46 th Interscience Conference on Antimicrobial Agents and Chemotherapy September 27 - 30, 2006 San...

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


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


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


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


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


% 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


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


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


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


“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


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


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


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


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


HDL Chol esterol

1

1.5

2

Baseline W48


LDL Chole ste rol

2.5

3

3.5

4

4.5

Baseline W48


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


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


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


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


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


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

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