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 Research10 April 2005

Barcelona, Spain

Study 934 Study Design

ART-naïve patients

(n = 517)

randomized 1:1

96 wks

96 wks

Any CD4 cell count

HIV RNA > 10,000 c/mL

TDF QD

FTC QD

Efavirenz QD

AZT/3TC BID

Efavirenz QD

Adequate Renal and Hepatic Function at baselineFTC/TDF Fixed dose combination tablet was not used

Study 934

Statistical 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

a. Median values

Study 934

Baseline Characteristics (ITT)

FTC/TDF (n = 255)

CBV (n = 254)

Agea 36 37

% Female 14% 13%

% White 56% 61%

% Black 25% 20%

% Hispanic 15% 16%

HIV RNA (log10 copies/mL)a 5.0 5.0

% HIV RNA > 100,000 52% 50%

CD4+ (cells/mm3)a 233 241

% < 200 41% 41%

% < 50 15% 11%

Study 934

Study Population

Never Dosed6 Patients

Treatment-experienced 2 Patients

Randomized Population(n=517)

ITT(n=509)

Safety Population(n=511)

Baseline NNRTI-R22 Patients

Modified ITT n=487

Study 934

Baseline 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

Treatment Outcome FTC/TDF (N=244)

CBV (N=243)

Responders 84% 73%a Non-Responders 16% 27% Virologic Failures 2% 4% Rebound <1% 3%

Never Suppressed thru Wk 48 0 0

Suboptimal Virologic Response <1% <1%

Death <1% <1% Discontinued due to AE 4% 9%b Discontinued due to Other 10% 14%

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

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

0

20

40

60

80

100

BL 8 16 24 32 40 48

Weeks

% R

esp

on

der

FTC/TDF 81%*CBV 70%*

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

p = 0.005

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

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

0102030405060708090

BL 8 16 24 32 40 48

Weeks

% R

esp

on

der

FTC/TDF 77%*CBV 68%*

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

p = 0.034

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

Study 934CD4 Mean Absolute Change from BaselineAs Treated

FTC/TDF 190CBV 158

FTC+TDF+EFV 238 234 223 218 209 198CBV+EFV 222 216 199 188 175 164

0

75

125

175

225

BL 8 16 24 32 40 48

Weeks

Mea

n C

han

ge

(cel

ls/m

m3)

p = 0.002 at Week 48p < 0.001 by AAUCMB

Study 934Resistance 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

FTC/TDF, n=244 N, (% mITT)

CBV, n=243 N (% mITT)

Genotyping Population112

(5%)

23

(9.5%)

Any EFV-R2 9 (4%)

16 (7%)

Any M184V/I2

(0.8%)7

(3%)

Any TAMs 01

(0.4%)

K65R 0 0

Wild-type3

(1%)5

(2%)

a. Occurring in more than 1 patient in either arm; patients may have > 1 eventb. p = 0.016

Study 934Adverse Events Leading to Study Drug Discontinuation Through Week 48

Safety PopulationFTC/TDF(n = 257)

CBV(n = 254)

No. w/ any Adverse Eventa 10 (4%) 23 (9%)b

Adverse Event

Anemia/ ↓ Hgb 0 14 (6%)

Nausea 1(<1%) 4 (2%)

Fatigue 0 3 (1%)

Vomiting 0 2 (<1%)

Dermatitis (NNRTI) 2 (<1%) 0

Neutropenia 0 2 (<1%)

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

Hem

ato

crit

%

05

10

15202530

35404550

5560

Baseline Nadir

40

47

31

22

33

11

0

2

4

6

8

10

12

14

16

18

20

Baseline Nadir

Hem

og

lob

in (

g/d

L) 13.8

16.0

10.8

6.9

3.7

9.3

0

2

4

6

8

10

12

14

16

18

20

Baseline Nadir

Hem

og

lob

in (

g/d

L) 13.8

16.0

10.8

6.9

3.7

9.3

Study 934 Serum Creatinine

Maximum Confirmed Toxicity Grade (mg/dL)a

FTC/TDF(n = 257)

CBV(n = 254)

1 (>1.5 - 2.0) 0 1 (<1%)

2 (2.1 - 3.0) 0 1 (<1%)

3 (3.1 - 6.0) 0 0

4 (>6.0) 0 0

a. Confirmed toxicity grade = two consecutive visits

• 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

Study 934 Week 48 Summary