1. Comparison of INSTI vs INSTI  QDMRK  SPRING-2

2. Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK  Design  Objective –Non inferiority of RAL QD: % HIV RNA < 50 c/mL by ITT, NC=F (lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power) RAL 400 mg BID + RAL 800 mg QD placebo TDF/FTC fdc QD RAL 800 mg QD + RAL 400 mg BID placebo TDF/FTC fdc QD > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to TDF or FTC *Randomisation was stratified by baseline HIV RNA ( 100,000 c/mL) and viral hepatitis co-infection status QDMRK Study: raltegravir QD vs BID, with TDF/FTC Randomisation* 1 : 1 Double-blind N = 386 N = 389 W96W48

3. RAL BIDRAL QD Randomised and received treatment, N388382 Median age, years38 Female18%23% White/Black/Other70% / 15% / 16%72% / 13% / 15% HIV RNA (log 10 c/mL), median4.84.9 HIV RNA > 100,000 c/mL38%37% CD4 cell count (/mm 3 ), median278285 CD4 < 200 per mm 3 26%23% HBsAg+ or HCV Ab+6%7% Discontinuation by W4825 (6.4%)42 (11.0%) For lack of efficacyN = 5N = 18 For adverse eventN = 2N = 3 Lost to follow-upN = 7 Other reasonsN = 11N = 14 Baseline characteristics and patient disposition Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK QDMRK Study: raltegravir QD vs BID, with TDF/FTC

4. BaselineRAL BIDRAL QD RNA < 5 log 10 c/mL RNA > 5 log 10 c/mL 91.9%* 84.2% 89.1%* 74.3% CD4 > 200/mm 3 CD4 < 200/mm 3 91.6% 80.8% 87.0% 70.8% HIV-1 B subtype Non-B subtype 90.3% 96.3% 88.5% 90.9% Response to treatment at week 48 * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment HIV RNA < 50 c/mL at W48 (NC=failure analysis) by baseline factors Mean CD4/mm 3 increase at W48 (observed-failure analysis): + 196 (RAL BID) vs + 210 (RAL QD) * 95% CI for the difference = - 8.3 ; 2.7 Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK QDMRK Study: raltegravir QD vs BID, with TDF/FTC HIV RNA < 50 c/mL 88.9 83.2 95% CI for the difference =( - 10.7 ; -0.8) 91.0 86.6 Per protocol, observed-failure* 95% CI for the difference = (- 9.0 ; 0.2) 386382377367 25 50 100 75 % Primary analysis RAL BIDRAL QD ITT NC = F N = 0

5. RAL BIDRAL QD Clinical adverse events Drug-related AE24.2%26.4% Serious drug-related AE0.5%0.3% Treatment discontinuation due to AE1.0% Laboratory adverse events Drug-related AE2.3%1.3% Treatment discontinuation due to AE00.3% Moderate to severe adverse events of any cause48%45% Diarrhoea4% Headache4%3% Depression2%3% Vomiting3%2% Grade 3 or 4 laboratory abnormality in > 2% of patients in either group Fasting LDL-cholesterol > 190 mg/dL (4.9 mmol/L)2.0%1.4% Creatine kinase5.4%3.9% ALT / AST3.4% / 3.4%2.9% / 1.8%  Safety at W48 Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK QDMRK Study: raltegravir QD vs BID, with TDF/FTC

6.  Virologic failure: definition –Non-response = never achieved 2 consecutive HIV RNA < 50 c/mL by week 24 or at time of premature study discontinuation –or rebound = after an initial response, confirmed HIV RNA > 50 c/mL Emergence of resistance in virologic failure RAL BID N = 388 RAL QD N = 382 Protocol-defined virologic failure35 (9%)53 (14%) Non-response1422 Rebound2131 Assessed for emergence of resistance mutations *1630 No result available (technical issue)22 Raltegravir resistance mutations + M184I/V2/129/27 M184I/V alone4/1311/28 No resistance8/148/28 * Genotyping was done only in patients with HIV RNA > 400 c/mL 2/2 (RAL BID) and 7/9 (RAL QD) patients who had emergence of RAL resistance had baseline HIV RNA > 100 000 c/mL Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK QDMRK Study: raltegravir QD vs BID, with TDF/FTC

7.  Pharmacokinetic Data –Trough raltegravir concentrations were more than six times higher with twice-daily dosing than they were with once-daily dosing –Although an association between trough RAL concentrations and efficacy was evident in the once-daily group, no clear threshold could be identified Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK

8.  Conclusion –At 48 weeks of treatment, RAL QD was not non-inferior to RAL BID, in combination with TDF/FTC –Virologic failure was more common with once-daily dosing especially in patients with baseline HIV RNA > 100 000 c/mL –More patients in the once-daily group than in the twice-daily group had resistance emergence to both RAL and FTC at the time of virological failure –Patients in the once-daily group with low pharmacokinetic values and high baseline viral loads were at particular risk of treatment failure –Despite a high response rate, RAL at 800 mg QD cannot be recommended in place of twice-daily dosing for first-line antiretroviral therapy Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK QDMRK Study: raltegravir QD vs BID, with TDF/FTC