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. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Design
Randomisation*
1 : 1
Open-label
W48
W96
> 18 years
ARV-naïve
HIV RNA > 2,500 c/mL
Any CD4 cell count
eGFR > 50 mL/min
Sensitivity to EFV, FTC and TDF
on genotype
No RPV resistance mutations**
N = 394
RPV/FTC/TDF QD STR
N = 392
EFV/FTC/TDF QD STR
Concomitant use of proton pump inhibitors was not allowed
* Randomisation was stratified by HIV RNA (< or > 100,000 c/mL)
** K101E/P, E138A/G/K/Q/R, Y181C/I/V, H221Y
Objective
Non inferiority of RPV/FTC/TDF at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (1-sided significance level of 2.5%, lower margin of the 97.5% CI for the difference = -12%, 95% power)
STAR
Cohen C. AIDS 2014;28:989-97 2

3. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Baseline characteristics and patient disposition
RPV/FTC/TDF
N = 394
EFV/FTC/TDF
N = 392
Median age, years 37 35
Female 7%
HIV RNA (log10 c/mL), median
4.8
HIV RNA > 100,000 c/mL
34%
36%
CD4 cell count (/mm3), mean
396
385
Discontinuation by W48 (N)
54 (13.7%)
72 (18.4%)
For lack of efficacy 12 3
For adverse event 10 34
Lost to follow-up 15
Non compliance 6 4
Withdrew consent 5 13
Protocol violation 1
Pregnancy 2
Investigator’s decision
Death
STAR
Cohen C. AIDS 2014;28:989-97 3

4. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Response to treatment (HIV RNA < 50 c/mL) at week 48 25 50
100 75
85.8
81.6
Adjusted difference
(95% CI) =
4.1% (-1.1 ; 9.2)
79.9
81.7
5.9% (0.6 ; 11.2)
ITT, snapshot
ITT snapshot, by baseline HIV-1 RNA
RPV/FTC/TDF
EFV/FTC/TDF
Primary analysis %
88.8
85.3
79.6
> 100,000 c/mL
< 100,000 c/mL
ITT, TLOVR
Difference (95% CI) =
7.2% (1.1 ; 13.4)
-1.8% (-11.1 ; 7.5)
Median CD4/mm3 increase at W48: RPV/FTC/TDF vs EFV/FTC/TDF
STAR
Cohen C. AIDS 2014;28:989-97 4

5. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Resistance analysis through week 48
RPV/FTC/TDF
EFV/FTC/TDF
Resistance analysis population*
20 (5%)
7 (2%)
Resistance to antiretrovirals
17 (4.3%)
3 (0.8%)
In patients with baseline HIV RNA < 100,000 c/mL
1.9%
0.8%
In patients with baseline HIV RNA > 100,000 c/mL
9.0%
0.7%
Any primary NNRTI resistance 16 3
Y181C/I 8 -
E138K/Q 6
K101E 5
K103N 1
Y188L
G190E/Q
Any primary NRTI resistance
M184V/I 15
K65R/N
* HIV RNA > 400 c/mL and suboptimal virologic response (confirmed < 1 log10 c/mL decrease in HIV RNA at W8) virologic rebound (2 consecutive visits with HIV RNA > 50 c/mL after achieving < 50 c/mL, 2 consecutive visits with > 1 log10 c/mL increase in HIV RNA from the nadir) or HIV RNA > 400 c/mL at W48 or last visit
STAR
Cohen C. AIDS 2014;28:989-97 5

6. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Safety through week 48
RPV/FTC/TDF
EFV/FTC/TDF
Grade 3-4 treatment-emergent adverse events
7.4%
13.8%
Related to study drug
1.8%
4.8%
Treatment-emergent adverse events of specific interest in > 5% in either arm
RPV/FTC/TDF
EFV/FTC/TDF
Nervous system events
29.7%
50.5%
Dizziness
6.6%
22.2%
Insomnia
9.6%
14.0%
Somnolence
2.5%
13.5%
Headache
12.4%
Psychiatric events
15.7%
37.5%
Abnormal dreams
5.8%
24.5%
Depression
8.9%
Anxiety
5.1%
8.4%
Rash events
17.3%
21.2%
Folliculitis
5.3%
1.0%
Rash
6.1%
12.0%
STAR
Cohen C. AIDS 2014;28:989-97 6

7. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Mean changes in fasting lipids (mg/dL) at week 48
p < for all between treatment groups using ANOVA
Mean baseline values (mg/dL)
164
163
104
103
121
129 44
RPV/FTC/TDF
EFV/FTC/TDF
Change in total cholesterol/HDL-cholesterol at week 48 was -0.2 in both arms
STAR
Cohen C. AIDS 2014;28:989-97

8. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Conclusion at week 48
In treatment-naive HIV-infected patients, RPV/FTC/TDF demonstrated non inferior efficacy and improved tolerability compared with EFV/FTC/TDF, at week 48
RPV/FTC/TDF was statistically significant superiority in efficacy for patients with baseline HIV-1 RNA ≤ 100,000 c/mL
Virologic efficacy was similar for patients with baseline HIV-1 RNA > 100,000 c/mL
More discontinuations due to adverse events in the EFV/FTC/TDF arm
Significantly lower rates of nervous system and psychiatric adverse events in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm
Differences primarily due to dizziness and abnormal dreams
Virologic failures rates were similar between the 2 treatment arms
A greater proportion of patients in the RPV/FTC/TDF arm developed primary emergent NRTI or NNRTI resistance mutations at virologic failure
STAR
Cohen C. AIDS 2014;28:989-97 8

9. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
ARV-trial.com
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Virologic outcomes at W96, snapshot analysis
RPV/FTC/TDF
N = 394
EFV/FTC/TDF
N = 392
Virologic success (HIV-1 RNA < 50 c/mL)
77.9%
72.4%
Difference (95% CI)
5.5 (- 0.6 to 11.5) ; p = 0.076
Virologic failure
9.4%
5.9%
HIV-1 RNA ≥ 50 c/mL
1.5%
Treatment discontinuation due to lack of efficacy
4.1%
1.0%
Treatment discontinuations due to other reasons and last HIV-1 RNA ≥ 50 c/mL
3.8%
3.3%
No data in the study window
12.7%
21.7%
Treatment discontinuation due to adverse event or death
3.0%
10.7%
Treatment discontinuations due to other reasons and last HIV-1 RNA < 50 c/mL
7.9%
Missing data while receiving study drug
1.8%
STAR
Van Lunzen J. AIDS 2016;30:251-9 9

10. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Response to treatment (HIV RNA < 50 c/mL) at week 96 20 40 60 80
100
231/ 260
204/ 250
205/ 260
178/ 250
107/ 134
116/ 142
102/ 134
106/ 142
RPV/FTC/TDF at W48
RPV/FTC/TDF at W96
EFV/FTC/TDF at W48
EFV/FTC/TDF at W96 89 82 79 71 76 75
< 100,000 c/mL
> 100,000 c/mL
Baseline HIV RNA %
W48
W96
1.1
7.2
13.4
15.1
7.6
0.2
7.5
-1.8
-11.1
-8.7
1.5
11.6
12%
-12%
p = 0.046
p = 0.78
> 100,000 c/mL
< 100,000 c/mL
HIV RNA at baseline
Favors EFV/FTC/TDF
Favors RPV/FTC/TDF
STAR
Van Lunzen J. AIDS 2016;30:251-9

11. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Response to treatment (HIV RNA < 50 c/mL) at week 96 20 40 60 80
100 53 51
341
RPV/FTC/TDF
EFV/FTC/TDF
60.4
68.6
80.6 73
< 200/mm3
> 200/mm3
Baseline CD4+ cell count %
14.0
7.7
1.3
- 26.7
-8.0
10.7
20%
-20%
p = 0.018
p = 0.40
> 200/mm3
< 200/mm3
CD4 at baseline
Favors EFV/FTC/TDF
Favors RPV/FTC/TDF
STAR
Van Lunzen J. AIDS 2016;30:251-9

12. Resistance analysis at week 96
STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Resistance analysis at week 96
RPV/FTC/TDF (N = 394)
EFV/FTC/TDF (N = 392)
Baseline-W48
W48-W96
Subjects in the Resistance Analysis Population
20 (5%)
+4 (1%)
7 (1.8%)
+2 (0.5%)
Subjects with Resistance Data
Subjects with Resistance to ARVs
17 (4%)
3 (0.8%)
+1 (0.3%)
Any primary NNRTI-R
Key NNRTI-R
16 (4%)
E138K/Q (N = 6) Y181C/I (N = 8)
K101E (N = 5)
V90I (N = 6) +4 +0 +2
3 (1%)
K103N (N = 1) Y188L (N = 1) G190E/Q (N = 1)
M230L (N = 0) +1
Any primary NRTI-R Key NRTI-R
M184V/I (N = 15) K65R/N (N = 3)
1 (0.3%)
M1841 (N = 1)
With baseline HIV RNA
< 100,000 c/mL
> 100,000 c/mL
5/260 (2%) 12/134 (9%)
2/250 (1%) 1/142 (0.7%)
+1 (0.4%)
STAR
Porter DP. HIV Clin Trials 2015;16:30-8 ; Van Lunzen J. AIDS 2016;30:251-9

13. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Most frequently reported treatment-emergent adverse events leading to permanent study drug discontinuation
RPV/FTC/TDF (N = 394)
EFV/FTC/TDF (N = 392)
W1- W4
W5-
W48
W48-W96
Total
Psychiatric disorder 1
1 (0.3%) 5 11 8
24 (6.1%)
Nervous system disorder 2
3 (0.8%)
8 (2.0%)
Skin and subcutaneous tissue disorder (e.g. rash) 7
7 (1.8%)
Clinical laboratory investigation
4 (1.0%)
2 (0.5%)
General disorder (e.g. fatigue) 3
5 (1.3%)
Gastrointestinal disorder
Grade 3–4 treatment-emergent adverse event deemed related to study drug : 2.3% RPV vs 5.6% EFV
Median changes from baseline to W96 in creatinine clearance : mL/min in the RPV group and mL/min in the EFV group
3 discontinuations for renal events : 1 in the RPV group and 2 in the EFV group
STAR
Van Lunzen J. AIDS 2016;30:251-9

14. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
HIV Symptom Index Questionnaire at W96
RPV/FTC/TDF: significant reduction in occurrence of 18/20 symptoms vs baseline (p < 0.039)
EFV/FTC/TDF: significant reduction in occurrence of 7/20 symptoms vs baseline (p < 0.033)
Significant between-group differences in symptom occurrence vs baseline for 8 symptoms, all favoring RPV/FTC/TDF
Overall satisfaction (HIV Treatment Satisfaction Questionnaire) at W96
High in both groups
Quality of life (SF-12V2)
The between-group difference in the median change from baseline at W96 for the physical health composite score was not significant
The difference for the mental health composite score was significant, favoring RPV/FTC/TDF (p = 0.014)
STAR
Van Lunzen J. AIDS 2016;30:251-9

15. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF
Conclusion at W96
In treatment-naive, HIV-1-infected adults, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF
Significant differences in virologic success between subgroups with HIV-1 RNA ≤ 100,000 c/mL and > 200 CD4/mmm3 could be related to the higher rate of discontinuations due to adverse events in the EFV/FTC/TDF group
The higher virologic failure rates observed for RPV/FTC/TDF with baseline HIV-1 RNA > c/mL and CD4+ cell count ≤ 200/mm3 were mainly due to a higher rate of discontinuation due to lack of efficacy in this group (limitation: low number of patients in those categories)
Rates of resistance development through W96 were low (5.3% RPV/FTC/TDF ; 1.0% EFV/FTC/TDF) with infrequent emergent resistance after W48
Development of resistance at failure: 88% RPV/FTC/TDF vs 44% EFV/FTC/TDF ; resistance in RPV/FTC/TDF group was more frequent if baseline HIV-1 RNA > 100,000 c/mL
Better safety and tolerability profile of RPV/FTC/TDF vs. EFV/FTC/TDF over 96 weeks of treatment (limitation: open-label trial)
STAR
Van Lunzen J. AIDS 2016;30:251-9