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Actualités des traitements ARV: du Sud au Nord
Pierre-Marie Girard
IMEA&
Hôpital ST Antoine
DU IMEA FOURNIER PARIS VII Novembre 2009Partie I
Les Cohortes au SUD
Castelnuovo B et al, CID, 2009
Castelnuovo B et al, CID, 2009
Castelnuovo B et al, CID, 2009
Second Line ARV in adults and children
96% 99%
4% 1%0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Adults Pediatric
% p
ati
en
ts
Renaud-Théry F, AIDS 2007
Cumulative proportion of patients needing 2nd Line ARV
Switch to 2d Line: mean 3% per year
5%6%
9%
12%
16%
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
2006 2007 2008 2009 2010
Renaud-Théry F, AIDS 2007
AIDS, 2009
Low performance of WHO criteria for the diagnosis of virological failure
CID, 2009
Smith AD et al, Lancet, 2009
Essais au SUD
Essai DART « Big-Dart »
REYADAK à Dakar « Small is beautiful »
Essais PTME et Pédiatrie « Hit hard, hit early »
IAS July 2009
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
TASO, Uganda
University of Zimbabwe, Harare, Zimbabwe
Joint Clinical Research Centre, Kampala, Uganda
Infectious Diseases Institute, Makerere University, Uganda
MRC Clinical Trials Unit, UK
Imperial College, UK
DFID, UK
GlaxoSmithKlineGilead SciencesBoehringer-IngelheimAbbott
RockefellerFoundation
MRC, UK
DART partnersDART partners
Support:
IAS July 2009
SurvivalSurvival
0.90
0.87
0.08
0.92
0.90
0.18
0.95
0.94
0.55
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion
aliv
e
Years from enrolment
Entebbe Cohort(Uganda):pre-ART 1996-2000, median CD4 75 at enrolment:57.7/100 PY
DARTLCM: 2.2/100 PYCDM: 2.9/100 PY
IAS July 2009
Resource allocationResource allocation
• 6.7 million adults and children in Sub-Saharan Africa were estimated to need ART in December 2007
– only 2.2 million were receiving ART
• Global economic crisis is threatening programme funding
• Using DART to help resource allocation
– what could be achieved in an ART programme with $1,000,000 over 5 years...
IAS July 2009
21
271
35
366
0
100
200
300
400
Number of patients
LCM: TREAT 292 CDM: TREAT 401 (extra 109)
treated, alive treated, died
For $1,000,000 over 5 yearsFor $1,000,000 over 5 years
Mean cost/patient: LCM $3,425, CDM $2,493
Assuming cost of patients not treated is $0. Based on difference in life-years from CEA.
IAS July 2009
36
73
21
271
35
366
0
100
200
300
400
Number of patients
LCM: TREAT 292 CDM: TREAT 401 (extra 109)
treated, alive treated, died
not treated, died not treated, alive
For $1,000,000 over 5 yearsFor $1,000,000 over 5 years
Mean cost/patient: LCM $3,425, CDM $2,493
Totaldeaths
94
from Entebbe Cohort data
Totaldeaths
35
Assuming cost of patients not treated is $0. Based on difference in life-years from CEA.
IAS July 2009
112326
341
35
366
0
100
200
300
400
Number of patients
LCM: TREAT 367 CDM: TREAT 401 (extra 34)
Excluding routine toxicity tests in LCM
Excluding routine toxicity tests in LCM
Mean cost/patient: LCM $2,726, CDM $2,493
Totaldeaths
49
treated, alive treated, died
not treated, died not treated, alive from Entebbe Cohort data
Totaldeaths
35
Assuming cost of patients not treated is $0. Based on difference in life-years from CEA.
Impact of « not-switching » on survival
Risk of death Switching pts vs no Switching = 3.3 [1.6-6.8] Ive P et al, CROI, 2009
Impact of « not-switching » on survival
Risk of death Switching pts vs no Switching = 3.3 [1.6-6.8] Ive P et al, CROI, 2009
Evaluation of didanosine/lamivudine and atazanavir QD first line regimen in HIV-1 infected adults in Senegal IMEA 031 trial
0
20
40
60
80
100
BL 4 12 24 36 48
Weeks
% VL < 400 c/ml
% VL < 50 c/ml%
0
20
40
60
80
100
BL 4 12 24 36 48
Weeks
% VL < 400 c/ml
% VL < 50 c/ml%
Les Cohortes au Nord
Nature 2009
Hunt, JID 2009
Les Essais au Nord
Stratégies abandonnées
Traitement tardif (< 200/mm3) Combinaisons initiales:
En quadrithérapie IN+INN+IP En épargne de nucléosidiques par IP+INN ??
Traitements intermittents à cycles longs Interruptions programmées chez patients avec
CD4 < 500/mm3 Initiation par nucléosidiques seuls Intensification simple (« Add on ») Immunothérapie non spécifique par IL2 Vaccinothérapie avec candidats-vaccins actuels
Première ligne: IP vs NNRTI
clinicaloptions.com/hiv
Weighing the Options: Choosing the Initial Antiretroviral Regimen
ACTG 5142: First-line EFV + NRTIs vsLPV/RTV + NRTIs Multicenter, prospective, open-label, randomized, phase III clinical trial
Primary endpoints: time to virologic failure and time to regimen completion
Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.
Antiretroviral-naive HIV-infected pts with
HIV-1 RNA = 2000 copies/mL
(N = 753)
EFV 600 mg QD + 2 NRTIs*(n = 250)
LPV/RTV SGC 400/100 mg BID + 2 NRTIs*(n = 253)
EFV 600 mg QD + LPV/RTV SGC 533/133 mg BID
(n = 250)
Wk 96Stratified by HIV-1 RNA < or = 100,000 copies/mL, presence or absence of chronic hepatitis infection (B, C, or both), and NRTI selection
*NRTIs = 3TC 150 mg BID or 300 mg QD + either ZDV 300 mg BID, d4T extended release 100 mg QD (participants < 60 kg received 75 mg QD), or TDF 300 mg QD.
clinicaloptions.com/hiv
Weighing the Options: Choosing the Initial Antiretroviral Regimen
ACTG 5142: HIV-1 RNA < 50 copies/mLand CD4+ Cell Count Increases at Wk 96 Multicenter, randomized, prospective, open-label phase III
clinical trial
89
7783
0
20
40
60
80
100
EFV + 2 NRTIs (n = 250)LPV/RTV + 2 NRTIs (n = 253)EFV + LPV/RTV (n = 250)
HIV
-1 R
NA
< 5
0 c/
mL
(%)*
P = .003
Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.
0
50
100
150
200
250
300 Median C
D4+ C
ell Count
Increase (cells/mm
3)
230
287 273
P = .01
P = .01
*ITT analysis including all pts on who remained on protocol; missing values were censored.
EFV vs LPV/r chez les patients naïfs à CD4+ < 200 : HIV-1 RNA <50 copies/mL à S48
0
20
80
100
0 16 32 48
Week8 24 40
Efavirenz (n = 95)
LPV/RTV (n = 94)
Nombre de Pts avec ARN VIH < 50 copies/mL
EFV 29 70 68 67LPV 8 53 56 50
70.5%
53.2%
0
20
40
60
80
100
HIV
-1 R
NA
< 5
0 co
pie
s/m
L (%
)
79%
49%
64%57%
P = 0.012 P = 0.15
EFVLPV/RTV
n = 42 45 53 49
≤ 50 cell/mm3 > 50 cell/mm3
EFV supérieur à LPV/RTV: Δ 17% (CI 95%: 3.5% to 31.0%; P = .017)
HIV
-1 R
NA
< 5
0 co
pie
s/m
L (%
)
Selon les CD4 à BL
60
40
Madero JS, et al. IAC 2008. Abstract TUAB0104.
clinicaloptions.com/hiv
Weighing the Options: Choosing the Initial Antiretroviral Regimen
Boosted PIs in ARV-Naive Pts: VirologicSuppression at Wk 48
0
10
20
30
40
50
60
70
80
90
100
This slide is an illustration only and not meant to be a cross-study comparison.*P < .05 between LPV/RTV QD and DRV/RTV QD; no other significant differences in any comparisons above. †Use of LPV/RTV BID or QD was not randomized and was dependent on site and pt preference. ‡SGC or tablet until Wk 8; tablet after Wk 8.
Pts
Wit
h H
IV-1
RN
A
< 5
0 c
op
ies
/mL
(%)
1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Ortiz R, et al. AIDS. 2008;22:1389-1397. 4. Molina JM, et al. Lancet. 2008;372:646-655. 5. Gathe J, et al. CROI 2008. Abstract 775.
440443
CASTLE[4]
(ITT) NRTIs: TDF/FTC
ATV/RTV300/100
QD
LPV/RTV400/100
BID
76 7878*
KLEAN[1]
(ITT-E, TLOVR) NRTIs: ABC/3TC
GEMINI[2]
(ITT) NRTIs: TDF/FTC
ARTEMIS[3]
(ITT) NRTIs: TDF/FTC
65
FPV/RTV700/100
BID
LPV/RTV400/100
BID
66
LPV/RTV†
400/100 BID or
800/200 QD
DRV/RTV 800/100
QD
84*
434444 343
65
SQV/RTV1000/100
BID
LPV/RTV400/100
BID
170 167
64
346n = 333331
M05-730[5]
(ITT, NC = F) NRTIs: TDF/FTC
LPV/RTV800/200
QD‡
LPV/RTV400/100
BID‡
75 76
Patients naïfs: Etudes en cours ou prochaines avec molécules disponibles
MERIT: CBV+EFV vs CBV+MVC COL11429: ABC/3TC + RAL APILOT-1: TDF/FTC+rATV vs rATV+MVC NEAT: TDF/FTC+rDRV vs RAL+rDRV CCTG589: rLPV+RAL vs Atripla ACTG A5262: rDRV+RAL Inv08: rLPV+RAL Merck072 RADAR: rDRV+RAL vs TDF/FTC+rDRV ANRS Optimal: Haart vs Haart + MVC chez pts CD4<200 A009: TDF/FTC + rLPV vs TDF/FTC+RAL M10-336 PROGRESS: TDF/FTC+ rLPV vs TDF/FTC+RAL GS001: TDF/FTC + rLPV vs TDF/FTC+RAL RAN: TDF/FTC + RAL vs TDF/FTC+rATV AI 424-376: TDF/FTC+rATV vs RAL+ATV bid ADARC 07-01: TDF/FTC+rATV ±RAL/MVC lors PI ANRS Optiprim: TDF/FTC+rDRV+RAL+MVC vs TDF/FTC+rDRV lors PI
ClinicalTrials.gov