011 (Boston)

SALTO ANRS 116 Treatment interruption in early treated patients with CD4 > 350 and VL < 50 000 cp/ml 95 patients Age 40 years (IQR: 36–45). Pre-cART values CD4 : 454 /mL (392–576) VL : 4.3 log10 cp/ml (3.9 – 4.5) CD4 nadir : 382 /mL (340–492). Duration of cART : 5.3 years (4.0–6.0)- Baseline values CD4 count : 813 cells/mL (695–988), DNA : 206 copies/106 PBMCs (IQR: 53–556) 12 months post TI - 7/95 patients still had a VL<400 cp/ml KP: 7.5%, CI: 3.7-14.6) - 4 kept a VL<400 copies/mL up to 36 months; - All had CD4 cell >500/mm3 HIV DNA was the only significant predictor of maintaining VL < 400 cp/ml med value : < 10 vs 233 cp / 106PBMCs p < 0.001 Piketty et al, J Med Virol, 2010;82:1020-3 Assoumou et al, CROI 2013

Why do we need a Cure for HIV ? How ? To control the HIV pandemics Current AntiRetroVirals NO AIDS Persistence of HIV Reservoirs Can we decrease the HIV reservoirs and stop ART? Functional Cure ? Reduce drug burden or eradicate HIV Sterilizing Cure ?

Potential strategies to reduce HIV reservoirs Massive CD4 T-cell depletion Bacterial translocation ARV Intervention Intensification Nevirapine Immune Intervention Anti-HIV vaccine IL7 Cellular Immunity CD8 CD4 Maraviroc Anti-inflammatory drugs - Statins - OH-Chlorochin Systemic Inflammation Pre-Probiotics Immune Activation Residual Replication Viral Co-Infections Antiviral drugs Gene therapy Anti-co-stimulatory molecules anti PD1 / anti PDL1 anti-CTLA4 anti-CD137 CD4 DC HIV Reservoirs Latency Quiescent T cells activation - IL7 Pre/post-transcriptional factors disruption HDACi HMBA

Goals of Anti RetroViral Therapy Normalized life expectancy No viral replication Normal CD4/CD8 Minimal Immune Activation/ inflammation Minimal HIV Reservoirs Prevent HIV Transmission

Need for individualized therapy in Long-term virological suppression Minimal ART Maximal viral suppression Optimal immune status and minimal activation Control of HIV Plasma Compartments Reservoirs ART Toxicity Cardio vascular risk Mitochondrial toxicity Bone disorders CNS ? AGING Cardiovascular risk Cancer Cognitive disorders Renal disorders 25

HIV is a global challenge Scientific Medical Social Human rights and dignity

Test any individual with sexual life Early treatment Maximal viral suppression Restore immunity > 500 CD4 Treatment as confort for life Treatment as a control for epidemics

ART for life Individualized therapy for each patient Unlikely that a single strategy could be administered life long Succession of different suppressive strategies according to different factors ( patient - HIV disease ) suppressive to mainain viral suppression Patient :age, sex, génétic , comorbidities Virus : pre ART level, resistance , reservoirs STRATEGIE 1 STRATEGIE 2 STRATEGIE3 STRATEGIE 4 STRATEGIE 5 Individualized therapy for each patient