une nouvelle donne - aei · change from baseline (on-treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72...
TRANSCRIPT
![Page 1: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/1.jpg)
Alléger, Simplifier ou InterrompreDe nouveaux produits : une nouvelle donne ?
Prof. Jacques REYNES
Centre Hospitalier Universitairede MONTPELLIERFRANCE
SFLS Tours 22 Octobre 2004
![Page 2: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/2.jpg)
J. Reynes Octobre 2004
France :Quels patients, quels besoins ?
![Page 3: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/3.jpg)
J. Reynes Octobre 2004
France :Quels patients, quels besoins ?
• Plus du 1/3 des patients en prise en charge tardive (CD4 < 200
et/ou SIDA) avec persistance d’une mortalité initiale
• Près de 60 % des patients avec contrôle virologique
(CV < 500 copies) mais lipodystrophiques!
• Environ 5 % en situation d’échec sévère
(CD4 < 200 et CV > 30 000/ml)
![Page 4: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/4.jpg)
J. Reynes Octobre 2004
Nouveaux antirétroviraux
• Inhibiteurs de protéase:
– Atazanavir
– Tipranavir
• Inhibiteurs d’entrée
– Fusion (gp41) : T20
– Attachement récepteurs (gp120/CD4, CCR5/CXCR4)
![Page 5: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/5.jpg)
J. Reynes Octobre 2004
Efficacy and Safety of Atazanavir (ATV) With Ritonavir (RTV) or Saquinavir (SQV)
vs Lopinavir/Ritonavir (LPV/RTV) in Patients Who Have Experienced Virologic Failure
on Multiple HAART Regimens
48-Week Results From BMS AI424-045
E DeJesus, B Grinsztejn, C Rodriguez, L Nieto-Cisneros, J Coco, A Lazzarin, K Lichtenstein, M Johnson, T Kelleher, A Rightmire, S Sankoh, and R Wilber
![Page 6: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/6.jpg)
J. Reynes Octobre 2004
*Both ATV regimens vs LPV/RTV:P*Both ATV regimens vs LPV/RTV:P--value < 0.0001value < 0.0001
BMS-045 : Bilan lipidique à S24BMS-045 : Bilan lipidique à S24
-8 -10 -7-2
-9 -11
-1
-14
3
-4
31
0
-30
-10
10
30
50
TC LDL-C HDL-C TG
% m
oyen
de
varia
tion
*
*
ATV 300/RTV
LPV/RTVLPV/RTV
ATV 400/SQVATV 400/SQV
Badaro IAS 2003, abs 118
![Page 7: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/7.jpg)
J. Reynes Octobre 2004
Primary Endpoint: Virologic Efficacy Through 48 Weeks
Time Averaged Difference Estimate: ATV/r - LPV/r: 0.13 log10 c/mL. [97.5% CI: -0.12, 0.39]ATV/SQV - LPV/r: 0.33 log10 c/mL. [97.5% CI: 0.07, 0.60]
BMSBMS--045: Experienced (boosted ATV vs boosted LPV)045: Experienced (boosted ATV vs boosted LPV)
-1.87-1.93
-1.55
Study Week
-3
-2
-1
0
2 4 8 12 16 24 32 40 48
Mea
n H
IV-1
RN
A
Cha
nge
from
Bas
elin
e(lo
g 10
c/m
l)
ATV/rLPV/rATV/SQV
baseline
![Page 8: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/8.jpg)
J. Reynes Octobre 2004
CD4 Cell Count Change from Baseline Through 48 Weeks
BMSBMS--045: Experienced (boosted ATV vs boosted LPV)045: Experienced (boosted ATV vs boosted LPV)
72
110121
baseline
ATV/r (n=120)
ATV 400/SQV (n=115)LPV/r (n=123)
2-20
0
20
40
60
80
100
120
140
160
4 8 12 16 24 32 40 48
Weeks
CD4
Chan
ge (c
ells
/mm
3)
![Page 9: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/9.jpg)
J. Reynes Octobre 2004
Entrée du VIH :quel paysage fin 2004?
![Page 10: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/10.jpg)
J. Reynes Octobre 2004
FusionComplète
Liaison au CD4
HR1-HR2interaction
CCR5 CXCR4
VIH
HIVgp120
Ancrage
CD4
Liaison au Corecepteur
Lymphocyte CD4
HIV
HIV
HIV
gp41
gp41
Entrée VIH : Etapes
gp120
![Page 11: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/11.jpg)
J. Reynes Octobre 2004
Entrée du VIHquel paysage ?
• T20
• Anti CCR5
– SCH-D
– UK-427,857
– GW 873140
![Page 12: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/12.jpg)
J. Reynes Octobre 2004
Réactions au site d’injection
![Page 13: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/13.jpg)
J. Reynes Octobre 2004
0
20
40
60
80
100
0 4 8 12 16 20 24
1. Minimes
2. Modérées
3. Sévères (limitant activités
ou nécessitant analgésique)Semaines
% d
e R
SI
TORO 1 et 2 : Prévalence des réactions au site d’injection
ΝΒ: seulement 3 % d’arrêts liés au Réactions locales
![Page 14: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/14.jpg)
J. Reynes Octobre 2004
T20non prescription = perte de chance ?
![Page 15: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/15.jpg)
J. Reynes Octobre 2004
TOROs :quelles données ?
![Page 16: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/16.jpg)
J. Reynes Octobre 2004
TORO 1: Continent américainTORO 2: Europe & Australie(TORO = T-20 vs. Optimized Regimen Only)
• Etudes randomisées ( 2 TO+T20 / 1TO)• Injection par le patient 90 mg BID sous-cutanée• Patients ayant reçu les 3 classes d’antirétroviraux
et CV > 5 000 copies/ml• Près de 1 000 patients (Toro 1: 491, Toro 2: 504)
Evaluation du T20 en addition à un traitement optimisé (TO)
![Page 17: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/17.jpg)
J. Reynes Octobre 2004
TORO 1 & TORO 2: Protocol study design
– 6
Stable regimen
Screening period
ENF+OB
OB
BL 8 16 24 48
– 4
Sample for GT/PT*
Weeks
Randomized 2:1, thenstart ENF+OB or OB
Switch permitted at virologicalfailure** or at week 48
*GT = Genotypic Testing; PT = Phenotypic Testing
**Criteria for virological failure based on 2 consecutive values: 1. <0.5 log10 decrease from baseline starting at week 6 and 82. <1.0 log10 decrease from baseline starting at week 14 and 163. ≥≥≥≥2 log response and >1 log rebound at any time
Data following virological failure not included in primary efficacy analyses
![Page 18: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/18.jpg)
J. Reynes Octobre 2004
Demographics and baseline characteristics
8 (2.4)18 (2.7)≥ 5
21 (6.3)44 (6.7)4
61 (18.3)108 (16.3)3
93 (27.8)174 (26.3)2
95 (28.4)194 (29.3)1
53 (15.9)112 (16.9)Baseline GSS score, n (%) 0
77Median duration of prior ARV exposure (years)
1212Median number of prior ARVs
286 (85.6)523 (79.1)
Prior AIDS-defining event, n (%)
9788Median CD4 counts (cells/mm3)
5.095.10Mean plasma HIV-1 RNA (log10 copies/ml)
334661Number of patients
OBENF + OB
![Page 19: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/19.jpg)
J. Reynes Octobre 2004
TORO 1 & 2: efficacy at week 48
-1.48
-0.63
-1.6
-1.2
-0.8
-0.4
0
Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)
Delta=0.85p<0.0001
ENF + OBn=661
OB n=334
Mea
n ch
ange
in H
IV-1
RN
Afr
om b
asel
ine
at w
eek
48
Based on combined TORO 1 and TORO 2 database
![Page 20: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/20.jpg)
J. Reynes Octobre 2004
Benefit seen at week 24 is maintained at week 48:Percent responders at week 24 and week 48 (ITT)
47.2
37.432.7 30.4
15.9 18.324.9
12.015.017.1
6.3 7.8
0
20
40
60
80
100
% o
f pat
ient
s
ENF+OB OB
Week< 50 copies/mL
48 48 48≥≥≥≥1 log drop
from BL< 400 copies/mL
N=661 N=334
24 24 24
![Page 21: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/21.jpg)
J. Reynes Octobre 2004
CD4+ cell count adjusted means change from baseline intent-to-treat population (LOCF) TORO 1 & TORO 2
+ 71
+ 91
+ 35+ 45
0
50
100
W 24 W 48Study week
Cha
nge
from
BL
(cel
ls/m
m3 )
ENF+OB OB
P<0.0001
P<0.0001
![Page 22: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/22.jpg)
J. Reynes Octobre 2004
TOROs à 96 semaines
![Page 23: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/23.jpg)
J. Reynes Octobre 2004
Patient disposition (%) at 96 weeks
6.5%1.9%10.3%Admin/other 00%< 1%Abnormality of laboratory test
9.6%0%7.2%Injection site reaction 9.1%11.5%12.1%Adverse events
Switch to FUZEON + OB
n = 230n = 104
1.3%1.9%1.2%Failure to return 5.6%10.5%5.6%Refused treatment 16.5%12.5%10.1%Insufficient therapeutic response
1.7%< 1%< 1% Death
50.4%39.4%47.7%Total number of patients withdrawn
YesNo
OB (n = 334)
FUZEON + OB (n = 663)
Arastéh et al. XVth IAC Bangkok, 2004, MoOrB1058
![Page 24: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/24.jpg)
J. Reynes Octobre 2004
FUZEON + OB RNA and CD4 mean change from baseline (On-Treatment)
-2.0
-1.0
0 8 16 24 32 40 48 56 64 72 80 88 96Study Week
RN
A m
ean
chan
gefr
om B
LC
D4
mea
n ch
ange
from
BL
Viral load0
50
100
150
CD4119
166
- 2.07- 1.90
661 495 352661 478 337
VLCD4
![Page 25: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/25.jpg)
J. Reynes Octobre 2004
TOROs :un bénéfice précocement observé
![Page 26: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/26.jpg)
J. Reynes Octobre 2004
Time to HIV-1 RNA ≥ 1 log10 copies/ml change from baseline up to week 24
(ITT, Median estimated from all patients, discontinuation = censored)1.00
Prop
ortio
n w
ith re
spon
se
0.75
0.50
0.25
0
Time to ≥≥≥≥ 1.0 log10 decrease from baseline, days
0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210
ENF + OBOB
![Page 27: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/27.jpg)
J. Reynes Octobre 2004
Median change in CD4 cell count from baseline over the first 28 days of therapy
(ITT and GSS subgroups)
ENF + OBOB
Cha
nge
from
bas
elin
e in
CD
4 co
unt (
cells
/mm
3 )
628 313ITT GSS = 0
106 49n =
4438
10
22
0
10
20
30
40
50
60
70
80
90
100
![Page 28: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/28.jpg)
J. Reynes Octobre 2004
TOROs :le temps perdu …
L’expérience des « switch » patients
![Page 29: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/29.jpg)
J. Reynes Octobre 2004
Patients who switch from OB arm to FUZEON + OB arm – “Switch” Patients
Switch permitted at virological failure* or at week 48
– 6
BL 8 16 24 48
– 4
Weeks 96
FUZEON + OB
“SWITCH” PATIENTS
OB
OB
* Criteria for virological failure based on 2 consecutive values: 1. < 0.5 log10 decrease from baseline starting at week 6 and 82. < 1.0 log10 decrease from baseline starting at week 14 and 163. ≥≥≥≥ 2 log10 response and > 1 log10 rebound at any time
![Page 30: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/30.jpg)
J. Reynes Octobre 2004
Mean HIV-1 RNA change from baseline
FUZEON+OB: 661
SW: 230
(All switch patients; including data before and after switch)
FUZEON+OBSW (OB →→→→ FUZEON+OB)
Study week
-2.5
-2
-1.5
-1
-0.5
00 8 16 24 32 40 48 56 64 72 80 88 96
Mea
n ch
ange
from
BL
in v
iral l
oad
(log 1
0co
pies
/ml)
495
171
352
121
![Page 31: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/31.jpg)
J. Reynes Octobre 2004
Mean CD4+ cell count change from original baseline
(All switch patients; including data before and after switch)
FUZEON+OBSW (OB →→→→ FUZEON+OB)M
ean
CD
4 ch
ange
from
BL
(cel
ls/m
m3 )
FUZEON+OB: 661
SW: 227
478
169
337
121
0
25
50
75
100
125
150
175
0 8 16 24 32 40 48 56 64 72 80 88 96
Study week
![Page 32: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/32.jpg)
J. Reynes Octobre 2004
TOROs :qui en profite ?
![Page 33: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/33.jpg)
J. Reynes Octobre 2004
TORO 1 & 2: influence du GSS (S24)
Genotypic Sensitivity Score
-2.5
-2
-1.5
-1
-0.5
00 1 2 3 4 5
*p≤≤≤≤0.05
*
*
***
Change frombaseline log10
HIV-1 RNA
Delfraissy et al. 10th CROI, 2003; abstract 568
ENF + OBn=661
OBn=334
![Page 34: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/34.jpg)
J. Reynes Octobre 2004
CD4+ cell count adjusted mean change from baseline, week 48 (ITT, LOCF) by BL GSS
+ 57
+ 88
+ 116
+ 31+ 47
+ 70
0
25
50
75
100
125
150
0 1 ≥≥≥≥2
Cha
nge
from
BL
(cel
ls/m
m3 )
**
GSS 0 1 ≥≥≥≥2
ENF+OB 110 191 340
OB 52 93 180
*
*P<0.05
Genotypic Sensitivity Score (GSS)
ENF+OB OBN=661 N=334
![Page 35: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/35.jpg)
J. Reynes Octobre 2004
49.221.6
Time to return to baseline
0
50
100
150
200
250
300
350
0 20 40 60 80 100Month
CD
4 co
unt (
cells
/mm
3 )
ENF + OBOB
290
212
Peak CD4 cell count at VF
CD4 cell count on ENF + OB or OB
![Page 36: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/36.jpg)
J. Reynes Octobre 2004
T20 :quelles limitations ?
![Page 37: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/37.jpg)
J. Reynes Octobre 2004
T20 :quelles limitations ?
• Coût• Acquisition rapide de résistance possible
• Administration sous-cutanée bi-quotidienneet réactions locales
![Page 38: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/38.jpg)
J. Reynes Octobre 2004
Résistance au T-20
CROI 2003 - D'après M.L. Greenberg, Durham, abstract 141, actualisé
Augmentation de l’IC50par rapport à la souche initiale
Mutations situées au niveau des AA 36 à 45 de
la gp41
9 (5-17)5N43N/D
15 (10-26)6V38M
26 (8- 401)19N43D
32 (15-60)6G36D
36 (8-324)8V38V/A
42 (10-185)27V38A
Moyennen
Fréquence et impact sur la résistance phénotypique selon le type de mutation sélectionné
![Page 39: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/39.jpg)
Adherence to enfuvirtide and to background antiretroviral
therapy over 48 weeks and its impact on treatment efficacy
Witek J et al.,XV International AIDS Conference,
11−16 July 2004Poster WePeB5822
![Page 40: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/40.jpg)
J. Reynes Octobre 2004
Overall adherence to treatment regimen
293 (87.7%)576 (87.1%)610 (92.3%)≥≥≥≥ 85%279 (83.5%)543 (82.1%)595 (90.0%)≥≥≥≥ 90%254 (76.0%)474 (71.7%)555 (84.0%)≥≥≥≥ 95%204 (61.1%)339 (51.3%)442 (66.9%)100%
Adherence, n (%)
334661661Number of patients
OBENF + OBENF component
OBENF + OB
![Page 41: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/41.jpg)
J. Reynes Octobre 2004
Virological response by treatment arm and overall adherence
p < 0.0001
p = 0.559
Patie
nts
(%) w
ith H
IV-1
RN
A <
400
copi
es/m
lat
48
wee
ks
ENF + OBOB
Adherence to entire regimen (ENF + OB or OB)≥≥≥≥ 85% < 85%
192/576 37/293 9/85 3/41n =
12.6 %
7.3 %
10.6 %
33.3 %
0
5
10
15
20
25
30
35
![Page 42: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/42.jpg)
J. Reynes Octobre 2004
T20 :quels avantages ?
![Page 43: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/43.jpg)
J. Reynes Octobre 2004
T20 :quels avantages ?
• Puissance ajoutée
• Résistance croisée évitée
• Action extra-cellulaire
– Prévention de l’infection
– Toxicité/ Interaction
![Page 44: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/44.jpg)
J. Reynes Octobre 2004
T20 :quelles ouvertures ?
![Page 45: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/45.jpg)
J. Reynes Octobre 2004
T20 :Ouvertures et nouveaux usages
• Accidents d’exposition
• Patients “naïfs”– Pb interactions (tuberculose, VHC)
– Induction-maintenance
• Patients prétraités
– Grossesse
– Induction-maintenance
![Page 46: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/46.jpg)
J. Reynes Octobre 2004
INDEED
INDuction withEnfuvirtide
in ExperienceD patients
![Page 47: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/47.jpg)
J. Reynes Octobre 2004
INDEED - Rationnel• Succès virologique chez le patient prétraité lié au
nombre de molécules actives utilisées (démonstration dans TORO)
• Pour certains nucléosidiques et inhibiteurs de protéase, l’acquisition de une ou deux mutations supplémentaires / à mutations déjà acquises est susceptibles de leur faire perdre leur activité
• Les contraintes d’injection pour le T20 rendent son utilisation prolongée peu attractive
![Page 48: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/48.jpg)
J. Reynes Octobre 2004
INDEED - Rationnel• L’utilisation du T20 sur une période initiale est
susceptible, en complément d’un traitement optimisé, d’augmenter la puissance antirétrovirale et de réduire le risque d’acquisition de résistance pour les autres produits
• L’arrêt du T20 est « tentant » une fois l’indétectabilitéobtenue mais cette possibilité d’interruption n’est pas validée
![Page 49: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/49.jpg)
J. Reynes Octobre 2004
INDEED - Schéma
S0
Patients en échec virologique(1 000 – 100 000 copies/ml)avec persistance d’au moins 2 ARV actifs sur génotype
Induction
TOp + T20
< 50 cp/ml
50 – 400
> 400 copies
S28 S52Relais
TOp
TOp + T20
TOp + T20
sortie
S24
![Page 50: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/50.jpg)
J. Reynes Octobre 2004
Anti CCR5 :quelles problématiques ?
![Page 51: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/51.jpg)
J. Reynes Octobre 2004
Etude SCH C chez sujets VIH+
Days0 5 10 15 20 25 30
Log1
0 C
hang
e fr
om B
asel
ine
-1.5
-1.0
-0.5
0.0
0.5
Placebo (n = 4)25 mg BID (n = 12)50 mg BID (n = 12)
Dosing Washout
Reynes
CROI 2002
![Page 52: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/52.jpg)
J. Reynes Octobre 2004
SCH-D• Diminution dose-dépendante de la charge virale
CROI 2004 - D'après D. Schurmann, Berlin, abstract 140LB, actualisé
Varia
tion
de C
V (lo
g 10
copi
es/m
l)
0,5
0,0
- 0,5
- 1,0
0 30
Période de traitement
10 20 25Jours
155
- 1,5
10 mg x 2/j 25 mg x 2/j Placebo50 mg x 2/j
![Page 53: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/53.jpg)
J. Reynes Octobre 2004
![Page 54: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/54.jpg)
J. Reynes Octobre 2004
Anti CCR5 :quelles problématiques ?
• Voie orale, faible toxicité
• Problématique de populations R5/X4
• Problématique de résistance et d’association
(interactions)
� Phases III
![Page 55: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/55.jpg)
J. Reynes Octobre 2004
IE: ce qui est envisageable
• ASSOCIATIONS– Avec ARV “classiques”– Interactions anti-CCR5 et CytP450– Entre eux (synergie)
• CONTRAINTES– Voie parentérale– Barrière génétique basse
• INNOVATION et PRUDENCE– Cible cellulaire– Populations virales
![Page 56: une nouvelle donne - AEI · change from baseline (On-Treatment)-2.0-1.0 0 8 16 24 32 40 48 56 64 72 80 88 96 Study Week RNA mean change from BL CD4 mean change from BL Viral load](https://reader030.vdocuments.net/reader030/viewer/2022040402/5e84fd2e4680b43735732afa/html5/thumbnails/56.jpg)
J. Reynes Octobre 2004
Fin(provisoire)…
Inhibiteurs d’entréeMontpellier24 juin 2005