1. NRTI-sparing SPARTAN PROGRESS RADAR NEAT001/ANRS 143 A4001078 VEMAN
ARV-trial.com
NRTI-sparing
SPARTAN
PROGRESS
RADAR
NEAT001/ANRS 143 A
VEMAN
MODERN 1

2. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
ARV-trial.com
Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Design
Randomisation*
1 : 1
Open label
W96
> 18 years
ARV-naïve
HIV RNA > 1,000 c/mL
CD4 < 500/mm3
HBs Ag negative
Creatinine clearance > 60 mL/min
No resistance mutations
N = 401
DRV/r 800/100 mg QD + RAL bid
DRV/r QD + TDF/FTC QD
N = 404
* Randomisation was stratified by country and participation in the viral and immunological dynamics and inflammation sub-study
Objective
Non inferiority of RAL compared to TDF/FTC : % of participants reaching the primary endpoint by week 96 estimated by the Kaplan-Meier method in intention-to-treat analysis (upper margin of the 2-sided 95% CI for the difference = 9%, 85% power)
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NEAT 001 / ANRS 143 2

3. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Endpoints
Primary endpoint : time to failure, as the first occurrence of any of the following components
Virological
Change of treatment before W32 because of insufficient virologic response
HIV-1 RNA reduction < 1 log10 c/ml by W18*
or HIV-1 RNA ≥ 400 c/ml at W24*
HIV-1 RNA ≥ 50 c/ml at W32*
HIV-1 RNA ≥ 50 c/ml at any time after W32*
Clinical
Death due to any cause
Any new or recurrent AIDS defining event**
Any new serious non AIDS defining event**
All patients followed-up until last patient reached W96, events recorded until end of F-U
Major secondary endpoints : safety, changes in CD4 and HIV RNA, genotypic resistance
* Confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

4. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
ARV-trial.com
Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Baseline characteristics and patient disposition
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404
Median age, years 37 39
Female
12%
11%
HIV RNA (log10 c/mL), median
4.78
4.75
HIV RNA > 100,000 c/mL
36%
32%
CD4 cell count (/mm3), median
340
325
CD4 < 200 per mm3
15%
16%
Hepatitis C coinfection 4%
Discontinuation by W96
N = 38
N = 22
Discontinuation by end of follow-up
N = 53
Data were censored at the first date of meeting the primary endpoint, completion of 96 weeks of follow-up, last time the primary endpoint status was known, or date of withdrawal
NEAT 001 / ANRS 143
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5. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Patients who met the primary endpoint
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404
Total patients meeting primary endpoint during follow-up
77 (19.2%)
61 (15.3%)
Change of regimen because of insufficient virologic response
< 1 log10 c/mL reduction in HIV RNA at W18 1
HIV RNA ≥ 400 c/mL at W24
HIV RNA ≥ 50 c/mL at W32 27 28
HIV RNA ≥ 50 c/mL after W32 33 22
Death 3
AIDS event 5
Serious non-AIDS event 8 7
If a patient reached more than one component, only the first was taken into account
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

6. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Probability of reaching primary endpoint
log rank p=0.12
0.25
0.50
0.75
1.00
402
395
393
361
350
340
331
215 90 12
400
383
375
346
327
315
306
210 89 11 8 18 32 48 64 80 96
112
128
144
Time (weeks)
Numbers of patients
DRV/r + RAL
DRV/r + TDF/FTC
Estimated proportion reaching primary endpoint at W96
RAL: 17.8% vs TDF/FTC: 13.8%
Adjusted difference: 4% (95% CI: -0.8, 8.8%)
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

7. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Kaplan-Meier estimates of proportion of patients in each group
reaching endpoints at W96
Primary and secondary analyses around the primary endpoint
Adjusted difference in
proportions of failure at W96 (%, 95% CI)
DRV/r
+ RAL
(%)
DRV/r + TDF/FTC (%) -3 -2 -1 1 2 3 4 5 6 7 8 9 10
Adjusted difference in proportions of failure at W96 (%, 95% CI)
Primary endpoint
4.0 (-0.8 ; 8.8)
13.8
17.8
Without SNAIDS endpoints
3.9 (-0.7 ; 8.6)
12.1
16.0
Without treatment change
3.7 (-1.0 ; 8.5)
14.0
17.7
> 200 copies per mL in place of > 50 copies per mL
5.5 (2.0 ; 9,0)
5.0
10.5
Virological components only
3.6 (-0.9 ; 8.2)
11.8
15.5
Clinical components only
1.5 (-0.6 ; 3.7)
2.4
3.9
Including treatment discontinuation for virological reason
4.0 (-0.8 ; 8.9)
13.6
Per-protocol analysis
3.2 (-1.3 ; 7.7)
12.6
15.8
Including treatment discontinuation for any reason
3.3 (-1.9 ; 8.5)
19.7
23.0
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

8. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Kaplan-Meier estimates of proportion of patients in each group reaching endpoint at W96 – Analyses by baseline HIV RNA and CD4 cell count
Adjusted difference in
proportions of failure at W96 (%, 95% CI)
DRV/r
+ RAL
(%)
DRV/r +
TDF/FTC (%) -5 10 15 20 25 30 35 40
Adjusted difference in proportions of failure at W96 (%, 95% CI)
Baseline HIV RNA < copies/mL
0.1 (-3.8 ; 4.0)
7.3
7.4
Baseline HIV RNA > copies/mL
9.6 (-0.1 ; 20.1)
27.3
36.8
CD4 cell count < 200 cells/mm3
22.3 (7.4 ; 37.1)
20.9
43.2
CD4 cell count > 200 cells/mm3
1.4 (-3.5 ; 6,3)
12.3
13.7 5
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

9. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Kaplan-Meier estimates of proportion of patients reaching primary endpoint at W96 according to combined baseline CD4 and HIV RNA
Endpoint N %
≠ (95% CI)
CD4 < 200/mm3 and HIV RNA < 100,000 c/mL (N = 46)
DRV/r + RAL
3/23
9.4%
0.4%
(-13.7 ; 14.6)
DRV/r + TDF/FTC
9.0%
CD4 ≥ 200/mm3 and HIV RNA < 100,000 c/mL (N = 484)
19/232
7.1% 0%
(-3.9 ; 3.9)
21/252
CD4 < 200/mm3 and HIV RNA ≥ 100,000 c/mL (N = 77)
23/37
60.1%
30.3%
(13.8 ; 46.8)
12/40
29.9%
CD4 ≥ 200/mm3 and HIV RNA ≥ 100,000 c/mL (N = 198)
32/109
26.5%
-1.9%
(-13.9 ; 10.0)
25/89
28.4%
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

10. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Data are proportions (95% CI) based on available viral load data 20 40
100 60 % 80 4 8 12 18 24 32 48 64 96
DRV/r + RAL, 89.4% (95% CI : )
DRV/r + TDF/FTC, 93.3% (95% CI : )
HIV RNA < 50 c/mL
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

11. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Virological failure and emerging resistance mutations per trial arm
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404
All PDVF 66 52
Total number of patients who met criteria for genotype testing* 36 15
PDVF patients meeting criteria for genotype testing 33 9
Patients without PDVF meeting criteria for genotype testing 3 6
Patients undergoing genotyping 29 13
Major resistance mutations
Reverse transcriptase
Protease
Integrase 1† 5‡
RAL = raltegravir. DRV/r = ritonavir-boosted darunavir. TDF-FTC = tenofovir-emtricitabine PDVF = protocol-defined virological failure
*Genotypic testing carried out by local laboratories when patients had a single HIV RNA > 500 copies/mL at or after week 32 up to the end of follow up
†K65R. ‡N155H
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

12. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Emergence of resistance mutations in full data set
(confirmed HIV RNA > 50 c/mL or any single HIV RNA ≥ 500 c/ml at or after W32)
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404
Patients meeting criteria for genotypic testing 69 58
Patients with available genotype (≥ 1 amplified gene) 61 49
≥ 1 major IAS resistance mutations
Reverse transcriptase (NRTI only)
Protease
Integrase
17*
3/53 (5.7%)
1**/57 (1.8%)
14***/55 (25.5%)
* 1 patient had 2 major IAS resistance mutations (1 NRTI + 1 INI)
** L76V
*** N155H = 12 ; N155H + Q148R = 1, Y143C = 1 ; HIV RNA at genotypic testing < 200 c/mL : 4/14
Predictor of integrase resistance mutations emergence : baseline HIV RNA, p=0.006, no association with baseline CD4 nor HIV RNA at time of testing
NEAT 001 / ANRS 143
Lambert-Niclot S, JAC 2015 (in press)

13. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Safety
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404
Adjusted difference (95% CI)
Discontinuation for any reason
14.8% (W96)
9.1% (W96)
5.8%
( )
Discontinued after reaching the primary endpoint
36/80 (44%)
8/51 (16%)
Discontinuation for treatment-limiting AE
1.5%
2.6%
AE leading to treatment modification, all grade
3.9 /100 patient-year
4.2/100 patient-year
AE leading to treatment modification, grade 3-4
N = 7
N = 6
Serious adverse events
10.2/100 patient-year
8.3/100 patient-year
Death 4*
1**
Grade 2-4 rash
1.3/100 patient-year
1.6/100 patient-year
* melanoma, Burkitt’s lymphoma, severe sepsis with organ failure after DRESS, suicide
** morphine overdose
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

14. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Laboratory parameters
DRV/r + RAL
N = 401
DRV/r + TDF/FTC
N = 404 p
Mean increase from baseline to W96
Total cholesterol (mmol/L)
+ 0.9
+0.5
< 0.001
HDL-cholesterol (mmol/L)
+0.2
+0.1
LDL-cholesterol (mmol/L)
+0.4
0.021
Estimated creatinine clearance (mL/min)
+ 0.8
- 4.6
Graded abnormality over 96 weeks
≥ Grade 2 creatinine
Grade 3-4 CK increase 6% 5% -
Grade 3-4 ALAT increase 3%
0.036
Conversion mmol/L to g/L : x 0.387
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384:

15. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
146 patients : 70 DRV/r + RAL vs 76 DRV/r + TDF/FTC
Randomised at same time as the main study
Baseline demographic and HIV characteristics similar in the 2 sub-groups
History of fractures : 12 % vs 20 % (p = 0.17)
Osteopenia/osteoporosis at baseline : 24 in DRV/r + RAL vs 21 in DRV/r + TDF/FTC
Compare changes in bone mineral density (BMD) between treatment arms
Whole body dual-energy x-ray absorptiometry (DXA) scans assessed BMD of total hip, lumbar spine and femoral neck, at baseline, W48 and W96
Evaluate clinical factors associated with BMD loss
Primary endpoint
Mean percentage change of BMD in lumbar spine and hip at 48 weeks
Secondary endpoints
Mean percentage change at 96 weeks
Proportion with WHO criteria for osteoporosis/osteopenia
Proportion with a Z score < -2
Incidence of fractures
Analyses by intent-to-treat exposed approach (ITT-e)
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

16. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
Mean % change in femoral neck BMD
Mean % change in total hip BMD -6 -5 -4 -3 -2 -1 1
Baseline
W48
S96 55 67 49 59
-1.41
-3.45
-5.99
-1.74
p =
p = 0.025 n -4 -3 -2 -1 1
Baseline
W48
W96 55 67 49 58
-0.73
-1.57
-3.30
-3.86
p <
p = n
DRV/r + RAL
DRV/r + TDF/FTC
Mean % change in lumbar spine BMD
-2.49
-2.80
-1.00
-0.43
p = 0.046
p = -3 -2 -1 1
Baseline
W48
W96 51 63 48 57 n
p : p value of mean values
between groups
New cases of osteopenia, osteoporosis or Z-score < - 2 : no difference between arms
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

17. Estimate of mean percentage difference (95% CI)
Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
Covariates associated with change in BMD at W48 (multivariate analysis)
Estimate of mean percentage difference (95% CI) p
Total hip
TDF/FTC + DRV/r (vs RAL + DRV/r)
( ; -1.17)
0.0003
BMI (per kg/m2 higher)
0.18 (0.00 ; 0.36)
0.054
HIV RNA at baseline (per log10 c/mL higher)
( ; 0.13) ns
Lumbar spine
( ; 0.28)
0.03 ( ; 0.25)
( ; – 0.77)
0.003
Femoral neck
( ; – 0.45)
0.02
0.01 ( ; 0.25)
( ; 0.04)
0.06
Sport versus no sport : ns at all sites
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

18. Bone biomarkers substudy
Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
Bone biomarkers substudy
Biomarkers measured on paired samples D0, W48
Bone formation: osteocalcin, bone specific alkaline phosphatase (BSAP), pro-collagen type 1 N pro-peptide (P1NP), osteoprotegerin
Bone resorption: serum C terminal collagen crosslinks (CTX-1), receptor activator of NFkb (RANKL), osteopontin, urine CTX-1/creatinine ratio
25-OH vitamin D, intact PTH
Inflammatory markers : IL-1b, IL-6, TNF-a
Compared to DRV/r + RAL, patients treated with DRV/r + TDF/FTC had significantly greater increases in bone turnover markers
Independently of ART regimen used
Baseline bone specific alkaline phosphatase, P1NP and osteopontin levels were associated with BMD loss ≥ 5 %
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

19. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
Median percentage changes in biomarkers at W48
Osteocalcin
250
200
150
100 50
p<0.0001
N = 38
N = 45
BSAP
P1NP
600
400
200
p=0.0082
N = 38
N = 47
200
400
600
800
p=0.0008
N = 38
N = 46
DRV/r + RAL
DRV/r + TVD
Osteoprotegerin
Osteopontin
CTX-1
1 000
800
600
400
200
p=0.048
N = 38
N = 46
200
400
600
p=0.033
N = 38
N = 45
6 000
4 000
2 000
p=0.27
N = 38
N = 46
PTH
RANK-L
25-OH D3
600
400
200
p=0.013
N = 37
N = 46
200
400
600
800
p=0.90
N = 38
N = 45
200
100
p=0.38
N = 12
N = 13
-100
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

20. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy
Loss of BMD ≥ 5% at any site greater in the standard group compared to the NtRTI-sparing group
At W48 : 29/68 (43%) vs 9/65 (14%) (p=0.0002)
At W96 : 34/68 (51%) vs 13/65 (20%) (p=0.0003)
Association between baseline biomarkers and changes in BMD ≥ 5 % (multivariate analysis)
Odds ratio (95% CI) p
Spine W48
Bone-specific alkaline phosphatase (BSAP) ≤ 9.4 mg/L
0.21 ( ) *
0.052
Spine W96
Osteopontin ≤ 5423 pg/mL
0.21 ( )
0.03
Femoral neck W96
Procollagen type 1 N-propeptide (P1NP) ≤ 44.7 ng/mL
4.29 ( )
Total hip W48
12.52 ( )
0.02
Each biomarker was categorised as > versus ≤ baseline median value. Data adjusted for baseline HIV RNA, sports, treatment group, and body-mass index. *Not adjusted for sports because model did not converge
NEAT 001 / ANRS 143
Bernardino JI, Lancet HIV 2015; 2:e464-e473

21. Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
ARV-trial.com
Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC
Conclusion
Overall, the NtRTI-sparing strategy of DRV/r + RAL, requiring twice daily medication intake, was well tolerated and had comparable efficacy to the once daily standard regimen of DRV/r + TDF/FTC at 96 weeks.
DRV/r + RAL was non inferior to DRV/r + TDF/FTC for the composite primary endpoint based on clinical and virological failure
Sensitivity analyses around the primary endpoint, as well as secondary analyses, including per-protocol analysis, supported non-inferiority
However, prespecified subgroup analyses showed that the NtRTI-sparing strategy was less efficacious than the standard regimen in patients with CD4 cell count < 200/mm3 at treatment start
Despite a low rate of virological failure in both arms, emergence of resistance mutations was higher in the raltegravir group
The final results of this head-to-head phase III strategic study suggest that the dual therapy DRV/r + RAL represents an alternative option to the standard combination of DRV/r + TDF/FTC for first line therapy in patients with CD4 cell > 200/mm3
NEAT 001 / ANRS 143
Raffi F. Lancet 2014;384: 21