superior outcome for tenofovir df (tdf), emtricitabine (ftc) and efavirenz (efv) compared to fixed...
DESCRIPTION
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 antiretroviralsTRANSCRIPT
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 QDFTC QDEfavirenz QD
AZT/3TC BIDEfavirenz 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
espo
nder
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
espo
nder
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
hang
e (c
ells
/mm3 )
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/I 2 (0.8%)
7 (3%)
Any TAMs 0 1 (0.4%)
K65R 0 0
Wild-type 3(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 Population FTC/TDF(n = 257)
CBV(n = 254)
No. w/ any Adverse Eventa 10 (4%) 23 (9%)b
Adverse EventAnemia/ ↓ 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
atoc
rit %
05
1015202530354045505560
Baseline Nadir
4047
31
22
33
11
02468
101214161820
Baseline Nadir
Hem
oglo
bin
(g/d
L) 13.816.0
10.8
6.9
3.7
9.3
02468
101214161820
Baseline Nadir
Hem
oglo
bin
(g/d
L) 13.816.0
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