Switch to RAL-containing regimen
- Canadian Study
- CHEER
- Montreal Study
- EASIER
- SWITCHMRK
- SPIRAL
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
 Design: 2 parallel trials, SWITCHMRK 1 and 2
Randomisation*
1:1
Double-blind
W24
N = 350 Switch to RAL 400 mg bid +
HIV+ ≥ 18 years
On LPV/r + ≥ 2 NRTIs
HIV RNA < 50 c/mL (PCR)
or < 75 c/mL (bDNA) > 3 months
placebo LPV/r bid + continue other
ARVs
N = 352 LPV/r bid + placebo RAL bid +
continue other ARVs
* Randomisation was stratified on LPV/r use before entry (≤ 1 year vs > 1 year)
 Primary endpoints
– Mean percentage changes in fasting lipid concentrations from baseline to week
12
– Proportion of patients with HIV-1 RNA < 50 c/mL at week 24
– Frequency of adverse events up to week 24
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
 Objectives
– Lipids: 99% power to detect a between-treatment difference of 11%,
53% and 13% in the mean percentage change from baseline in total
cholesterol, triglycerides, and non-HDL cholesterol, respectively, and
71% power to detect a between-treatment difference of 4% in the mean
percentage change from baseline in LDL cholesterol
– Viral load: non inferiority of RAL vs LPV/r: % HIV-1 RNA < 50 c/mL
at week 24 (lower limit of the 95% CI for the difference = - 12%,
90% power)
– Adverse events: for adverse events occurring in 20% of patients, each
study had 80% power to declare with 95% confidence that the true
difference between treatment groups was 12% or lower
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
Baseline characteristics and patient disposition
SWITCHMRK 1
SWITCHMRK 2
RAL
LPV/r
RAL
LPV/r
Randomized, N
177
175
176
179
Treated eligible patients, N
174
174
176
178
Female
16%
26%
22%
22%
Region: Australia/Europa ;
USA/Canada ; Latin America ;
Other
67% ; 33% ;
0% ; 0%
70% ; 30% ;
0% ; 0%
11% ; 18% ;
43% ; 28%
11% ; 19%
47% ; 23%
CD4 cell count (/mm3), median
436
479
436
426
Suppressed viraemia
94%
93%
96%
96%
LPV/r therapy > 1 year
83%
82%
82%
81%
LPV/r as first regimen
42%
43%
32%
31%
History of previous virologic
failure (reported by investigator)
28%
33%
36%
37%
14.1%
9.7%
5.7%
3.4%
Discontinuation before W24
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
Mean* % changes in fasting lipid concentrations from baseline to W12
SWITCHMRK 1
10
0
0.7%
2.3%
3.6%
SWITCHMRK 2
1.3%
2.1%
-0.9% 0.8%
-2.4%
2.9%
8.2% 4% 0.6%
-0.6%
-2.5%
-10
p = 0.7
-12.8%
NT**
-20
p = 0.2
-12.4%
-15.2%
NT**
-14.8%
p < 0.0001
p < 0.0001
p < 0.0001
p < 0.0001
-30
RAL + ARV
LPV/r + ARV
-40
-41.5%
-42.8%
p < 0.0001
Mean
(mmol/L)
Total
Non Triglycerides* LDL-C
cholesterol HDL-C
Baseline
5.6 5.3
4.3 4.1
2.1 1.8
W12
4.8 5.3
3.6 4.1
1.3 1.9
SWITCHMRK
p < 0.0001
3
HDL-C
Total
Non Triglycerides* LDL-C
cholesterol HDL-C
HDL-C
2.7
1.3 1.2
5.6 5.5
4.3 4.2
2.4 2.5
2.7 2.7
1.2 1.2
2.8 2.7
1.2 1.2
4.7 5.5
3.6 4.3
1.4 2.7
2.7 2.7
1.2 1.2
* median changes for triglycerides
** not tested
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
Proportion of patients with HIV-1 RNA < 50 c/mL
%
%
SWITCHMRK 1
100
SWITCHMRK 2
93.8%
100
87.4%
90
90
80
80
70
80.8%
88%
70
(95% CI) : - 6.6 (-14.4 ; 1.2)
(95% CI) : - 5.8 (-12.2 ; 0.2)
60
60
50
50
0
4
8
12
24
0
4
8
24
Weeks
Weeks
RAL + ARV
RAL + ARV
12
LPV/r + ARV
174
166
169
173
172
176
176
176
176
175
LPV/r + ARV 174
171
171
171
174
178
178
177
177
178
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
Proportion of patients with HIV-1 RNA < 50 c/mL at W24*
RAL
LPV/r
Difference (95% CI)
LPV/r-based therapy as the first regimen
SWITCHMRK 1
Yes
No
86.1%
77.0%
86.7%
87.9%
-0.6% (-12.2 to 10.9)
-10.9% (-21.6 to -0.3)
SWITCHMRK 2
Yes
No
89.3%
87.4%
94.5%
93.5%
-5.3% (-16.9 to 5.7)
-6.1% (-14.1 to 1.4)
Combined studies
Yes
No
87.5%
82.6%
90.0%
91.0%
-2.5% (-10.6 to 5.4)
-8.3% (-14.8 to -2.1)
Investigator report of a history of previous virologic failure (exclusion of patients with missing data)
SWITCHMRK 1
Yes
No
72.3%
85.1%
89.7%
85.8%
-17.3% (-33.0 to -2.5)
-0,7% (-9.9 to 8.6)
SWITCHMRK 2
Yes
No
79.7%
92.5%
93.8%
93.5%
-14.2% (-26.5 to -2.6)
-1.0% (-8.5 to 6.3)
Combined studies
Yes
No
76.6%
88.6%
91.9%
89.6%
-15.3% (-24.9 to -6.2)
-1.0% (-6.9 to 4.9)
* Patients who did not complete the trial were regarded as failures
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
Grade 3 or 4 laboratory abnormalities
SWITCHMRK 1
SWITCHMRK 2
RAL
LPV/r
RAL
LPV/r
0.6%
0
0.6%
0.6%
0
0
0
0
Platelets
1.2%
0
0
0
Fasting LDL cholesterol
1.3%
1.3%
1.2%
1.2%
Fasting total cholesterol
0
1.9%
1.7%
4.1%
Fasting triglycerides
0
1.9%
1.2%
4.7%
Fasting glucose
0
0
0
0
Creatinine
0
0.6%
0
0
Lipase
0%
0.6%
0
0
ASAT
1.1%
1.1%
0
0
ALAT
4%
0.6%
1.7%
1.1%
Neutrophils
Haemoglobin
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
 Safety, resistance data
– Similar frequency of clinical and laboratory events in both groups
– No serious drug-related adverse event
– Diarrhoea of moderate to severe intensity: 3% in LPV/r group vs 0%
in RAL group
– Discontinuation because of adverse events: 4 in LPV/r group vs 6
in RAL group
– 49 patients had confirmed virologic failure:
• 32 in the RAL group: for 27 (84%), LPV/r was not their first ARV regimen
and 18 (67%) of these patients had a history of virologic failure on previous
regimens
• 17 in the LPV/r group: for 8 (47%), LPV/r was not their first ARV regimen
and 4 (50%) of these patients had a history of virologic failure on previous
regimens
• Raltegravir-associated resistance mutations were found at failure in
8/11 assessable patients
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407
SWITCHMRK Study: Switch to RAL vs continuation
of LPV/r
 Conclusions
– In patients with virologic suppression on a LPV/r-containing
regimen, switching from LPV/r to RAL was associated, at W24,
with:
• Greater reductions in lipid concentrations than was continuation
of LPV/r
• Lower rate of HIV suppression, especially in patients who had a
history of virologic failure before entry. Results did not establish
non inferiority of RAL to LPV/r
– In the post-hoc analysis, patients without previous virologic
failure had similar viral suppression rates in both treatment
groups (switch to RAL or continuation of LPV/r)
SWITCHMRK
Eron JJ, Lancet 2010;375:396-407