1. Switch to RAL-containing regimen
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Switch to RAL-containing regimen
Canadian Study
CHEER
Montreal Study
EASIER
SWITCHMRK
SPIRAL
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2. SWITCHMRK Study: Switch to RAL vs continuation of LPV/r
Design: 2 parallel trials, SWITCHMRK 1 and 2
Randomisation*
1 : 1
Double-blind
W24
Switch to RAL 400 mg bid + placebo LPV/r bid + continue other ARVs
N = 350
HIV+ ≥ 18 years
On LPV/r + ≥ 2 NRTIs
HIV RNA < 50 c/mL (PCR)
or < 75 c/mL (bDNA) > 3 months
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:

3. 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:

4. SWITCHMRK Study: Switch to RAL vs continuation of LPV/r
Baseline characteristics and patient disposition
SWITCHMRK 1
SWITCHMRK 2
RAL
LPV/r
Randomized, N
177
175
176
179
Treated eligible patients, N
174
178
Female
16%
26%
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
426
Suppressed viraemia
94%
93%
96%
LPV/r therapy > 1 year
83%
82%
81%
LPV/r as first regimen
42%
43%
32%
31%
History of previous virologic failure (reported by investigator)
28%
33%
36%
37%
Discontinuation before W24
14.1%
9.7%
5.7%
3.4%
SWITCHMRK
Eron JJ, Lancet 2010;375:

5. SWITCHMRK Study: Switch to RAL vs continuation of LPV/r
Mean* % changes in fasting lipid concentrations from baseline to W12
Total
cholesterol
Triglycerides*
LDL-C
HDL-C
5.6
5.3
4.3
4.1
2.1
1.8 3
2.7
1.3
1.2
4.8
3.6
1.9
2.8
Mean (mmol/L)
Baseline
W12
2.1%
0.7%
2.3%
-15.2%
-2.4%
3.6%
-41.5%
0.8%
-0.9%
-12.8%
p <
p = 0.7
NT**
-40
-30
-20
-10 10
SWITCHMRK 1
Non HDL-C
SWITCHMRK 2
2.7
1.2
Total
cholesterol
Non HDL-C
Triglycerides*
LDL-C
HDL-C
5.6
5.5
4.3
4.2
2.4
2.5
4.7
3.6
1.4
0.6%
1.3%
2.9%
-14.8% 4%
8.2%
-42.8%
-2.5%
-0.6%
-12.4%
p <
p = 0.2
NT**
RAL + ARV
LPV/r + ARV
* median changes for triglycerides
** not tested
SWITCHMRK
Eron JJ, Lancet 2010;375:

6. SWITCHMRK Study: Switch to RAL vs continuation of LPV/r
Proportion of patients with HIV-1 RNA < 50 c/mL %
176
175
178
177 % 4 8 12 24
93.8%
88%
(95% CI) : (-12.2 ; 0.2) 50 60 70 80 90
100
Weeks
SWITCHMRK 1
SWITCHMRK 2
RAL + ARV
LPV/r + ARV
174
166
169
173
172
171 50 60 70 80 90
100 4 8 12 24
80.8%
87.4%
(95% CI) : (-14.4 ; 1.2)
Weeks
RAL + ARV
LPV/r + ARV
SWITCHMRK
Eron JJ, Lancet 2010;375:

7. 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
89.3%
87.4%
94.5%
93.5%
-5.3% (-16.9 to 5.7)
-6.1% (-14.1 to 1.4)
Combined studies
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)
72.3% 85.1%
89.7%
85.8%
-17.3% (-33.0 to -2.5)
-0,7% (-9.9 to 8.6)
79.7% 92.5%
93.8%
-14.2% (-26.5 to -2.6)
-1.0% (-8.5 to 6.3)
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:

8. SWITCHMRK Study: Switch to RAL vs continuation of LPV/r
Grade 3 or 4 laboratory abnormalities
SWITCHMRK 1
SWITCHMRK 2
RAL
LPV/r
Neutrophils
0.6%
Haemoglobin
Platelets
1.2%
Fasting LDL cholesterol
1.3%
Fasting total cholesterol
1.9%
1.7%
4.1%
Fasting triglycerides
4.7%
Fasting glucose
Creatinine
Lipase 0%
ASAT
1.1%
ALAT 4%
SWITCHMRK
Eron JJ, Lancet 2010;375:

9. 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:

10. 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: