Switch to RAL-containing regimen - Canadian Study - CHEER - Montreal Study - EASIER - SWITCHMRK - SPIRAL

 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: SWITCHMRK Randomisation* 1 : 1 Double-blind HIV+ ≥ 18 years On LPV/r + ≥ 2 NRTIs HIV RNA < 50 c/mL (PCR) or 3 months N = 352 N = 350 W24 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 Eron JJ, Lancet 2010;375: SWITCHMRK SWITCHMRK Study: Switch to RAL vs continuation of LPV/r

SWITCHMRK 1SWITCHMRK 2 RALLPV/rRALLPV/r Randomized, N Treated eligible patients, N Female16%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 (/mm 3 ), median Suppressed viraemia94%93%96% LPV/r therapy > 1 year83%82% 81% LPV/r as first regimen42%43%32%31% History of previous virologic failure (reported by investigator) 28%33%36%37% Discontinuation before W2414.1%9.7%5.7%3.4% Baseline characteristics and patient disposition Eron JJ, Lancet 2010;375: SWITCHMRK SWITCHMRK Study: Switch to RAL vs continuation of LPV/r

* median changes for triglycerides ** not tested Mean* % changes in fasting lipid concentrations from baseline to W12 Eron JJ, Lancet 2010;375: SWITCHMRK SWITCHMRK Study: Switch to RAL vs continuation of LPV/r SWITCHMRK 2 RAL + ARV LPV/r + ARV Total cholesterol Non HDL-C Triglycerides* LDL-CHDL-C % 1.3%2.9% -14.8% 4%8.2% -42.8% -2.5% -0.6% -12.4% p < p = 0.2 NT** Total cholesterol Triglycerides* LDL-CHDL-C 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** SWITCHMRK 1 Non HDL-C

Proportion of patients with HIV-1 RNA < 50 c/mL Eron JJ, Lancet 2010;375: SWITCHMRK % SWITCHMRK Study: Switch to RAL vs continuation of LPV/r RAL + ARVLPV/r + ARV SWITCHMRK 1SWITCHMRK 2 RAL + ARV LPV/r + ARV % 87.4%  (95% CI) : (-14.4 ; 1.2) Weeks % % 88%  (95% CI) : (-12.2 ; 0.2) Weeks

RALLPV/rDifference (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) Eron JJ, Lancet 2010;375: SWITCHMRK SWITCHMRK Study: Switch to RAL vs continuation of LPV/r Proportion of patients with HIV-1 RNA < 50 c/mL at W24* * Patients who did not complete the trial were regarded as failures

SWITCHMRK 1SWITCHMRK 2 RALLPV/rRALLPV/r Neutrophils0.6%0 Haemoglobin0000 Platelets1.2%000 Fasting LDL cholesterol1.3% 1.2% Fasting total cholesterol01.9%1.7%4.1% Fasting triglycerides01.9%1.2%4.7% Fasting glucose0000 Creatinine00.6%00 Lipase0%0.6%00 ASAT1.1% 00 ALAT4%0.6%1.7%1.1% Grade 3 or 4 laboratory abnormalities Eron JJ, Lancet 2010;375: SWITCHMRK 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 Eron JJ, Lancet 2010;375: SWITCHMRK 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) Eron JJ, Lancet 2010;375: SWITCHMRK SWITCHMRK Study: Switch to RAL vs continuation of LPV/r