1. Comparison of PI vs PI ATV vs ATV/r BMS 089
ARV-trial.com
Comparison of PI vs PI
ATV vs ATV/r BMS 089
LPV/r mono vs LPV/r + ZDV/3TC MONARK
LPV/r QD vs BID M M A5073
LPV/r + 3TC vs LPV/r + 2 NRTI GARDEL
ATV/r vs FPV/r ALERT
ATV/r vs DRV/r ATADAR
FPV/r vs LPV/r KLEAN
SQV/r vs LPV/r GEMINI
ATV/r vs LPV/r CASTLE
DRV/r vs LPV/r ARTEMIS 1

2. ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Design
Randomisation
1: 1
Open-label
W24
W96
ATV/r 300/100 mg + TDF/FTC qd
≥ 18 years
Antiretroviral naïve
HIV RNA > 1,000 c/mL
No diabetes, BMI < 30 kg/m2
No current use of drugs affecting lipid or glucose metabolism
N = 91
DRV/r 800/100 mg + TDF/FTCqd
N = 89
Objective
Primary Endpoint : mean change in total cholesterol at W24 (ITT analysis)
90 patients per arm needed to detect a difference ≥ 21 mg/dL between arms in total cholesterol change, power 80%, 5% bilateral significance
Secondary endpoints : mean change in other lipid parameters, insulin resistance, total bilirubin, eGFR (MDRD equation), CD4 and CD8 cell counts, HIV RNA, discontinuation for AEs
ATADAR
Martinez E. HIV Medicine 2014;15:330-8

3. Baseline characteristics and disposition
ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Baseline characteristics and disposition
ATV/r + TDF/FTC, N = 90
DRV/r + TDF/FTC, N = 88
Age, years 35 37
Female
13%
11%
HIV RNA log10c/mL
4.8
CD4/mm3
328
341
Total cholesterol, mg/dL
158
LDL-cholesterol, mg/dL 97 98
HDL-cholesterol, mg/dL 39
Total cholesterol:HDL-cholesterol ratio
4.5
4.4
Triglycerides, mg/dL
106
108
HOMA-IR
2.4
2.5
Total bilirubin, mg/dL
0.54
0.58
eGFR (MDRD), mL/min/1.73 m2
110
Discontinued at W24
N = 8 (9%)
Adverse event 5 3
Withdrew consent / lost to follow-up
1 / 2
0 / 5
Data expressed as mean
ATADAR
Martinez E. HIV Medicine 2014;15:330-8

4. Virological efficacy and overall tolerability at W24
ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Virological efficacy and overall tolerability at W24
ATV/r + TDF/FTC,
N = 90
DRV/r + TDF/FTC,
N = 88
Confirmed HIV RNA > 50 c/mL, n 7 8
Any AE, all grade, %
63.3
62.5
Grade 3-4 AEs, %
22.4
8.0 (p< 0.01)
Bilirubin elevations, n 17
Jaundice
3/17
AEs leading to study drug discontinuation, n (%)
5 (5.6%)
3 (3.4%)
Jaundice, n 3
Rash, n 1 2
Suicide attempt, n
Gastrointestinal symptoms, n
ATADAR
Martinez E. HIV Medicine 2014;15:330-8

5. ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Lipid changes from baseline to W24
ATV/r + TDF/FTC
N = 90
DRV/r + TDF/FTC
N = 88 p
Total cholesterol, mg/dL
± 26.76
± 25.85
0.29
LDL-cholesterol, mg/dL
± 21.45
± 21.97
0.12
HDL-cholesterol, mg/dL
± 10.36
± 8.42
0.26
Total:HDL-cholesterol ratio
± 6.38
± 0.86
0.07
Triglycerides
± 61.76
± 64.24
0.83
No participant was prescribed lipid-lowering agents or other drugs potentially affecting plasma lipids
Other laboratory changes from baseline to W24
ATV/r + TDF/FTC
N = 90
DRV/r + TDF/FTC
N = 88 p
HOMA-IR
± 0.24
± 0.34
0.38
Total bilirubin, mg/dL
± 1.30
± 0.30
< 0.01
eGFR, mL/min/1.73m2
/ 22.16
± 14.54
0.67
ATADAR
Martinez E. HIV Medicine 2014;15:330-8

6. ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Metabolic sub-study in 86 participants (ATV/r = 45, DRV/r = 41)
LDL subfraction phenotype and Lp-PLA2 at W48, Framingham risk score change. Patients assessed at W48 : 40/45 and 37/41
LDL subfraction phenotype : predominance of the more favorable phenotype at baseline (around 75% of participants)
ATV/r : increase in cholesterol content in small and dense LDL particles, associated with coronary artery disease risk (p = 0.015) at W48
DRV/r : increase in LDL size (p = 0.017) and large LDL particles (p = 0.008) (improved atherogenic properties) at W48
No change in total Lp-PLA2 activity and no shift in its relative distribution in LDL or HDL particles at W48, with no differences between arms
Framingham score very low at baseline (1%) with no changes at W48
Insulin increased only in the ATV/r group (p = 0.017), but HOMA-IR showed no changes in either arm at W48
BMI increased in the ATV/r arm (+1.01 kg/m2 at W48, p = 0.004) [p= 0.06 vs DRV/r]
Waist increased in the DRV/r arm (+ 3 cm at W48, p < 0.001) [p = vs ATV/r]
ATADAR
Saumoy M. J AntimicrobChemother 2015;70:1130-8

7. ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
W96 results (efficacy and resistance)
ATV/r + TDF/FTC
N = 90
DRV/r + TDF/FTC
N = 88
Discontinuation by W96
21 (23%)
17 (19%)
For AE / virologic failure
7 / 2
5 / 2
% free of treatment failure
62%
70%
95% CI : to 21.6
% free of virologic failure (VF)
79%
85%
95% CI : to 17.6
Resistance testing♯
6/17 VF
5/13 VF
PI mutations detected (none major)
4*/6
4**/5
♯ no baseline resistance test
* V45M ; E35D + K43K/N + D60E + I93L ; A71V + E35D + M36I + I62V + I93L ; L24I/V
** I15V ; E35D + L63P ; E35D + L63P ; I13V + M36I/M + I62I/V + L63H/Q
ATADAR
Martinez E. CID 2015;60:811-20

8. Lipid and other laboratory changes, mean
ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
W96 results (safety)
Overall safety
ATV/r + TDF/FTC, N = 72
DRV/r + TDF/FTC, N = 74 p
Serious AEs
26% 8%
0.002
Grade 3-4 AEs
44%
14%
<
AE leading to discontinuation
7.8%
5.7%
0.25
Lipid and other laboratory changes, mean
ATV/r
DRV/r p
Total cholesterol, mg/dL
All non significant
LDL-cholesterol, mg/dL
+ 1.86
+ 8.22
HDL-cholesterol, mg/dL
+ 4.8
+ 4.9
Total:HDL-cholesterol ratio
- 0.82
- 0.29
Triglycerides
eGFR (MDRD), mL/min/1.73 m2
- 8.63
-7.27
ATADAR
Martinez E. CID 2015;60:811-20

9. Changes in body composition (DXA and abdominal CT-scan) at W96
ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Changes in body composition (DXA and abdominal CT-scan) at W96
ATV/r + TDF/FTC, N = 78
DRV/r + TDF/FTC, N = 80 p
BMI, kg/m2
+ 1.25
+ 0.67
0.13
Body fat, g
+ 3373
+ 1096
0.009
Body fat-free mass, g
+ 894
+ 661
0.71
Limb fat, g
+ 1235
168
0.007
Trunk fat, g
+ 1566
+ 541
0.10
Subcutaneous abdominal adipose tissue, cm2
+ 38.8
+ 14.9
0.036
Visceral adipose tissue, cm2
+ 30.1
0.47
Total abdominal adipose tissue, cm2
+ 77.3
+ 45.1
0.06
Bone mineral content, g
- 79.8
- 80.2
0.99
Data expressed as mean
In the ATV/r arm : significant correlations between changes in HOMA-IR and changes in BMI, body fat, and SAT
In the DRV/arm : no correlations between HOMA-IR changes and changes in BMI and body fat parameters
ATADAR
Martinez E. CID 2015;60:811-20

10. ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC
Conclusion
No major differences between ATV/r + TDF/FTC and DRV/r + TDF/FTC in efficacy, clinically relevant side effects, or plasma cholesterol fractions, over 96 weeks
However, ATV/r led to higher triglycerides and more total and subcutaneous fat than DRV/r
Fat gains with ATV/r were associated with insulin resistance
In contrast with what occurred in the ATV/r arm, the LDL subfraction phenotype improved with DRV/r at W48. This difference was associated with a lower impact on plasma triglycerides with DRV/r
Most Grade 3-4 AE were due to hyperbilirubinemia, in the ATV/r arm
ATADAR
Martinez E. CID 2015;60: ; Saumoy M. J AntimicrobChemother 2015;70:1130-8