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

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Présentation au sujet: "How to best manage HIV patient ? HIV therapy = a long life therapy Treatment success Treatment Failure 1 1 2 2."— Transcription de la présentation:

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

2 Why do we want to change a suppressive ART ? Reservoir Side effect Reduce drug burden Prevention Comorbidities How to modify ART? Simplification 2

3 Lipodystrophy increases inflammation and metabolic disorders

4 Time Viral load Induction Maintenance strategy Concepts in Induction Maintenance ART 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 ? 2–5 log drop Which markers can we use ? Viral DNA ? Activation markers ?

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

6 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

7 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 Aug 3. [Epub ahead of print]. DOI: /aid ; 5. Taiwo B, et al. AIDS 2011;25:2113–22; 6. Mills A, et al. AIDS 2012, Washington, USA. Oral Presentation TUAB0102. DRV/r QD + RAL BID (n=112) LPV/r BID + RAL BID (n=101) ATV BID + RAL BID (n=63) ATV/r QD + MVC QD (n=60) LPV/r BID + FTC/TDF (n=105) ATV/r QD + FTC/TDF (n=30) ATV/r QD + FTC/TDF (n=61) EFV + LPV/r (n=250) EFV + 2 NRTI (n=250) LPV/r + 2 NRTI (n=253) Modern dual-therapy studies : 48-week results % of patients HIV-1 RNA <50 copies/mL ACTG 5142* SPARTANPROGRESSACTG 5262Study 1078** HIV-1 RNA <200 copies/mL

8 Dual therapy TrialArm VFs with genotypic data (%) Resistance detected at VF (%) *ACTG (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) SPARTAN 3 (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) PROGRESS 4 (N=206) LPV/r BID + FTC/TDF (n=105)3 (3)1 (33) LPV/r BID + RAL BID (n=101)4 (4)1 (25) ACTG (N=112) DRV/r + RAL BID (n=112)28 (25)5 (18) Study (N=121) ATV/r QD + FTC/TDF (n=61)1 (2)0 (0) ATV/r QD + MVC QD (n=60)4 (7)0 (0) VF and resistance development 1

9 Dual therapy StudyRegimenFollow upLipidsRenalBoneOther ACTG LPV/r + EFV 96 weeksElevated Not reported - PROGRESS 2 LPV/r + RAL 96 weeksElevatedImproved CPK ↑ SPARTAN 3 ATV † + RAL 96 weeksNeutral Not reported Bilirubin ↑ ACTG DRV/r + RAL 48 weeksElevated Not reported - Study ,6 ATV/r + MVC 96 weeks Not reported ImprovedBilirubin ↑ Summary of safety outcomes in studies of dual-therapies in ARV-naïve patients*

10 PI/r monotherapy 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. Discontinued On study, HIV-1 RNA >400 copies/mL On study, HIV-1 RNA 50–400 copies/mL On study, HIV-1 RNA <50 copies/mL MONARK Initial therapy M Induction/Maintenance Week Wk OK04 Simplification 024 Patients (%) NAÏVE SUPPRESSED (SHORT † ) SUPPRESSED (LONG ‡ ) Monotherapy with LPV/r* 1 *Boosted PI monotherapy is an off-label approach. † Short-term suppression: ≤24 weeks; 2 ‡ Long-term suppression: >6 months. 3

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

12 J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB 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

13  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) ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART Puls R, et al. IAS Abstract WELBB01. EFV* 400 mg + placebo + TDF/FTC 300/200 mg (n = 324) EFV* 600 mg + TDF/FTC 300/200 mg (n = 312) ART-naive pts, CD cells/mm 3, HIV-1 RNA > 1000 copies/mL (N = 636) Wk 48 Stratified by clinical site and HIV-1 RNA at screening (< 100,000 or ≥ 100,000 copies/mL) *EFV administered as 200-mg tablets. HIV-1 RNA < 200 c/mL at Wk 48, % NC = F

14 Is HIV cure achievable ?

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

16 Is Cure achievable ? 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

17 Guérison fonctionnelle chez un nouveau-né Le bébé du Mississipi (1) Persaud D, CROI 2013, Abs. 48LB Enfant né à 35 semaines de gestation par voie naturelle Test rapide VIH mère et CV réalisé au cours du travail positif (CV = 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 31 e heure jusqu’à 7 jours puis ZDV/3TC/LPV/r de 7 jours à 18 mois c/ml c/ml 516 c/ml 265 c/ml < 48 c/ml ZDV/3TC/LPV/r J7-M18 ZDV/3TC/NVP H31-J Suivi de la charge virale 36

18 Persaud D, CROI 2013, Abs. 48LB Born 35 weeks gestation ;mother tested at delivery low VL 2423 cp/ml ART started at H cp/ml up M18 then lost to FU M24 : functionnal cure 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 37 Mississipi baby

19 MesureEchantillon Age au moment du test Quantité (pour 1 x 10 6 cellules) Nb cellules testées par puits (nombre de tests positifs) ADN VIH total PBMC 24 mois< 2,7 (0) (0/2) 26 mois4,2# (0) (1/6) Cellules CD4 latentes 24 mois< 3,5 (0) (0/3) 26 mois< 2,5 (0) (0/6) Enrichies avec des cellules CD4 activées 24 mois< 2,2 (0) (0/6) 26 mois< 2,6 (0) (0/6) Cellules monocytaires 24 mois37,6* (0) (1/3) 26 mois< 11,5 (0) (0/6) Virémie résiduellePlasma 24 mois1- c/mlND 26 mois< 2 c/mlND Virus infectieuxCellules CD4 latentes24 mois < 1 pour 22 x 10 6 IUPM (aucune détection) ND 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 # Seuil de détection = 2,9 c/10 6 cellules ; * Seuil de détection = 23,3 c/10 6 cellules Le Bébé du Mississipi 38

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

21 SALTO ANRS 116 Treatment interruption in early treated patients with CD4 > 350 and VL < cp/ml 95 patients Age 40 years (IQR: 36–45). Pre-cART values CD4 : 454 /mL (392–576) VL : 4.3 log 10 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/10 6 PBMCs (IQR: 53–556) 12 months post TI - 7/95 patients still had a VL<400 cp/ml KP: 7.5%, CI: ) - 4 kept a VL<400 copies/mL up to 36 months; - All had CD4 cell >500/mm 3 - HIV DNA was the only significant predictor of maintaining VL < 400 cp/ml med value : < 10 vs 233 cp / 10 6 PBMCs p < Piketty et al, J Med Virol, 2010;82: Assoumou et al, CROI 2013

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

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

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

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

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

27 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

28 J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB ART for life 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


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