1. Switch to RAL-containing regimen
ARV-trial.com
Switch to RAL-containing regimen
Canadian Study
CHEER
Montreal Study
EASIER
SWITCHMRK
SPIRAL
Switch ER 1

2. EASIER Study: Switch ENF to RAL
Design
Randomisation
1 : 1
Open-label
W24
193 HIV+ adults
History of triple class (NRTI, NNRTI, PI)
failure or intolerance
HIV-1 RNA < 400 c/mL > 3 months on an ENF-based regimen
Integrase inhibitor-naïve
N = 85
Continue ENF regimen
+ other ARVs
N = 85
Switch to RAL 400 mg bid
+ continue other ARVs
Objective
Non inferiority in the proportion of patients with virologic failure at W24 (Intent-to-treat analysis) ; upper limit of the 95% CI for the difference = 10%, 80% power
Virologic failure : confirmed HIV-1 RNA ≥ 400 c/mL, or a single HIV-1 RNA ≥ 400 c/mL followed by treatment modification or last HIV-1 RNA ≥ 400 c/mL without confirmation
EASIER
De Castro N, CID 2009;49:

3. EASIER Study: Switch ENF to RAL
ARV-trial.com
EASIER Study: Switch ENF to RAL
Baseline characteristics and patient disposition
ENF, N = 85
RAL, N = 84
Median age, years
48.4
47.6
Female
14%
17%
History of CDC class C diagnosis
55%
50%
Hepatitis B or C co-infection 5% 8%
CD4 cell count at baseline ; at nadir, /mm3
374 ; 56
410 ; 39
HIV-1 RNA < 50 c/mL at baseline
88%
85%
Duration of prior ENF therapy, median years
2.2
2.5
Number of ARV drugs in baseline regimen (including ENF), median 4
ARV drugs in regimen: PI* ; NNRTI ; NRTI
(TDF)
100% ; 6% ; 95% (54%)
99% ; 10% ; 94% (60%)
Discontinuation before W24, N (%) 3 2
For adverse event
For virologic failure 1
* TPV/r in 34% vs 44% and DRV/r in 40% vs 36%, in ENF vs RAL groups, respectively
EASIER
De Castro N, CID 2009;49:

4. EASIER Study: Switch ENF to RAL
ARV-trial.com
EASIER Study: Switch ENF to RAL
Outcome at week 24
Virologic failure
Other endpoints
1.2 88 89
ITT analysis
ENF
RAL % 20 40 60 80
100
95% CI for the difference = -6.7 ; 6.8
HIV-1 RNA
< 50 c/mL
On-treatment analysis
95% CI for the difference = -5.6 ; 8.1
Median CD4 increase
ENF: +15/mm3
RAL: +11/mm3
No AIDS events
No difference in the overall incidence of adverse reactions between both groups
Higher incidence of grade 1 to 4 laboratory abnormalities in the RAL arm (p = 0.001)
Median increases in triglycerides and total cholesterol were significantly higher in the RAL group
EASIER
De Castro N, CID 2009;49:

5. EASIER Study: Switch ENF to RAL
Grade 3 or 4 emerging adverse events or laboratory abnormalities
ENF
RAL
Adverse events occurred in 7 patients on ENF and 11 patients on RAL, with a total of 8 and 13 events, respectively
Coronary events 2
Gastrointestinal 1
Infection 3
Nervous system
Psychiatric
Respiratory
Other 4
Laboratory abnormalities occurred in 6 patients on ENF and 12 patients on RAL, with a total of 8 and 14 abnormalities, respectively
Aminotransferase > 5 ULN
Gamma GT > 5 ULN 6
Alkaline phosphatase > 5 ULN
CPK > 5 ULN
Triglyceride > 8.6 mmol/L
Lipase > 3 ULN
Potassium < 2.7 mmol/L
EASIER
De Castro N, CID 2009;49:

6. EASIER Study: Switch ENF to RAL
Conclusions from W24 data
In patients infected with multidrug-resistant HIV-1 receiving suppressive enfuvirtide-containing antiretroviral therapy, a switch from enfuvirtide to RAL is:
Safe
Well-tolerated
And virologically non-inferior to the maintenance of ENF
EASIER
De Castro N, CID 2009;49:

7. EASIER Study: Switch ENF to RAL
At week 24
ENF arm switched to RAL (deferred RAL), n = 84
RAL arm continued on RAL (immediate RAL), n = 84
Week 48 analyses
Primary : cumulative proportion of patients with confirmed HIV RNA ≥ 400 c/mL, or last HIV RNA ≥ 400 c/mL or treatment change after a single HIV RNA ≥ 400 c/mL (on-treatment and intent-to-treat analyses)
Secondary
Proportion of patients with HIV RNA < 50 c/mL
Emergence of resistance in patients with virologic failure
Changes from baseline in CD4 cell counts
Proportion of patients with permanent discontinuation of RAL
Safety
Baseline GSS assessed on cumulative historical genotypes
GSS ≥ 1 : 86% ; 0.5 : 11% ; 0 : 3% (n = 5)
EASIER
Gallien S, JAC 2011;66:

8. EASIER Study: Switch ENF to RAL
Deferred switch
Immediate switch 0%
10%
70%
80%
90%
100%
Proportion of patients with HIV RNA < 50 copies/ml W0 85 84 W4 W8
W24
W28 79
W32
W16
W40 82
W48 83
Def
Imm
N patients
88%
89%
85%
On-treatment analysis : 1 virologic failure (W8) in immediate arm ; baseline GSS = 0, no emergence of RAL-associated resistance mutations
No significant changes in the median CD4 cell counts following RAL switch in either arm
No significant changes between baseline and W48 in glucose levels or fasting lipids in either arm
EASIER
Gallien S, JAC 2011;66:

9. EASIER Study: Switch ENF to RAL
Grade 3 or 4 emerging adverse events or laboratory abnormalities
In both arms between weeks 24 and 48 (N = 168) n
Grade 3-4 adverse events
occurred in 12 patients (7%)
Coronary events 1
Gastrointestinal 2
Infection 8
Nervous system
Psychiatric
Respiratory
Other 10
Grade 3-4 laboratory abnormalities
occurred in 20 patients (12%)
Aminotransferase > 5 ULN
7 (all patients on TPV/r)
Gamma GT > 5 ULN 7
Alkaline phosphatase > 5 ULN
CPK > 5 ULN
7 (all asymptomatic)
Hyperbilirubinemia > 5 ULN
Lipase > 3 ULN
Hypoglycemia < 2.2 mmol/L
EASIER
Gallien S, JAC 2011;66:

10. EASIER substudy: Inflammatory and coagulation biomarkers
164 patients, Immediate switch (n = 83) ; deferred switch (n = 81)
Biomarkers
IL-6
hsCRP
D-dimer
Primary objective : changes in IL-6, hsCRP and D-dimer plasma levels from baseline to W24 between the immediate and deferred arms
Log10 transformation of levels
Median changes from baseline assessed by 1-sample t tests
Comparison between arms used 2-sample t tests with no adjustment for baseline factors
Similar analyses to compare changes from baseline to W48
EASIER
Silva EF, JID 2013;208:892-7

11. Values are median (IQR)
EASIER substudy: Inflammatory and coagulation biomarkers
IL-6 (log10 pg/ml)
hsCRP (log10 mg/ml)
0.0
0.4
0.8
1.2
1.6
2.0 W0 81 83
W24 78 79
W48 75 72
0.56
0.61
0.28
p<0.001
0.54
0.23
0.18
RAL
ENF
0.0
-0.4
-0.8
0.4
0.8
1.2
1.6
2.0 W0 81 83
W24 78 79
W48 75 71
0.63
0.74
0.20
p=0.0003
0.66
0.32
ENF
RAL
D-dimer (mg/ml)
Deferred Switch
Immediate Switch
0.5
0.4
0.3
0.2
0.1
0.0 W0 81 83
W24 78 79
W48 75 72
0.369
0.387
0.189
p<0.0001
RAL
ENF
Values are median (IQR)
0.198
EASIER
Silva EF, JID 2013;208:892-7