1. Phase 2 of new ARVs TAF (TFV prodrug) - Study 292-0102 - Study 299-0102

2. Sax PE. JAIDS 2014;67:52-8 2920102/TAF phase 2  Design  Primary objective –Determine virologic efficacy of EVG/c/FTC/TAF –150 patients provide 76% power to detect a 1.5% (SD of 3.3%) difference in hip bone mineral density in the EVG/c/FTC/TAF arm relative to the EVG/c/FTC/TDF arm EVG/c/FTC/TAF 150/150/200/10 mg QD STR EVG/c/FTC/TDF placebo EVG/c/FTC/TDF 150/150/200/300 mg QD STR EVG/c/FTC/TAF placebo Randomisation* 2 : 1 Double-blind > 18 years ARV-naïve HIV RNA > 5,000 c/mL CD4 cell count > 50/mm 3 eGFR > 70 mL/min *Randomisation was stratified by HIV RNA ( 100,000 c/mL) at screening Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2) N =58 N = 112 W24W48

3.  Baseline characteristics –Median viral load at baseline : 4.6 log 10 c/mL (21% > 100,000 c/mL), median CD4+ cell count : 391 cells/mm 3 (15% > 200/mm 3 )  Main results –Discontinuation due to adverse events by W48 : 4 in TAF arm vs 0 in TDF arm –HIV RNA < 50 c/mL at W24 : 87.5% E/c/F/TAF vs 89.7% E/c/F/TDF –3 patients in each arm met criteria for resistance testing (virologic failure [2 consecutive HIV RNA > 50 c/mL] with HIV RNA > 400 c/mL). Genotype was performed on confirmatory sample E/c/F/TAF : no resistance detected E/c/F/TDF : 2 patients developed resistance, 1 to NRTI, 1 to INSTI + NRTI –PK substudy : plasma TFV exposure was 91% lower with E/c/F/TAF than with E/c/F/TDF, as measured by AUC tau. Conversely, intracellular TFV-DP levels in PBMCs were 5.3-fold higher with E/c/F/TAF Sax PE. JAIDS 2014;67:52-8 2920102/TAF phase 2 Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2)

4.  Safety –Significantly less change in the E/c/F/TAF arm in BMD at hip (-0.62% vs -2.39%, p < 0.001) and lumbar spine (-1.0% vs -3.37%, p < 0.001) at W48, which were also significant at week 24 –In the E/c/F/TAF arm, 32% of patients had no decrease in hip BMD vs 7% in the E/c/F/TDF arm (p < 0.001) –Median change in eGFR by Cockcroft–Gault = -5.5 mL/min for E/c/F/TAF vs -10.1 mL/min for E/c/F/TDF (p = 0.041) –Renal tubular proteinuria [urine retinol-binding protein/creatinine ratio and urine  -2 microglobulin/creatinine ratio] was significantly lower in patients who received E/c/F/TAF : no cases of proximal tubulopathy –Grade 3-4 adverse events : 9.8% TAF vs 5.2% TDF –Most common treatment-emergent adverse events : nausea (21% vs 12%), diarrhea (16% in each arm) –Higher elevations in lipids with TAF Sax PE. JAIDS 2014;67:52-8 2920102/TAF phase 2 Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2)

5. E/C/F/TAFE/C/F/TDF Any25%17% LDL-cholesterol9%3% Creatine phosphokinase6%3% Neutropenia5%2% Amylase3% Urine red blood cells2%0 Total cholesterol2%0 ALT / AST1% / 1%2% / 0 Gamma glutamyl transferase1%2% White blood cells1%0 Hypophosphatemia1%0 Urine protein1%0 Glucose1%2% Triglycerides1%2%  Grade 3 or 4 laboratory abnormalities Sax PE. JAIDS 2014;67:52-8 2920102/TAF phase 2 Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2)

6.  Summary of week 48 results –In this phase 2, randomised clinical trial, HIV-positive treatment-naive adults received STRs of E/c/F/TAF or E/c/F/TDF. Both STRs demonstrated high and comparable rates of virologic suppression through 48 weeks of therapy –Both regimens were well tolerated, with few discontinuations due to adverse events. Nausea occurred more frequently with E/c/F/TAF –Plasma concentrations of TFV were substantially (91%) lower with E/c/F/TAF than with E/c/ F/TDF, and the TAF regimen delivered 5.3 times the intracellular, physiologically active metabolite, TFV-DP, to PBMCs, which could translate into less end-organ toxicity and/or improved virologic control –Significant smaller decreases in bone mineral density through 48 with E/c/F/TAF than with E/c/F/TDF –Urinary RBP/creatinine and  -2 microglobulin/creatinine ratios were significantly lower in the E/c/F/TAF arm, which suggests that TAF has a lesser effect than TDF on the proximal renal tubular cell Sax PE. JAIDS 2014;67:52-8 2920102/TAF phase 2 Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2)