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

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;375:396-407

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 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;375:396-407

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 < 0.0001 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 < 0.0001 p = 0.2 NT** RAL + ARV LPV/r + ARV * median changes for triglycerides ** not tested 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 % 176 175 178 177 % 4 8 12 24 93.8% 88% (95% CI) : - 5.8 (-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) : - 6.6 (-14.4 ; 1.2) Weeks RAL + ARV LPV/r + ARV 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 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;375:396-407

SWITCHMRK Study: Switch to RAL vs continuation of LPV/r Grade 3 or 4 laboratory abnormalities SWITCHMRK 1 SWITCHMRK 2 RAL LPV/r 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;375:396-407

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