EFV vs LPVr vs EFV LPVr A5142 Mexican Study NVP vs ATVr ARTEN EFV vs ATVr A5202 DOR vs DRVr DRIVEFORWARD Design Objective Non inferiority of DOR at W48 HIV RNA lt 50 cmL by intention to treat ID: 574747
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Slide1
Comparison of NNRTI vs PI/r
EFV vs LPV/r vs EFV + LPV/r
A5142
Mexican
Study
NVP vs ATV/r
ARTEN
EFV vs ATV/r
A5202
DOR vs DRV/r
DRIVE-FORWARDSlide2
Design
Objective
Non inferiority of DOR at W48: % HIV RNA < 50 c/mL by intention to treat,
non completer = failure, snapshot analysis (lower margin of the 95% CI
for the difference = - 10%, 90% power)
DOR 100 mg QD + DRV/r placebo + 2 NRTI**
DRV/r 800/100 mg QD + DOR placebo+ 2 NRTI**
Randomisation*1 : 1Double-blind
> 18 yearsARV-naïve HIV RNA > 1 000 c/mLAny CD4 cell counteGFR (CG) ≥ 50 mL/minNo primary resistance to DOR, DRV/r, NRTI
* Randomisation (DOR vs DRV/r) was stratified by HIV RNA (< or > 100 000 c/mL) at screening and NRTI backbone
N = 340
N = 340
W48
W96
DRIVE-FORWARD
** NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) was selected by investigator
DRIVE-FORWARD
Study
: DOR + 2 NRTI vs DRV/r
+ 2 NRTI
Molina JM, Lancet HIV 2018, March 25 (
Epub
ahead
of
print
)Slide3
DRIVE-FORWARD
Study
: DOR + 2 NRTI vs DRV/r + 2 NRTI
DOR + 2 NRTI
(N = 383)
DRV/r + 2 NRTI
(N = 383)
Mean age, years
35
35
Female, %
17
15
AIDS, %
9
10
HIV RNA (log
10
c/mL), mean
4.4
4.4
HIV RNA > 100 000 c/mL, %
22
19
CD4 cell count (/mm
3
), mean
433
412CD4 < 200 per mm3, %1117Selected NRTI: TDF/FTC / ABC/3TC, %87 / 1388 / 13Discontinuation at W48, N (%)Lack of efficacy, NAdverse event, NDeath, NLost to follow-up / Consent withdrawal, NNon-compliance / Other, N56 (15%)124117 / 107 / 571 (19%)1412019 / 134 / 9
Baseline characteristics and patient disposition
DRIVE-FORWARD
Molina JM, Lancet HIV 2018, March 25 (
Epub
ahead
of
print
)Slide4
DRV/r
DOR
0
‒ 10%
+ 10%
9.4
-1.6
3.9
Difference (95 % CI)
84
11
5
80
13
7
0
20
40
60
80
100
Virologic
response
Virologic
non-response
No data
DOR + 2 NRTI (N = 383)
DRV/r + 2 NRTI (N = 383)
%58DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTIPrimary endpoint: HIV RNA < 50 c/mL at W48 (ITT, snapshot)CD4 increase at W48 (ITT, NC = F)DOR: + 193/mm3DRV/r: + 186/mm3DRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide5
59
* Discontinuation due to lack of efficacy counted as failures, data missing for other reasons excluded
DRIVE-FORWARD
Study
: DOR + 2 NRTI vs DRV/r + 2 NRTIHIV RNA < 50 c/mL, observed failure approach *
81.0
76.4
88.9
89.1
0
20
40
60
80
100
> 5 log10 c/mL
71
79
72
323
NRTI
backbone
82.9
72.1
≤ 200/mm
3
41
61
Baseline CD4 88.286.2364355Allparticipants%Baseline HIV RNA90.288.7≤ 5 log10 c/mL285282TDF/FTCABC/3TC89.683.74843> 200/mm388.086.5316312294N =DOR + 2 NRTIDRV/r + 2 NRTIDRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide6
DOR 100 + 2 NRTI
(N = 383)
DRV/r 800/100 + 2 NRTI
(N = 383)
Virologic failure, N
19 (5.0%)
24 (6.3%)
Non response / Rebound
2
17
5
19
Genotype successfully performed, N
Primary NNRTI resistance
Primary NRTI resistance
Primary PI resistance
7
0
0
0
8
0
0
0
Phenotype successfully performed, N
With any phenotypic drug resistance
6
0
80DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTIDefinitionNon response: HIV RNA ≥ 200 c/mL at W24 or W36 or confirmed HIV RNA ≥ 50 c/mL at W48Rebound: confirmed HIV RNA ≥ 50 c/mL after obtaining HIV RNA < 50 c/mLResistance tests (genotype and phenotype) performed on confirmatory sampleif HIV RNA > 400 c/mL60Protocol-defined virologic failures (PDVF)DRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide7
DOR 100 + 2 NRTI
(N = 383 *)
DRV/r 800/100 + 2 NRTI
(N = 383)
Discontinuation without PDVF, N (%)
40 (10.4%)
53 (13.9%)
Genotype successfully performed, N
Primary NNRTI resistance
Primary NRTI resistance
Primary PI resistance
2 *
1
1
0
3
0
0
0
Phenotype successfully performed, N
With any phenotypic drug resistance
2 *
2
3
0
* 1 discontinuation for non-compliance at W24, with emergence of resistance to DOR (V106I + H221Y ; > 90 fold increased IC
50
) and FTC (M184V) ; 1 discontinuation for rash at W2, with increased DOR IC
50 2.8 fold WT (resistance cutoff = 2.5 fold), but no genotypic resistance mutations61DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTIEmergence of drug resistance in participants with discontinuationsDRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide8
DOR 100 + 2 NRTI
(N = 383)
DRV/r 800/100 + 2 NRTI
(N = 383)
Serious adverse event
Drug-related
5.0 (N = 19)
0.3 (N = 1)
6.0 (N = 23)
0.3 (N = 1)
Discontinuation due to
adverse event
Drug-related
1.6 (N = 6 *)
1.0 (N = 4)
3.1 (N = 12 **)
2.1 (N = 8)
Discontinuation due to serious adverse event
Drug-related
0.3 (N = 1)
0
0.5 (N = 2)
0.3 (N = 1)
Adverse event in
≥ 10 % in either group
Diarrhea
Nausea
NasopharyngitisHeadache14.110.77.813.822.512.010.210.7Adverse event of clinical interestRashNeuropsychiatric711813* Death = 1, rash = 2, nausea = 2, abdominal pain = 1, kidney injury = 1** Abdominal pain = 2, diarrhea = 1, nausea = 1, flatulence = 1, hiatus hernia = 1, ALT and AST increase = 2, hepatitis B or C = 2, peripheral edema = 1, pyrexia = 1, rash = 1, tuberculosis = 2 62DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTIAdverse events, %DRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide9
63
DRIVE-FORWARD
Study
: DOR + 2 NRTI vs DRV/r + 2 NRTI
Fasting lipids, changes from baseline at W48 (mg/dL)
p < 0.0001LDL-CNon HDL-CTotal cholesterol
TriglyceridesHDL-C
0
10
-
1
0
- 5
5
15
25
20
- 3.1
- 1.4
-
5.
3
- 4.5
9.9
13.8
17.9
22
3.9
4.2p < 0.0001DORDRV/rDRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)Slide10
DRIVE-FORWARD
Study
: DOR + 2 NRTI vs DRV/r + 2 NRTI
Conclusion at Week 48
DOR 100 mg QD, in combination with either TDF/FTC or ABC/3TCAchieved high virologic success at Week 48And was non-inferior to DRV/r + 2 NRTI regardless of baseline HIV RNA Resistance mutations through 48 weeks None were detected in protocol-defined virologic failures
Only 1/383 participants on DOR developed genotypic and phenotypic resistance to DOR + FTC/3TCAdverse events leading to discontinuation occurred with low frequency for both DOR and DRV/rLow rate of discontinuation due to rash or neuropsychiatric adverse eventsLipid changes were less pronounced for DOR than for DRV/rOnce-daily DOR in combination with fixed-dose NRTIs represents an effective treatment option for HIV-1-infected, treatment-naive patients
DRIVE-FORWARDMolina JM, Lancet HIV 2018, March 25 (Epub ahead of print)