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46th Interscience Conference on Antimicrobial Agents and ChemotherapySeptember 27 - 30, 2006
San Francisco, CaliforniaPoster #78
Tenofovir DF + Efavirenz (TDF+EFV) vs Tenofovir DF + Efavirenz + Lamivudine
(TDF+EFV+3TC) Maintenance Regimen in Virologically Controlled Patients: COOL Trial
PM Girard,1 A Cabié,2 C Michelet,3 R Verdon,4 C Katlama,5 P Mercié,6 L Morand Joubert,1 G Chêne,7 P Pétour,8 and A Trylesinski8
1Hop. St Antoine, Paris, France; 2Hop. Zobda Quitman, Fort de France, France; 3Hop. Pontchaillou, Rennes, France; 4Hop. Caen, Caen, France; 5Hop. Pitie Salpêtrière, Paris, France; 6Hop. St André,
Bordeaux, France; 7INSERM U593, Bordeaux, France; 8Gilead Sciences, Inc., Paris, France
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Introduction
• HIV-1 infection is a long term illness requiring long term therapy
• Antiretroviral therapy may induce metabolic abnormalities and fat tissue redistribution
• Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with such toxicity
• A 48 week randomized study (the COOL Study) enrolled 143 virologically controlled (BLQ) patients who were switched to 2 simplified new regimens TDF+3TC+EFV vs TDF+EFV
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Objectives
• Primary objective: Evaluation of the efficacy of TDF+3TC+EFV versus TDF+EFV QD to maintain plasma HIV-1 RNA BLQ (< 50 copies/mL) (c/mL) at 48 weeks (W48)
• Main Secondary objectives:
• – Comparison of the two arms for genotypic resistance profile in case of virological failure – CD4 changes from baseline– Evolution of the lipid profile and morphological changes in fat distribution, and safety
• Efficacy and genotypic profile data, results of lipid markers, morphological changes and main biological parameters are presented
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Methods
• Main Eligibility Criteria:– Stable HAART ≥ 3 months– HIV-1 RNA < 50 c/mL ≥ 6 months– No HAART failure history– Weight > 45 kg– No CD4+ cell count criteria– No significant laboratory or clinical abnormalities– Creatinine Clearance > 60 mL/min
• Follow-up was performed at Week 4, 12, 24, 36 and 48 including clinical examination, adverse events assessment, CD4 cell count, HIV-1 RNA level, metabolic parameters and morphologic evaluation. Creatinine Clearance was calculated according to the Cockcroft-Gault equation
• Success rate was defined as maintained VL BLQ (< 50 c/mL) without study drug modification at W48• Non inferiority limit:14%• L4 CT-Scans were performed at baseline and Week 48 (SAT and VAT measurement)• Two DSMB meetings were scheduled for formal unblinded statistical review of the first 40 and 80 patients at Week 12
for HIV-1 RNA, CD4, and AE• Clinical and biological data were collected via an Electronic Data Capture system (eCRF) allowing a tight follow-up by
DSMB in a timely manner• Statistical analysis was performed with SAS, version 8.2
– Intent To Treat (ITT) Population defined as all included patients having received at least one dose of study treatment
– As Treated (AT) Population defined as all included patients having received at least one dose of study treatment, with at least one evaluation at baseline and after baseline and with no major deviation to the protocol
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Study Design
Stable HAARTMonths
VL < 50c/mLMonths
No history ofVirologic Failure
TDF + EFV
TDF + EFV +3TC
DSMB data review
randomization 1:1N = 143 patients
W4 .. W12 …… W24 …… W36…..
W48
W48
A 48 Week, pilot, open label, multicenter, randomised clinical trialA 48 Week, pilot, open label, multicenter, randomised clinical trial
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Baseline Characteristics of the ITT Population
TDF + 3TC + EFVn = 72
TDF + EFVn = 71
AllN = 143
Demographics
Median Age (years) [range] 42 [22 to 73] 39.5 [22 to 70] 40 [22 to 73]
Mean Weight (kg) [SD] 68 [12] 70 [10] 69 [11]
Female (%) 29 27 28
HIV Infection
CDC stage C in % 35 35 35
Median CD4 (cells/mm3) [range]
497.5[78 to 1775]
410[104 to 1332]
473 [78 to 1775]
Median HIV RNA (c/mL) [range]
50 [20 to 88]
50 [20 to 4700]
50 [20 to 4700]
HAART history prior to switch
Median Duration (years) [range] 3.6 [0.5 to 7.5] 3.7 [1.0 to 7.7] 3.7 [0.5 to 7.7]
HAART types before randomisation (%) 2 NRTI + 1 NNRTI 2 NRTI + 1 PI Others
394912
484210
43.545.511
3TC / ZDV as part of the Combination (%) 69 73 71
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
% of Patients with Viral Load < 50 c/mL (ITT / AT Populations)
97 100
8290
0
50
100
ITT AT
TDF + 3TC + EFV
TDF + EFV
: 15.5%95% CIa: 23.7%
: 10%95% CIa: 15.5%
N= 72 71 7 0 60
N=70 N=58 N=70 N=54
a. Upper bound of 95% CI
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Main Reasons for Failure at W48 (ITT Population)
TDF + 3TC + EFVN = 72
TDF + EFVN = 71
HIV-1 RNA > 50 c/mL
% of patients (N)% Patients with emergent NNRTIs Mutations
0% (0) 4.2% (3)
0% 100%
Study Drug Regimen Discontinuationa
% of patients (N) 2.7% (2) 14.0% (10)
% AE/SAE (N) Unrelated to Study Drugs Related to Study Drugs
- 1.4% (1)b
- 4.2% (3)c
% lost to follow-up / Patient request (N) 2.7% (2) 8.4% (6)
a. Except study drug discontinuation of patients with HIV-1 RNA > 50 c/mLb. 1 SAE: « Suicide Attempt »c. 2 SAE and 1 AE: « Transaminases Increase », « Vertigo » and « Transaminases Increase » respectively
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
RT Mutations Emergence from Baseline
Patient IDTime to
Emergence(Weeks)
ViralLoad (c/mL)
Major RT Mutation(s) Emergence from Baseline
NRTIs NNRTIs PIs
TDF + EFV (N = 3)
009-007 W 24 1490 - Y188L -
015-011 W 25 257,720 -K101EK103Ra
G190A-
016-005 W 48 1600 - G190E -
TDF + 3TC + EFV (N = 0) - - - - -
a. Pre-existing at baseline
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Patients with Virological Failure (Only TDF / EFV Arm): Evolution of HIV-1 RNA through W48
TDF + EFV
[N=3/71]
1
10
100
1000
10000
100000
1000000
Baseline W4 W12 W24 W36 W48
009-007
015-011
016-005
AR V modificationa
AR V modification b
Lo
g H
IV-1
RN
A (
c/m
L)
a. ZDV + 3TC + ATV
b. ZDV + 3TC + IDV + RTV
Note: For patient 016-005, a decrease of study drug compliance was observed (based on drug returns at study visits) to reach < 50% at W36.
For patients 009-007 and 015-011, compliance evaluation was not possible since no bottle returns were recorded
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
“Blips” through W48 Follow-Up: Viral Load > 50 c/mL and Subsequently BLQ
TDF + 3TC + EFV
[N=13/72]
1
10
100
1000
10000
100000
1000000
Baseline W4 W12 W24 W36 W48
Lo
g H
IV-1
RN
A (
cp
/ml)
001-002 001-003002-001 002-003002-010 009-006010-004 011-008015-008 016-002023-003 023-004024-001
TDF + EFV [N=11/71]
1
10
100
1000
10000
100000
1000000
Baseline W4 W12 W24 W36 W48
Lo
g H
IV-1
RN
A (c
p/m
l)
001-008 002-002002-009 004-007008-001 015-003015-005 019-001019-002 021-002022-004
Note: Patient # 001-008 displayed a K103N mutation at W24 and VL BLQ at W48 with no ARV modification
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Biological Parameters: W48 Change from Baseline
Baseline W48 Change from Baseline
Both Arms TDF + 3TC + EFV
TDF + EFV pa Both Arms pb
CD4 Median [IQR]
(cells/mm3)N = 137 N = 71 N = 66 N = 137
473 [345; 663]
+35 [-62; 101]
+14 [-59; 96]
p = 0.94 +24 [-59; 96]
p = 0.007
HemogoblinMedian [IQR] (g/dl)
N = 139 N = 71 N = 68 N = 139
13.6 [12.70; 14.40]
+0.80 [0.10; 1.30]
+0.45 [-0.05; 0.90]
p = 0.14 +0.60 [0.00; 1.30]
p < 0.001
Lactatemia Median[IQR](ml/min)
N = 111 N = 59 N = 52 N = 111
1.49[1.02; 2.00]
-0.2[-0.60; 0.20]
-0.05[-0.43; 0.28]
p = 0.32 -0.14[-0.5; 0.24]
p = 0.006
CreatinineClearancec
Median [IQR]
(ml/min)
N = 130 N = 68 N = 62 N = 130
100.8[86.9; 115.9]
-3.3[-11.3; 4.5]
+1.7[-11.3; 12.2]
p = 0.17 -1.3[-11.2; 8.2]
p = 0.31
PhosphatemiaMedian [IQR]
(mmol/l)
N = 109 N = 57 N = 52 N = 109
1.10[0.84; 1.10]
+0.03[-0.14; 0.13]
-0.02[-0.14; 0.14]
p = 0.70 0.00[-0.14; 0.14]
p = 0.97
a. Wilcoxon test (TDF + 3TC + EFV vs TDF + EFV); significant for p < 0.05b. Wilcoxon Rank-Sum test on overall TDF switched population (Baseline vs W48); significant for p < 0.05c. According to the Cockcroft-Gault equation
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Lipids: W48 Change from Baseline (As Treated Population)
*W48 change from baseline for Total, HDL cholesterol and Triglycerides were not significantly different between arms. **Wilcoxon signed rank test, Significant when p < 0.05
Total Cholesterol
4
4.5
5
5.5
6
6.5
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
Triglycerides
0.5
1
1.5
2
2.5
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
HDL Chol esterol
1
1.5
2
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
LDL Chole ste rol
2.5
3
3.5
4
4.5
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
All population*
-0.31 mmol/l
p<0.0001**
All population*
: -0.25 mmol/l
p<0.001**
All population*: +0.05 mmol/lp=0.0041**
3-drug Arm: -0.20mmol/lp=0.015**
2-drug Arm: +0.15 mmol/l
p=0.50**
All population: -0.02 mmol/l
p=0.15**
mm
ol/
lm
mo
l/l
mm
ol/
lm
mo
l/l
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
L4 CT Scans: Visceral and Subcutaneous Abdominal Fat [Patients Subgroup of AT Population for Whom Baseline and
W48 Data were Available (N = 79)]
Subcutaneous Abdominal Fat (SAT)
0
50
100
150
200
250
Baseline W48
TDF+3TC+EFV TDF+EFV All PopulationVisceral A bdominal Fat (VAT)
0
30
60
90
120
150
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
Total Abdominal Fat (TAT) [(VAT + SAT)]
100
150
200
250
300
350
Baseline W48
TDF+3TC+EFV TDF+EFV All PopulationVAT/SAT Ratio
0
0.5
1
1.5
Baseline W48
TDF+3TC+EFV TDF+EFV All Population
All population*+9.0 cm2
p=0.017**
All population*-0.05
p=0.06**
All population*+14 cm2
p=0.10**
All population*-1.5 cm2
p=0.84**
cm/2
cm/2
cm/2
cm/2
*W48 change from baseline for VAT, SAT,TAT and VAT/SAT ratio were not significantly different between arms **Wilcoxon signed rank test, significant when p < 0.05
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Conclusions
• TDF + 3TC + EFV demonstrates an optimal success rate (97%) as a maintenance regimen when compared to TDF + EFV (82%)
• TDF + EFV demonstrated lower efficacy due to:
– Virological Failure: 4%
– Study Drug Discontinuation: 14%
• Switching to a QD tenofovir based regimen can significantly improve lipid profile even when lipids are within the median normal range at baseline
• Other improvements in biological parameters were observed following a switch from BID HAART to QD TDF-based HAART
• No glomerular filtration rate decrease or hypophosphatemia was observed
Girard, ICAAC 2006 September 27-30, 2006, San Francisco, CA. Poster #H-1383.
Acknowledgements
• French COOL Investigators and Experts– Dr BENTATA, Hôpital Avicennes, Bobigny; Pr BESNIER, CHU Tours; Dr CABIÉ, Hôpital Paul Zobda Quitman, Fort de France;
Pr CHÊNE, Inserm U593, Bordeaux; Pr DELFRAISSY, CHU Kremlin-Bicêtre; Dr DURANT, CHU de Nice; Pr GALLAIS, Hôpital La Conception, Marseille; Pr GIRARD, CHU Saint-Antoine, Paris; Pr HOEN, Hôpital Saint Jacques, Besançon; Pr KATLAMA, CHU Pitié-Salpêtrière; Dr LIVROZET, Hôpital Edouard Herriot, Lyon; Pr MAY, CHU de Nancy; Pr MERCIÉ, CHU de Bordeaux; Pr MICHELET, CHU de Rennes; Dr MORAND-JOUBERT, CHU Saint-Antoine, Paris; Dr PARTISANI, Hôpital Civil de Strasbourg; Pr PELLEGRIN, Hôpital Haut-Lévêque, Pessac; Dr PRAZUCK, CHR d’Orléans; Pr ROZENBAUM, Hôpital Tenon Paris; Pr SALMON, Hôpital Cochin, Paris; Pr SERENI, Hôpital Saint-Louis, Paris; Dr SIMON, Hôpital Pitié-Salpêtrière, Paris; Dr STRADY, Hôpital de Reims; Pr VERDON, CHU de Caen; Pr VITTECOQ, Hôpital Paul Brousse, Villejuif; Pr WEISS, Hôpital Européen Georges Pompidou, Paris; Dr ZUCMAN, Hôpital Foch, Suresnes
• Gilead Sciences, Inc.– Dr C. AUBRON-OLIVIER, A. FIREK; N. FORGET; Dr F. MONCHECOURT.
• Study Sites Personnel and Patients