Superior Outcome for Tenofovir DF (TDF), Emtricitabine (FTC) and Efavirenz (EFV) Compared to Fixed D...
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Superior Outcome for Tenofovir DF (TDF), Emtricitabine (FTC) and Efavirenz (EFV) Compared to Fixed Dose Zidovudine/Lamivudine (CBV) and EFV in Antiretroviral Naïve Patients. JR Arribas 1 , AL Pozniak 2 , JE Gallant 3 ,E DeJesus 4 , R Campo 5 ,

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JR Arribas 1 , AL Pozniak 2 , JE Gallant 3 ,E DeJesus 4 , R Campo 5 ,

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Superior Outcome for Tenofovir DF (TDF), Emtricitabine (FTC) and Efavirenz (EFV) Compared to Fixed Dose Zidovudine/Lamivudine (CBV) and EFV in Antiretroviral Naïve Patients

JR Arribas1, AL Pozniak2, JE Gallant3,E DeJesus4, R Campo5,

B Gazzard2, MJM Hitchock6, B Lu6, D McColl6,

J Enejosa6 and A Cheng6 for the Study 934 Team

1Univ Hospital La Paz, Madrid, Spain; 2Chelsea and Westminster Hosp., London, UK; 3Johns Hopkins Univ School of Medicine, Baltimore, MD; 4Orlando Immunology Center, Orlando, FL; 5Univ Miami, Miami, FL; 6Gilead Sciences, Foster City, CA

18th International Conference on Antiviral Research

10 April 2005

Barcelona, Spain


Study 934Study Design

96 wks

TDF

QD

FTC

QD

Efavirenz

QD

ART-naïve patients

(n = 517)

randomized 1:1

Any CD4 cell count

HIV RNA > 10,000 c/mL

96 wks

AZT/3TC

BID

Efavirenz

QD

Adequate Renal and Hepatic Function at baseline

FTC/TDF Fixed dose combination tablet was not used


Study 934Statistical Analysis

  • Non inferiority Trial

  • Primary Endpoint < 400 c/mL at Week 48 -Time to Loss of Virologic Response (TLOVR)

    • FDA-required endpoint

    • Similar to ITT Missing = Failure, Switch = Failure

    • Requires confirmation for success

    • Used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals


Study 934

Baseline Characteristics (ITT)

a. Median values


Study 934Study Population

Randomized Population

(n=517)

Never Dosed

6 Patients

Safety Population

(n=511)

Treatment-experienced

2 Patients

ITT

(n=509)

Baseline NNRTI-R

22 Patients

Modified ITT n=487


Study 934Baseline NNRTI Resistance (ITT)

  • 22 patients (11 FTC/TDF vs. 11 CBV)

  • Investigators notified if affected

  • FDA recommended excluding these patients for Week 48 primary endpoint analysis (n = 487)

  • Primary Efficacy Endpoint (HIV RNA < 400 c/mL) at Week 48 analyzed for both populations, excluding NNRTI-R (n = 487) and ITT (n = 509)


Study 934Summary Outcomes at Week 48

a. p value = 0.002 b. p value = 0.016


100

80

60

% Responder

40

20

0

BL

8

16

24

32

40

48

Weeks

Study 934Proportion with HIV-RNA <400 c/mL (TLOVR)ITT (n = 509)

p = 0.005

FTC/TDF 81%*CBV 70%*

*95% CI: (+3.4%, +18.1%)

Exclude NNRTI-R (n=487): FTC/TDF 84%,CBV 73%, p=0.002 (+4.3%,18.6%)


90

80

70

60

50

% Responder

40

30

20

10

0

BL

8

16

24

32

40

48

Weeks

Study 934Proportion with HIV-RNA <50 c/mL (TLOVR)ITT (n = 509)

p = 0.034

FTC/TDF 77%*CBV 68%*

*95% CI: (+0.9%, +16.2%)

Exclude NNRTI-R (n=487): FTC/TDF 80%,CBV 70%, p=0.021 (+1.6%,16.6%)


225

)

3

175

125

Mean Change (cells/mm

75

0

BL

8

16

24

32

40

48

Weeks

Study 934CD4 Mean Absolute Change from BaselineAs Treated

FTC/TDF 190CBV 158

p = 0.002 at Week 48

p < 0.001 by AAUCMB

FTC+TDF+EFV 238 234 223 218 209 198

CBV+EFV 222 216 199 188 175 164


Study 934

Resistance Development in all Patients with >400 HIV RNA Copies/mL (mITT)

  • 1.All patients (after wk 8) with confirmed >400 copies/mL of HIV RNA at Week 48 or early discontinuation analyzed.

  • Patients w/ baseline NNRTI-resistance excluded (n = 22). Genotyping of 1 Combivir patient failed.

  • 2.K103N developed in 21/25 patients. Other NNRTI mutations that developed included K101E, K103E, V108I, V179D, Y188H, G190A/S/E, P225H, M230L


Study 934

Adverse Events Leading to Study Drug Discontinuation Through Week 48

  • Occurring in more than 1 patient in either arm; patients may have > 1 event

  • p = 0.016


20

60

20

55

18

18

50

16

47

16.0

45

16

16.0

14

40

40

13.8

14

13.8

12

35

33

12

31

10.8

Hematocrit %

10

30

10.8

Hemoglobin (g/dL)

10

9.3

22

25

9.3

Hemoglobin (g/dL)

8

8

20

6.9

6

6.9

15

11

6

4

10

3.7

4

3.7

2

5

2

0

0

Nadir

Baseline

Nadir

Baseline

0

Nadir

Baseline

Study 934Median (Range) Hemoglobin and Hematocrit ValuesDiscontinuations due to Anemia on CBV arm (n=14)


Study 934Serum Creatinine

a. Confirmed toxicity grade = two consecutive visits


Study 934Week 48 Summary

  • Superior overall response in the FTC/TDF arm compared to CBV arm

  • No patient developed K65R

    • M184V developed less frequently in the TDF/FTC arm than in the Combivir arm

  • Significantly more CBV patients discontinued due to adverse events

  • Similar renal safety profile

    • No confirmed abnormalities in serum creatinine or phosphorus in FTC/TDF arm


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