Switch studies in virologically suppressed patients

Switch to RAL-containing regimen

Canadian Study CHEER Montreal Study EASIER SWITCHMRK SPIRAL Switch ER

Design: 2 parallel trials, SWITCHMRK 1 and 2

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

Switch to RAL 400 mg bid + placebo LPV/r bid + continue other ARVs

LPV/r bid + placebo RAL bid + continue other ARVs

* Randomisation was stratified on LPV/r use before entry (≤ 1 year vs > 1 year)

Eron JJ, Lancet 2010;375:396-407 SWITCHMRKSWITCHMRK

Randomisation*1 : 1

Double-blind

Randomisation*1 : 1

Double-blind

HIV+ ≥ 18 yearsOn LPV/r + ≥ 2 NRTIs

HIV RNA < 50 c/mL (PCR) or < 75 c/mL (bDNA) > 3 months

HIV+ ≥ 18 yearsOn LPV/r + ≥ 2 NRTIs

HIV RNA < 50 c/mL (PCR) or < 75 c/mL (bDNA) > 3 months N = 352

N = 350

W24W24

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 1 SWITCHMRK 2

RAL LPV/r RAL LPV/rRandomized, 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%

Discontinuation before W24 14.1% 9.7% 5.7% 3.4%

Baseline characteristics and patient disposition



* median changes for triglycerides** not tested

Mean* % changes in fasting lipid concentrations from baseline to W12



SWITCHMRK 2

RAL + ARVLPV/r + ARV

2.7 2.7 1.2 1.2

2.7 2.7 1.2 1.2

Totalcholesterol

NonHDL-C

Triglycerides* LDL-C HDL-C

5.6 5.5 4.3 4.2 2.4 2.5

4.7 5.5 3.6 4.3 1.4 2.7

0.6%1.3% 2.9%

-14.8%

4%8.2%

-42.8%

-2.5%-0.6%

-12.4%

p < 0.0001p < 0.0001

p < 0.0001

p = 0.2 NT**

Totalcholesterol

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 5.3 3.6 4.1 1.3 1.9 2.8 2.7 1.2 1.2

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 < 0.0001p < 0.0001

p < 0.0001

p = 0.7 NT**

-40

-30

-20

-10

0

10 SWITCHMRK 1

NonHDL-C

Proportion of patients with HIV-1 RNA < 50 c/mL


%


RAL + ARV LPV/r + ARV


RAL + ARV

LPV/r + ARV

174 166 169 173 172

174 171 171 171 174

50

60

70

80

90

100

0 4 8 12 24

80.8%

87.4%

(95% CI) : - 6.6 (-14.4 ; 1.2)

Weeks

176 176 176 176 175

178 178 177 177 178

%

0 4 8 12 24

93.8%

88%

(95% CI) : - 5.8 (-12.2 ; 0.2)

50

60

70

80

90

100

Weeks

RAL LPV/r Difference (95% CI)LPV/r-based therapy as the first regimenSWITCHMRK 1YesNo

86.1%77.0%

86.7%87.9%

-0.6% (-12.2 to 10.9)-10.9% (-21.6 to -0.3)

SWITCHMRK 2YesNo

89.3%87.4%

94.5%93.5%

-5.3% (-16.9 to 5.7)-6.1% (-14.1 to 1.4)

Combined studiesYesNo

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 1YesNo

72.3%85.1%

89.7%85.8%

-17.3% (-33.0 to -2.5)-0,7% (-9.9 to 8.6)

SWITCHMRK 2YesNo

79.7%92.5%

93.8%93.5%

-14.2% (-26.5 to -2.6)-1.0% (-8.5 to 6.3)

Combined studiesYesNo

76.6%88.6%

91.9%89.6%

-15.3% (-24.9 to -6.2)-1.0% (-6.9 to 4.9)



Proportion of patients with HIV-1 RNA < 50 c/mL at W24*

* Patients who did not complete the trial were regarded as failures


RAL LPV/r RAL LPV/rNeutrophils 0.6% 0 0.6% 0.6%

Haemoglobin 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%

Grade 3 or 4 laboratory abnormalities



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



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 continuationof LPV/r

• Lower rate of HIV suppression, especially in patients who had a history of virologic failure before entry. Results did not establishnon 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)



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Switch studies in virologically suppressed patients