Comparison of NRTI combinations
 ZDV/3TC vs TDF + FTC
– Study 934
 ABC/3TC vs TDF/FTC
– HEAT Study
– ACTG A5202 Study
– ASSERT Study
 FTC/TDF vs FTC/TAF
– Studies GS-US-292-0104 and GS-US-292-0111
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
 Design
Randomisation*
1:1
Open-label
N = 255
517 ARV-naïve patients
> 18 years
HIV RNA > 10,000 c/mL
Any CD4 cell count
W48
TDF 300 mg
QD
FTC 200 mg
QD
EFV 600 mg
QD
N = 254 ZDV/3TC 300/150 mg
EFV 600 mg
W144
BID
QD
*Randomisation was stratified on CD4 cell count < 200 or > 200/mm3
 Objective
– Non inferiority of TDF + FTC + EFV vs ZDV/3TC + EFV at W48:
% HIV RNA < 400 c/mL, TLOVR algorithm (lower margin of the 95% CI
for the difference = -13%, 85% power)
Study 934
Gallant JE. NEJM 2006;354:251-60
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
Baseline characteristics
TDF + FTC
ZDV/3TC fdc
Randomized, N
258
259
Treated eligible patients, N
255
254
Median age, years
36
37
14%
13%
56% / 25% / 19%
61% / 20% / 19%
HIV RNA (log10 c/mL), median
5.0
5.0
HIV RNA > 100,000 c/mL
52%
50%
CD4 cell count (/mm3), median
233
241
CD4 < 200/mm3
42%
41%
CD4 < 50/mm3
15%
11%
Baseline NNRTI resistance mutations, N
11*
11*
Female
White/Black/Other
* Excluded from primary endpoint analysis
Note : TDF, FTC and EFV taken without regards to meals and preferably at bed time;
Substitution of NVP for EFV allowed if EFV intolerance; not considered as treatment failure
Study 934
Gallant JE. NEJM 2006;354:251-60
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
Response to treatment at week 48
Primary
endpoint
%
TDF + FTC
ZDV/3TC
/mm3
100
200
84
80
80
73
77
70
68
60
120
40
80
20
40
N=
244
243
244
243
255
158
254
0
0
HIV RNA < 400 c/mL
TLOVR
95% CI for
the difference
= 4; 19
(p = 0.002)
Study 934
160
190
HIV RNA < 50 c/mL
TLOVR
95% CI for
the difference
= 2; 17
(p = 0.02)
HIV RNA < 50 c/mL
ITT
95% CI for
the difference
= 1; 16
(p = 0.03)
Mean CD4
increase
(p = 0.002)
Gallant JE. NEJM 2006;354:251-60
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
 Safety and tolerability: TDF + FTC vs ZDV/3TC
– Similar frequency of clinical adverse events grade 2 to 4 and laboratory
abnormalities grade 2 to 4 in both groups, respectively 63% vs 63%
and 56% vs 57%
– Significantly more discontinuations for adverse events in the ZDV/3TC group:
9% vs 4% (p = 0.02); mainly for anemia (N = 14 vs 0)
– Renal safety was similar in both groups and no patients discontinued because
of renal events. Change in median GFR (MDRD) at W48 was similar in both
groups (< - 1 mL/min/1.73 m2). No Fanconi’s syndrome occurred
– Mean increase significantly lower in the TDF + FTC group for total cholesterol,
LDL-cholesterol and HDL-cholesterol; increase in triglycerides modest and not
different between groups
– At week 48, DEXA substudy in 100 patients (no baseline evaluation):
significantly less total limb fat with ZDV/3TC (mean 6.9 vs 8.9 kg; p = 0.03)
Study 934
Gallant JE. NEJM 2006;354:251-60
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
 Resistance data
– Genotypic analysis was done in patients without baseline NNRTI resistance if
1) viral rebound (2 consecutive HIV RNA > 400 c/mL after achieving < 400 c/mL
2) HIV RNA > 400 c/mL at W48
3) discontinuation before W48 with HIV RNA > 400 c/mL at the last visit
– Patients with baseline resistance (11 in each group) were excluded from this
analysis of resistance
TDF + FTC
N = 244
ZDV/3TC
N = 243
Patients in genotypic analysis
12
23 *
Wild-type
3
5
Any resistance mutation
9
17
K65R
0
0
M184V/I
2
7
TAM
0
1
EFV resistance mutation **
9
16
EFV resistance mutation + M184V
2
6
* 1 technical failure; ** K103N mutation developed in 21 of 25 patients
Study 934
Gallant JE. NEJM 2006;354:251-60
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
 Study extended to 3 years of follow-up (W144)
– At week 96, patients on TDF + FTC swithed to fixed-dose combination TDF/FTC
Results at week 144
TDF/FTC
ZDV/3TC
p
HIV RNA < 400 c/mL
71%
58%
0.004
HIV RNA < 50 c/mL
64%
56%
0.08
CD4 increase (/mm3)
312
271
0.09
Discontinuation for virologic failure
2%
6%
0.038
Discontinuation for adverse events*
5%
11%
0.01
Median GFR (MDRD) W144 minus baseline (mL/min/1.73m2)
- 12
+1
< 0.001
7.9 kg
5.4 kg
< 0.001
Mean total limb fat (DEXA)
* No discontinuation for renal events
Study 934
Arribas JR. JAIDS 2008;47:74-8
Study 934: zidovudine/lamivudine fixed dose
combination vs tenofovir + emtricitabine
 Conclusions
– TDF + FTC + EFV is non inferior to ZDV/3TC + EFV
– Greater virologic response rates to TDF + FTC + EFV as compared
with ZDV/3TC + EFV
– Significantly greater CD4 response with TDF + FTC
– Greater tolerability of TDF + FTC
– This study shows superior outcome in the tenofovir-emtricitabine group
– At week 144, TDF/FTC + EFV demonstrates superior durability of viral
load suppression and an improved safety and morphologic profile
compared with ZDV/3TC and EFV
Study 934
Gallant JE. NEJM 2006;354:251-60; Arribas JR. JAIDS 2008;47:74-8