1. Comparison of NNRTI vs NNRTI
ARV-trial.com
Comparison of NNRTI vs NNRTI
ENCORE
EFV vs RPV
ECHO-THRIVE
STAR
EFV vs ETR
SENSE
DOR vs EFV
DRIVE-AHEAD 1

2. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Design
Randomisation*
1 : 1
Double-blind
W48
W96
> 16 years
ARV-naïve
HIV RNA > 1,000 c/mL
CD4 cell count: /mm3
Creatinine clearance
> 50 mL/min
N = 324
TDF/FTC + EFV 400 mg (2 x 200 mg pills + 1 placebo pill) QD
N = 312
TDF/FTC + EFV 600 mg (3 x 200 mg pills) QD
*Randomisation was stratified by clinical site and by HIV RNA (< or > 100,000 c/mL) at screening
Objective
Non inferiority of EFV 400 mg at W48: % HIV RNA < 200 c/mL by modified intention to treat analysis (all randomised participants who received at least 1 dose of study drug and at least one follow-up visit), 2-sided significance level of 5%, lower margin of the 95% CI for the difference = -10%, 90% power
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: ; ENCORE1 Study Group. Lancet Infect Dis 2015;15: 2

3. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Baseline characteristics and patient disposition
EFV TDF/FTC
N = 321
EFV TDF/FTC
N = 309
Mean age, years 36
35.8
Female
31%
33%
HIV RNA (log10 c/mL), median
4.76
4.73
HIV RNA > 100,000 c/mL
33.3%
34.6%
CD4 cell count (/mm3), mean
273
272
CD4 < 200 per mm3
24%
26%
Hepatitis B / hepatitis C coinfection
5% / 2%
4% / 19%
Discontinuation by W48
10 (3.1%)
14 (3.6%)
Died
N = 2
N = 3
Withdrew consent
Lost to follow-up
N = 4
Missed week 48 visit
N = 1
N = 5
Discontinuation by W96
22 (7%)
23 (7%)
Died / withdrew / lost to follow-up, N
5 / 9 / 8
5 / 5 / 13
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: ; ENCORE1 Study Group. Lancet Infect Dis 2015;15: 3

4. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Response to treatment at week 48, globally and by baseline
HIV RNA (< 100,000 c/mL or > 100,000 c/mL)
HIV RNA
< 200 c/mL 25 50
100 75
94.1
92.2 %
Difference
(95% CI) =1.8%
(-3.7 ; 7.4)
82.3
80.4
mITT
88.3
86.3
< 5 log
90.4
88.9
ITT, NC= F
> 5 log
All patients
80.6
77.7
87.7
86.1
HIV RNA < 50 c/mL
Per protocol
(-2.1 ; 5.8)
86.0
84.1
84.3
78.7
90.6
(95% CI) =1.5%
(-3.5 ; 6.5)
EFV TDF/FTC
EFV TDF/FTC
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: 4

5. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Response to treatment at week 96, globally and by baseline
HIV RNA (< 100,000 c/mL or > 100,000 c/mL)
HIV RNA
< 200 c/mL 25 50
100 75
90.0
90.6 %
Difference
(95% CI) : -0.4%
(-5.8 ; 4.9)
86.3
87.5
EFV TDF/FTC
EFV TDF/FTC
mITT
< 5 log
94.3
95.3
ITT, NC= F
> 5 log
All patients
83.1
82.1
94.5
94.8
HIV RNA < 50 c/mL
Per protocol
(95% CI) : - 0.6%
(- 5.2 ; 4.0)
86.7
81.7
78.2
94.1
95.6
Difference
(95% CI) : - 1.1%
(- 4.9 ; 2.8)
ENCORE1
ENCORE1 Study Group. Lancet Infect Dis 2015;15: 5

6. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Mean CD4 cell counts increase at W96
+ 235/mm3 in the EFV 400 group
+ 209/mm3 in the EFV 600 group (p = 0.018)
No difference between groups in the mean change
In CD4 cell percentage
In CD8 cell counts
Of total lymphocyte counts
At 96 weeks,
Change in DASS-21 depression, anxiety, and stress Z scores did not differ between the groups
ENCORE1
ENCORE1 Study Group. Lancet Infect Dis 2015;15:

7. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Adverse events at week 48
EFV TDF/FTC
EFV TDF/FTC p
Patients with adverse events
89.1%
88.4%
Grade 1
72.9%
73.1%
Grade 2
22.5%
21.5%
Grade 3
4.1%
5.0%
Grade 4
0.4%
Serious adverse events, N patients
23 (7.1%)
22 (7.1%)
Related to study drugs
N = 3
N = 4
Adverse events definitively or probably related to study drug, N patients
118 (36.8%)
146 (47.2%)
0.008
Discontinuation due to drug-related adverse event
N = 6 (1.9%)
N = 18 (5.8%)
0.01
Adverse events of specific interest
Neuro-psychiatric
45%
51% NS
CNS
N = 231
N = 272
Psychiatric
N = 13
N = 12
Rash
N = 68
N = 105
Gastrointestinal
N = 62
N = 78
Hepatotoxicity
N = 1
N = 0
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: 7

8. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Other safety aspects at week 48
By week 48, discontinuation of EFV : 26 (8%) in EFV 400 vs 34 (11%) in EFV 600
Frequency of serious adverse events was similar in both groups
No difference between randomised groups in quality of life, depression, anxiety and stress, and EFV-related symptoms over 48 weeks
No significant differences between EFV 400 and EFV 600 in change from baseline to week 48 for most laboratory parameters, except
Neutrophils
Mean change in creatinine clearance : 1.29 mL/min vs – 2.17 mL/min
Mean alkaline phosphatase increase : + 26 vs + 33 IU/L
At Week 96
Only significant between-group difference : mean change in alkaline phosphatase : + 21 vs + 27 U/L (p = 0.046)
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: ; ENCORE1 Study Group. Lancet Infect Dis 2015;15: 8

9. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Adverse events at week 96
EFV TDF/FTC
N = 321
EFV TDF/FTC
N = 309 p
Patients with adverse events
91%
92% ns
% of AE of Grade 3 4% 5%
% of AE of Grade 4 1%
Serious adverse events, N events (N patients)
32 (24)
48 (32)
Related to EFV
N = 2 *
N = 4 **
Adverse events related to EFV (N patients)
126 (39%)
148 (48%)
0.03
Discontinuation of EFV due to drug-related adverse event
N = 16 (5%)
N = 34 (11%)
* Grade 3 dizziness ; possible Stevens Johnson syndrome
** Rash with fever and septic shock ; rash with labial oedema ; suicide ; attempted suicide
Mean changes in fasting lipids at W96
Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride concentrations increased modestly, but mean changes did not differ between the groups
ENCORE1
ENCORE1 Study Group. Lancet Infect Dis 2015;15: 9

10. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Virologic response in patients with baseline NNRTI resistance
570 patients with baseline genotypic test : NNRTI resistance, N = 18
10 assigned EFV 400
6 suppressed at W96 (all on EFV)
4 not suppressed at W96 (3/4 on EFV, 1/4 with also baseline FTC resistance)
8 assigned EFV 600
7 suppressed at W96 (6/7 on EFV)
1 not suppressed at W96 (not on EFV)
Virologic failure*
EFV TDF/FTC
N = 321
EFV TDF/FTC
N = 309
Resistance testing available, N 10 13
NNRTI resistance, N 2 3
* 2 consecutive HIV RNA > 500 c/mL
Among the 36 virologic failures, 5 had baseline NNRTI resistance and 8 were not amplifiable, 23 genotypes could be interpreted
ENCORE1
ENCORE1 Study Group. Lancet Infect Dis 2015;15:

11. ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
ARV-trial.com
ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC
Conclusion
A reduced dose of 400 mg EFV QD is non-inferior to the standard dose of 600 mg QD, when combined with TDF/FTC over 96 weeks in ART-naive adults with HIV-1 infection
Overall, the frequency of adverse events did not differ and there was no evidence of difference in treatment cessation between groups
However, adverse events related to the study drug were more frequent with 600 mg EFV than with 400 mg, and discontinuation due to adverse events more frequent with EFV 600 mg
Quality of life, negative emotional state, and efavirenz side-effect based on specific questionnaires did not differ between EFV and 400 mg QD
These findings provide an opportunity to reduce the unit costs of treatment and care models that are based on EFV use (caution when used with rifampicin)
ENCORE1
ENCORE1 Study Group, Puls R. Lancet 2014;383: ; ENCORE1 Study Group. Lancet Infect Dis 2015;15: 11