1. Switch to RAL-containing regimen - Canadian Study - CHEER - Montreal Study - EASIER - SWITCHMRK - SPIRAL

2. SPIRAL Study: Switch PI/r to RAL
Design
Randomisation*
1 : 1
Open-label
W48
N = 142
Switch to RAL 400 mg bid + continue other ARVs
HIV+ ≥ 18 years
On 2 ARV + PI/r
HIV RNA < 50 c/mL > 6 months**
Raltegravir-naïve
N = 140
Continue PI/r + other ARVs
* Randomisation was stratified by current use of lipid-lowering therapy
** Median time with virologic suppression was > 6 years
Endpoints
Primary: non inferiority in the proportion of patients with treatment failure at W48* (non completer = failure, intent-to-treat analysis), lower limit of the 95% CI for the difference = %, 80% power ;
* events occurring in the 2 weeks after W48 were included in the analysis
Secondary: virologic failure (confirmed HIV-1 RNA > 50 c/mL), CD4, fasting lipids, adverse events
SPIRAL
Martinez E, AIDS 2010;24:

3. SPIRAL Study: Switch PI/r to RAL
Treatment failure (intention-to-treat)
Progression to AIDS
Death
Virologic failure
Discontinuation of study medication
Consent withdrawn, lost to follow-up
Virologic failure (on-treatment)
Virologic failure during treatment
Patients who withdrew consent, were lost to follow-up, switched or stopped study medication were censored
Changes in plasma lipids
Analysis by intention-to-treat
SPIRAL
Martinez E, AIDS 2010;24:

4. SPIRAL Study: Switch PI/r to RAL
Baseline characteristics and patient disposition
RAL
PI/r
Patients included in the efficacy analysis
139
134
Female
19%
28%
ARV backbone: TDF + FTC/3TC ; ABC + 3TC/FTC
58% ; 19%
55% ; 20%
PI/r at entry: LPV/r ; ATV/r ; FPV/r
43% ; 37% ; 11%
45% ; 33% ; 13%
Patients on their first ARV regimen
12%
10%
Patients with previous suboptimal ARV therapy*
41%
35%
Patients with previous virologic failure
40%
36%
Patients with previous suboptimal ARV therapy or virologic failure
57%
49%
CD4 cell count (/mm3), median (IQR)
529 ( )
509 ( )
Lipid-lowering therapy at entry
21%
Discontinuation before W48, n (%)
13 (9%)
14 (10%)
For adverse event 3
For virologic failure 2
* 1 or 2 NRTI exclusively
SPIRAL
Martinez E, AIDS 2010;24:

5. SPIRAL Study: Switch PI/r to RAL
Results: Efficacy analyses
Absence of treatment failure
95% CI for the ≠ = -5.2 ; 10.6
Primary
efficacy
endpoint
Absence of virologic failure
- 5.9 ; 17.6
; 10.9
- 3.5 ; 7.5
- 3.9 ; 13.9
- 9.3 ; 7.6
Prior virologic failure or
suboptimal therapy %
89.2
88.6 90
96.9
97.2
96.4
86.6
83.1
89.9
95.1
93.1 20 40 60 80
100
139 N=
134 79 65 69 72 58 56 64
All patients
Yes No
128
122
RAL
PI/r
SPIRAL
Martinez E, AIDS 2010;24:

6. SPIRAL Study: Switch PI/r to RAL
Time to treatment failure by treatment group
Time to virologic failure by treatment group
RAL
PI/r
134
131
124
121
116
139
138
132
130
Log rank p =
Weeks
0.6 4 8 12 16 20 24 28 32 36 40 44 48
0.7
0.8
0.9 1
134
122
119
116
139
128
126
125
124
Log rank p =
0.6 4 8 12 16 20 24 28 32 36 40 44 48
0.7
0.8
0.9 1
Weeks
SPIRAL
Martinez E, AIDS 2010;24:

7. SPIRAL Study: Switch PI/r to RAL
At entry, median total cholesterol (TC) was 198 mg/dL, 15% of the patients had TC > 240 mg/dL, 12% LDL-cholesterol > 160 mg/dL, 40% triglycerides > 200 mg/dL
Percentage changes in fasting lipid concentrations from baseline to W48
p <
p < 0.001
p < 0.05
-22.09
-11.18
-6.49
-3.17
-4.85
4.72
1.82
2.96
5.84
-1.28
-20
-15
-10 -5 5 10
Triglycerides
Total
cholesterol
LDL cholesterol
HDL cholesterol
Total to HDL cholesterol ratio %
-25
RAL
PI/r
SPIRAL
Martinez E, AIDS 2010;24:

8. SPIRAL Study: Switch PI/r to RAL
At W48, significantly less patients had triglycerides > 200 mg/dL or total cholesterol > 240 mg/dL in the RAL group compared to the PI/r group: 14.6% vs 28.9% and 3.7% vs 17.2%, respectively
Differences in total cholesterol and triglycerides changes in patients assigned to RAL were significant when switching from LPV/r but not from ATV/r
There were no difference in the overall incidence of adverse events in the 2 groups
The incidences of serious adverse events and events leading to drug discontinuation were similarly low in both groups
SPIRAL
Martinez E, AIDS 2010;24:

9. SPIRAL Study: Switch PI/r to RAL vs continuation of PI/r
Conclusions
In HIV-infected adults with sustained plasma HIV-1 RNA < 50 c/mL on PI/r-containing ARV therapy, switching from the PI/r component to raltegravir results
In non inferior efficacy
And a better lipid profile
SPIRAL
Martinez E, AIDS 2010;24:

10. Markers of inflammation Endothelial dysfunction
SPIRAL Study: Switch PI/r to RAL
Cardiovascular biomarkers: median (95% CI) difference of percent change from baseline to W48, RAL (N = 119) minus PI/r (N = 114)
Markers of inflammation
Endothelial dysfunction
Insulin
resistance
Hyper-
coagulability
MCP-1
hsCRP
OPG
IL-6
IL-10
TNF-a
ICAM-1
VCAM-1
E-selectin
P-selectin
Adiponectin
D-dimer - 70 60 50 40 30 20 10 %
SPIRAL
Martinez E, AIDS 2012;26:

11. Correlations between ∆ biomarkers and ∆ lipids
SPIRAL Study: Switch PI/r to RAL
Correlations between ∆ biomarkers and ∆ lipids
∆ Triglycerides
∆ Total cholesterol
∆ LDL cholesterol
∆ HDL cholesterol
∆ hsCRP -
(p=0.0016)
∆ MCP-1
(p=0.032)
(p=0.0202)
∆ Insulin
(p=0.0001)
(p=0.004)
Data expressed Spearman’s rho (p)
No correlations between ∆ OPG, ∆ IL-6, ∆ IL-10, ∆ TNF-alpha, ∆ ICAM-1, ∆ VCAM-1,
∆ E-selectin, ∆ P-selectin, ∆ Adiponectin, ∆ D-dimer and any changes in lipids
Conclusion
Switching from PI/r to RAL led not only to significant changes in plasma lipids but also to significant changes in several cardiovascular biomarkers associated with inflammation, insulin resistance and hypercoagulability
There were few and weak significant correlations between changes in lipids and changes in biomarkers suggesting that decreases in biomarkers were rather independent of lipid changes
SPIRAL
Martinez E, AIDS 2012;26:

12. SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
Procedures at baseline and W48
Whole body, lumbar and hip DEXA scans
CT scan of abdomen (single cut 5 mm thick, at L4)
Standardized protocol performed by a single radiologist unaware of patient’s treatment
Endpoints
Primary: change in visceral adipose tissue (VAT) area (cm2)
Secondary: changes in limb fat, trunk fat, total fat, total adipose tissue area, subcutaneous adipose tissue (SAT) area, SAT/VAT ratios, changes in bone mineral density and T scores in total body, spine (L1-L4) and hip (femoral neck and total hip)
SPIRAL
Curran A, AIDS 2012;26:475-81

13. Baseline characteristics of the 74 participants
SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
Baseline characteristics of the 74 participants
RAL
PI/r
Patients included in the SPIRAL-LIP substudy, n 39 35
Female
20%
31%
ARV backbone: TDF ; ABC ; ZDV
62% ; 33% ; 3%
69% ; 23% ; 17%
PI/r at entry: LPV/r ; ATV/r ; FPV/r
43% ; 51% ; 3%
46% ; 34% ; 0%
Time on previous PI/r, months (median)
35.7 30
HCV co-infection
28%
17%
Weight, kg (median) 70
68.5
BMI, kg/m2 (median)
23.4
23.6
SPIRAL
Curran A, AIDS 2012;26:475-81

14. * p not significant for all measures
SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
Body fat distribution (median change from baseline to week 48)
RAL
PI/r
Difference* (IQR)
PI/r vs RAL
CT scan
VAT (cm2)
10.9
20,7 (p=0.002)
11.4 (- 9.5 ; 38.2)
VAT (%)
12.8
11.9
1.6 (- 1.4 ; 1.9)
TAT (cm2)
3.7
21.4 (p=0.013)
10.9 ( ; 44.8)
SAT (cm2)
- 3.2
5.1
2.1 (-18.0 ; 18.5)
SAT (%)
- 1.9
3.6
- 1.1 (- 4.1 ; 1.9)
SAT/VAT
- 0.25
- 0.11
(-0.66 ; 0.15)
DEXA scan
Limb fat (kg) 32
171
85 (- 383 ; 795)
Trunk fat (kg)
- 28
382
323 (- 988 ; 1768)
Total fat (kg)
- 389
307
293 ( ; 2816)
Limb/trunk ratio
- 0.02
( ; 0.05)
* p not significant for all measures
SPIRAL
Curran A, AIDS 2012;26:475-81

15. SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
382
RAL
PI/r
21.4
23.7
3.6
11.9
12.8
10.9
20.7
5.1
-3.2
-1.9
-0.11
-0.25
171 32
- 28
307
-359
-0.02
cm2 %
TAT
SAT
VAT
SAT/VAT
Limb
fat
Trunk
Total
Limb/trunk
ratio g
Median values
All differences PI/r vs RAL not significant + -
SPIRAL
Curran A, AIDS 2012;64:475-81

16. Bone composition (median change from baseline to week 48)
SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
Bone composition (median change from baseline to week 48)
RAL
PI/r
Difference (IQR)
PI/r vs RAL p
DEXA scan
Total BMD (g/cm2)
0.01 (p=0.002)
0.01 ( ; 0.02)
0.079
Femoral neck BMD (g/cm2)
- 0.01
0.01 ( ; 0.02)
0.032
Femoral neck T score
0.04
- 0.10
0.01 ( ; 0.18)
0.016
Total hip BMD (g/cm2)
0.01 (p=0.015) ns
Total hip T score
0.12 (p=0.004)
0.01
0.11 ( ; 0.20)
L1-L4 BMD (g/cm2)
0.02
0 ( ; 0.04)
L1-L4 T score
0.03
0.10
0.09 ( ; 0.31)
BMD: bone mineral density
No significant differences in BMD or T scores in either group even when controlling for TDF use
SPIRAL
Curran A, AIDS 2012;26:475-81

17. SPIRAL Study: Switch PI/r to RAL SPIRAL-LIP substudy (body composition)
Conclusion
Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT
Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups
SPIRAL
Curran A, AIDS 2012;26:475-81

18. SPIRAL Study: Comparison of ABC/3TC vs TDF/FTC
Switch to RAL
Continuation of PI/r
NRTI
ABC/3TC
(N = 27)
TDF/FTC
(N = 73)
(N = 70)
Treatment failure*
3 (11.1%)
8 (11%)
4 (14.8%)
12 (17.1%)
Virologic failure (confirmed HIV-1 RNA > 50 c/mL)
1 (3.7%)
3 (4.1%)
2 (7.4%)
4 (5.7%)
Discontinuation due to AE
4 (GFR decrease, N = 3), BMD decrease, N = 1)
* Treatment failure: virologic failure, discontinuation of NRTI due to adverse event, consent withdrawal, loss to follow-up
In the RAL group, decrease in triglycerides and increase in HDL cholesterol at W48 tended to be more pronounced with ABC/3TC than with TDF/FTC
Differences in total-to-HDL cholesterol ratio between both combinations of NRTIs tended to be higher in the RAL group although differences at 48 weeks were not significant
SPIRAL
Martinez E, AIDS Res Hum Retroviruses Feb;29(2):235-41

19. SPIRAL-MET substudy: LDL subclasses and lipoprotein-phospholipase A2 activity
81 patients, PI/r group (n = 41), RAL group (n = 40)
Baseline and week 48 assessment :
LDL size and phenotype :
Phenotype A : LDL size > 26.8 nm with predominance of large buoyant LDL subfractions
Phenotype intermediate : LDL size nm
Phenotype B : LDL size < 26.0 nm with a predominance of small, dense LDL subfractions
Total lipoprotein-associated phosholipase A2 (Lp-PLA2)
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
Standard lipid parameters
Insulin, C-peptide, HOMA index
Cardiovascular risk assessment (Framingham equation)
SPIRAL
Saumoy M, Atherosclerosis 2012;225:200-7

20. SPIRAL-MET substudy Baseline characteristics RAL (n = 40)
PI/r (n = 41)
Age, years (median) 44 43
Female
15%
27%
ARV backbone: TDF/FTC ; ABC/3TC
43% ; 35%
74%
PI/r at entry: LPV/r ; ATV/r ; FPV/r
43% ; 38% ; 10%
37% ; 39% ; 12%
Time on previous PI/r, months (median)
35.7 30
Weight, kg (median) 73 71
BMI, kg/m2 (median)
24.5
24.4
Cardiovascular risk estimation (Framingham)
7.42
8.27
Lipid lowering therapy
17.5%
22.8%
Lipid parameters were not significantly different between groups, except Apo B, which was lower in the RAL arm (p = 0.035)
SPIRAL
Saumoy M, Atherosclerosis 2012;225:200-7

21. SPIRAL-MET substudy Results Insulin, waist
Significant difference in insulin levels between arms favorable to RAL at W48 (p = 0.020)
HOMA index decreased in RAL group (p = 0.032) at W48, remaining unchanged in the PI/r arm
At W48, increase in waist circumference (3.95 cm ; p = 0.004) and waist-to-hip ratio (0.01; p = 0.022) in the PI/r arm, where as no change in RAL group
No change in number of patients on lipid-lowering therapy
Cardiovascular risk assessment at W48
Increase in the PI/r arm (0.8% ; p = 0.032)
No change in the RAL arm
No change between arms at W48
Significant increase of systolic (+ 5 mm Hg; p = 0.016) and diastolic (+ 8,5 mm Hg; p = 0.005) blood pressure in the RAL arm, no change in the PI/r group
SPIRAL
Saumoy M, Atherosclerosis 2012;225:200-7

22. SPIRAL-MET: median changes in lipid parameters between baseline and W48 according to therapy
0.6
0.06
-0,81
0.07
-0.36
-0.04
-0.11
0.10
-0.71
0.05
-0.49
0.29
-0.32
-0.01
-0.12
0.03
0,.11
0.4
0.2
0.0
-0.2
-0,4
-0.6
-0.8
-1.0
0.15
0.00
-0.05
-0.10
-0.15
-0.20
-0.25
< 0.001
0.023
0.108
0.026
0.004
0.073
PI/r (n = 41)
RAL (n = 40)
Median change mmol/l (W48 – baseline)
Median change g/l (W48 – baseline) TC
LDL-c
HDL-c
Non-HDL-c TG
TC/HDL-c
Apo A1
Apo B
Apo A1/Apo B p
SPIRAL
Saumoy M, Atherosclerosis 2012;225:200-7

23. % LDL-c particles phenotype
SPIRAL-MET: median changes in the percentage of LDL-c phenotype in RAL arm and PI arm stratified by PI/r used (group 1 vs group 2) at W48
LDLc phenotype
100 80 60 40 20 A
Intermediate B
Baseline
W48
Group 1 (n = 21)**
Group 2 (n = 19)
RAL (n = 40)
Group 1: LPV/r, FPV/r
Group 2: ATV/r, SQV/r
0.439*
0.088*
< 0.001*
% LDL-c particles phenotype
* Homogeneity marginal test to compare proportions at baseline and W48 in each arm ** Statistically significant difference between LPV and RAL at W48 (Pearson Chi-square test)
LDLc phenotype A: large & low density of cholesterol esters (non-atherogenic)
LDLc phenotype B: small & high density of cholesterol esters (atherogenic)
SPIRAL
Saumoy M, Atherosclerosis 2012;225:200-7

24. SPIRAL substudy: endothelial function
35 patients, PI/r group (n = 16), RAL group (n = 19)
Endothelial function was evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline, W24 and W48
Total cholesterol, LDL cholesterol and triglycerides decreased at W16 and W32 in the RAL arm, while no changes were observed in the PI/r arm
Triglyceride levels were significantly lower in the RAL arm than in the PI/r arm at W16, 32 and 48
No significant changes from baseline occurred in FMD at W24 and W48 within or between the RAL and PI/r arms. Adjustment for baseline artery diameter did not have a significant effect on the FMD differences
Median baseline FMD values within normal range ( > 5%) + limited sample size might have precluded detection of any RAL effect or clinically relevant differences
SPIRAL
Masia M, JAC 2013;68: