Comparison of NRTI combinations ARV-trial.com Comparison of NRTI combinations ZDV/3TC vs TDF + FTC Study 934 ABC/3TC vs TDF/FTC HEAT Study ACTG A5202 Study ASSERT Study FTC/TDF vs FTC/TAF Studies GS-US-292-0104 and GS-US-292-0111 1

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Design Randomisation* 1 : 1 Double-blind placebo-matched W48 W96 N = 343 ABC/3TC + TDF/FTC placebo QD LPV/r 800/200 mg 694 ARV-naïve patients > 18 years HIV RNA > 1,000 c/mL Any CD4 cell count No HLA-B*5701 screening N = 345 TDF/FTC + ABC/3TC placebo QD LPV/r 800/200 mg *Randomisation was stratified on HIV RNA < 100,000 c/mL or > 100,000 c/mL Objective Non inferiority of the 2 fixed dose NRTI combinations at W48: % HIV RNA < 50 c/mL, ITT-exposed, missing = failure [ITT-E, M = F] (lower margin of the 95% CI for the difference = - 12%, 90% power) Primary safety endpoint: incidence of adverse events at W96 HEAT Smith KY. AIDS 2009;23:1547-56 2

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Patient disposition and baseline characteristics Randomized ABC/3TC N = 347 TDF/FTC N = 347 Treated eligible patients, N 343 345 Median age, years 38 Female 16% 20% White/Black/Other 52% / 36% / 13% 51% / 36% / 13% HIV RNA (log10 c/mL), median 4.9 4.8 HIV RNA > 100,000 c/mL 45% 41% CD4 cell count (/mm3), median 214 193 CD4 < 200/mm3 47% 52% CD4 < 50/mm3 18% HBV positive/HCV positive 6% / 8% 3% / 7% Discontinuation by W96 N = 109 (32%) N = 124 (36%) For virologic failure/adverse event, N 8 / 20 6 / 21 Lost to follow-up/subject decision/non compliance, N 45 / 13 / 10 52 / 23 / 11 Note: change of NRTI (to NRTI other than ABC or TDF) allowed if intolerance; change of LPV/r QD to BID allowed if gastrointestinal intolerance, or to other PI if LPV/r-limiting intolerance. LPV/r was administered as soft-gel capsules (6/d) to week 48 then as tablets (4/d) HEAT Smith KY. AIDS 2009;23:1547-56 3

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Proportion of patients with HIV RNA < 50 c/mL at week 48 % ABC/3TC TDF/FTC 100 Primary efficacy endpoint 87 84 80 71 68 69 67 63 64 65 61 62 63 60 40 20 N = 343 345 343 345 343 345 188 205 155 140 ITT-E, M/D = F TLOVR ITT, M/D = F Observed analysis, ITT-E ITT-E, M/D = F stratified by baseline HIV RNA (c/mL) 95% CI for the difference = - 6.6; 7.4 < 100 000 > 100 000 Median CD4 increase at W96: 250/mm3 (ABC/3TC) vs 247/mm3 (TDF/FTC) ITT-E, M = F: ITT-exposed, missing/discontinuation = failure HEAT Smith KY. AIDS 2009;23:1547-56 4

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Safety and tolerability (median exposure = 96 weeks) ABC/3TC N = 343 TDF/FTC N = 345 Grade 2-4 drug related adverse events Any 50% 46% Diarrhoea 19% Nausea 8% 6% Increased triglycerides Increased cholesterol 7% 4% Decreased Glomerular Filtration Rate 5% Suspected Hypersensitivity Reaction to ABC 3% <1% Any drug-related serious adverse events N = 18 * (5%) N = 10 ** (3%) Discontinuation for adverse event * Including suspected ABC HSR (N = 14), immune reconstitution syndrome (N = 2), hepatotoxicity (N = 1) ** Including suspected ABC HSR (N = 3), renal failure (N = 2), decreased creatinine renal clearance (N = 1) HEAT Smith KY. AIDS 2009;23:1547-56 5

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Change in laboratory parameters (lipids, renal, biomarkers) Median change from baseline at W96 ABC/3TC TDF/FTC Total cholesterol (mg/dL) + 36 + 28 HDL-cholesterol (mg/dL) + 10 + 12 Total cholesterol: HDL-cholesterol ratio - 0.27 - 0.44 LDL-cholesterol (mg/dL) + 9 + 8 Triglycerides (mg/dL) + 54 + 42 GFR, MDRD equation (mL/min/1.73 m2) Proximal renal tubular dysfunction occurrence N = 0 N = 5 (1%) Biomarkers (% change from baseline) W48 W96 sVCAM-1 - 49 - 51 - 48 - 50 IL-6 - 26 - 19 - 23 - 25 hs-CRP - 12 - 5 - 20 - 17 HEAT Smith KY. AIDS 2009;23:1547-56 6

HEAT Study: ABC/3TC vs TDF/FTC ARV-trial.com HEAT Study: ABC/3TC vs TDF/FTC Conclusions As initial antiretroviral regimens, ABC/3TC and TDF/FTC, each in combination with LPV/r QD, have the same efficacy rate HIV RNA responses by baseline HIV RNA strata (< or > 100,000 c/mL) were similar between groups at W48 and W96 Rate of virologic failure was similar in both groups (14%) CD4 response at W96 was similar in the 2 groups Both treatments were well tolerated More gastrointestinal intolerance with TDF/FTC More lipid abnormalities with ABC/3TC Of note, rate of discontinuation was high (34% at W96) Smith KY. AIDS 2009;23:1547-56 7