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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Jr arribas 1 al pozniak 2 je gallant 3 e dejesus 4 r campo 5

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 934 study design

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 934 statistical analysis

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


Jr arribas 1 al pozniak 2 je gallant 3 e dejesus 4 r campo 5

Study 934

Baseline Characteristics (ITT)

a. Median values


Study 934 study population

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 934 baseline nnrti resistance itt

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 934 summary outcomes at week 48

Study 934Summary Outcomes at Week 48

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


Study 934 proportion with hiv rna 400 c ml tlovr itt n 509

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%)


Study 934 proportion with hiv rna 50 c ml tlovr itt n 509

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%)


Study 934 cd4 mean absolute change from baseline as treated

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


Jr arribas 1 al pozniak 2 je gallant 3 e dejesus 4 r campo 5

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


Jr arribas 1 al pozniak 2 je gallant 3 e dejesus 4 r campo 5

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


Jr arribas 1 al pozniak 2 je gallant 3 e dejesus 4 r campo 5

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 934 serum creatinine

Study 934Serum Creatinine

a. Confirmed toxicity grade = two consecutive visits


Study 934 week 48 summary

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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