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

2. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Design
Randomisation*
1 : 1
Double-blind
W48
W96
> 18 years
ARV-naïve
HIV RNA > c/mL
Any CD4 cell count
eGFR (CG) ≥ 50 mL/min
No primary resistance
to DOR, EFV, NRTI
N = 364
DOR 100 mg/3TC/TDF QD + placebo
EFV/FTC/TDF + placebo
N = 364
* Randomisation was stratified by HIV RNA (< or > c/mL) at screening and chronic hepatitis B or C
DOR/3TC/TDF : 1 tablet QD as STR
Objectives
Non inferiority of DOR at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (lower margin of the 95% CI for the difference = - 10%, 90% power)
Superiority of DOR for neuropsychiatric adverse events by W48
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

3. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Baseline characteristics and patient disposition
DOR/3TC/TDF
(N = 364)
EFV/FTC/TDF
Median age, years 32 30
Female, % 16 15
AIDS, % 13
HIV RNA (log10 c/mL), mean
4.4
4.5
HIV RNA > c/mL, % 20 23
CD4 cell count (/mm3), mean
435
416
CD4 < 200/mm3, % 12
Discontinuation at W48, N (%)
Lack of efficacy, N
Adverse event, N
Death, N
Lost to follow-up / Consent withdrawal, N
Non-compliance / Other, N
51 (14%) 18 10 1
6 / 8
1 / 7
61 (17%)
10 23 3
7 / 11
2 / 5
Discontinuation at W96 (N (%)
68 (19%) 31 11
88 (24%) 26
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

4. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF58
Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, snapshot)
EFV/FTC/TDF (N = 364) 84 11 5 81 10 9 20 40 60 80
100
Virologic
response
non-response
No data
DOR/3TC/TDF (N = 364) %
EFV
DOR
‒ 10%
+ 10%
9.0
-2.0
3.5
Difference (95 % CI)
CD4 increase at W48 (ITT, NC = F)
DOR: + 198/mm3
EFV: + 188/mm3
HIV RNA < 50 c/mL at W48 (observed failure approach)
Baseline HIV RNA ≤ c/mL: DOR: 90.6% vs EFV: 91.1 %
Baseline HIV RNA > c/mL: DOR: 81.2 % vs EFV: 80.8 %
DRIVE-AHEAD
Orkin C. Clin Infect Dis 2019; 68:

5. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
HIV RNA < 50 c/mL at W96
(ITT, snapshot)
HIV RNA < 50 c/mL at W96
(Observed failure approach)
DOR
EFV
All patients
83.7
85.9
Baseline HIV RNA
≤ c/mL
> c/mL
86.9
71.0
87.5
79.7
Baseline CD4
≤ 200/mm3
> 200/mm3
82.1
86.4 %
DOR/3TC/TDF (N = 364)
100
EFV/FTC/TDF (N = 364)
77.5 80
73.6 60 40
Mean increase in CD4 at W96
DOR/3TC/TDF = + 238/mm3
EFV/FTC/TDF = + 223/mm3 20
Difference: 3.8%
(95% CI: to 10,0)
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

6. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF60
Protocol-defined virologic failures (PDVF) at W48
Definition
Non response: HIV RNA ≥ 200 c/mL at W24 or W36 or confirmed HIV RNA ≥ 50 c/mL at W48
Rebound: confirmed HIV RNA ≥ 50 c/mL after obtaining HIV RNA < 50 c/mL
DOR /3TC/TDF
(N = 364)
EFV/FTC/TDF
Virologic failure, N
22 (6.0%)
14 (3.8%)
Non response / Rebound 6 16 4 10
Discontinuation without PDVF, N 35 50
Genotype successfully performed, N
Primary NNRTI resistance
Primary NRTI resistance 23
6 *
5 * 24
12 **
5 **
* NNRTI mutations : Y188L; V106I, F227C; V106V/I, H221H/Y, F227C; F227C; V106A, P225H, Y318Y/F; V106M/T, F227C/R ; NRTI mutations : M41L, M184V; M184V; M184V; K65R; K65K/R, M184V
** NNRTI mutations : K103N; K103N, E138E/G; K103N; G190E; K103N; K103N, M230L; G190E; K103N, V108V/I, T369T/A/I/V; K103N; K103N; K101K/N, K103N, P225P/H ; NRTI mutations : V118I, M184V; M184V; M184V; M184V, K219K/E; K65K/R, M184M/I
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

7. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Virologic failure and resistance, W96
DOR/3TC/TDF
(N = 364)
EFV/FTC/TDF
D0-W48
W48-W96
Virologic failure, N (%)
Non-response
Rebound
22 (6.0%)
6 16
34 (9%) 6 28
14 (3.8%) 4 10
28 (8%) 24
Discontinuation without protocol- defined virologic failure, N (%)
35 (9.6%)
39 (11%)
50 (13.7%)
62 (17%)
Genotype successful, N
NNRTI major resistance
NRTI major resistance 23
6 (1.6%)
5 (1.4%) 11
11 (3.3%) 9 2
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

8. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF62
Adverse events at W48, %
DOR/3TC/TDF
(N = 364)
EFV/FTC/TDF
Drug-related adverse event 31 63
Serious adverse event 4 6
Discontinuation due to adverse event
Drug-related 3 2 7
Discontinuation due to serious adverse event 1
< 1
Adverse event in ≥ 10% in either group
Headache
Diarrhea
Nasopharyngitis
Dizziness
Nausea
Abnormal dreams
Rash
Grade 3-4 laboratory abnormalities
Fasting LDL-cholesterol
Fasting triglycerides
Creatinine
AST / ALT
Lipase
Creatine kinase
< 1 / 1
/ 1
1 3
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

9. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
% with Predefined Neuropsychiatric Adverse Events at W48
DOR/3TC/TDF
EFV/FTC/TDF 10 20 30 40
Dizziness
Sleep disorders and disturbances
Altered sensorium
Depression and suicide/ self-injury
Psychosis and psychotic disorders
8.8
37.1
12.1
25.5
4.4
8.2
4.1
6.6
0.3
1.1
p < 0.001
p = 0,033 %
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

10. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Fasting Lipids (mg/dL): change from Baseline at W48
-15
LDL-C
p < 0,0001
Non-HDL-C
Cholesterol
Triglycerides
HDL-C
DOR/3TC/TDF
EFV/FTC/TDF
-10 -5 5 10 15 20 25
-1.6
8.7
-3.8
13.3
-2.0
21.8
-12.4
22.0
1.9
8.5
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44

11. DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Summary at week 48
In treatment-naïve adults with HIV-1 infection, DOR/3TC/TDF administered once daily demonstrated:
Antiviral potency with non-inferior efficacy to EFV/FTC/TDF regardless of baseline HIV-1 RNA
Low rate of resistance, with only 1.6% of participants developing resistance to any study drug through W48
DOR/3TC/TDF was generally well tolerated and safe:
Neuropsychiatric profile superior to EFV/FTC/TDF, as measured by lower proportion of participants with neuropsychiatric adverse events in categories of dizziness, sleep disorders and disturbances, and altered sensorium
Lipid profile superior to EFV/FTC/TDF, as assessed by difference from baseline in fasting LDL-C and non-HDL-C
Summary at week 96
DOR/3TC/TDF continued to be non-inferior to EFV/FTC/TDF, with no additional emergence of resistance to DOR between W48 and W96
Rate of discontinuation for adverse event was lower with DOR/3TC/TDF (3% vs 7%)
DRIVE-AHEAD
Orkin C. Clin Infect Dis ;68:535-44