ARV-trial.com Switch from TDF to TAF GS-US-292-0109 Study 1

GS-US-292-0109 Study: Switch TDF to TAF Design Randomisation 2 : 1 Open-label W48 W96 N = 959 HIV+ ≥ 18 years On E/C/F/TDF or EFV/FTC/TDF or boosted ATV + FTC/TDF > 96 weeks HIV RNA < 50 c/mL eGFR (Cockroft-Gault) > 50 mL/min Switch to E/C/F/TAF Continue TDF-based regimen N = 477 *Randomisation was stratified by previous treatment regimen Endpoints Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (ITT, snapshot) ; non-inferiority if lower margin of a two-sided 95% CI for the difference = -12%, 99% power Secondary: percentage change in hip and spine bone mineral density, change in serum creatinine, and change in EFV-related symptom score at W48 GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF ARV-trial.com GS-US-292-0109 Study: Switch TDF to TAF Baseline characteristics and patient disposition E/C/F/TAF N = 959 TDF-based regimens N = 477 Median age, years 41 40 Female 11% 10% Race: white / black / asian 68% / 18% / 6% 66% / 21% / 7% HIV-1 RNA < 50 c/mL 98% CD4 cell count (/mm3), median 675 662 eGFR, mL/min, median Cockroft-Gault CKD-EPI 105.7 92.8 107.7 93.9 Dipstick proteinuria: grade 1 / grade 2 9% / < 1% Discontinuation by W48, N (%) For adverse event For lack of efficacy Investigator discretion Consent withdrawal Loss to follow-up Non-compliance Death 32 (3.3%) 9 1 2 8 6 4 40 (8.4%) 12 3 16 7 GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52 3

GS-US-292-0109 Study: Switch TDF to TAF Virologic outcome at W48 and W96 (ITT, snapshot) E/C/F/TAF (N = 959) TDF-based regimens (N = 477) HIV RNA < 50 c/mL Virologic failure No virologic data 97.2 93.1 % 20 40 60 80 100 Difference (95% CI) = 4.1% (1.6 to 6.7) 1* 1.3 N=10 N=6 1.8 5.7 Superiority of E/C/F/TAF Week 48 Week 96 ≠ (95% CI) = 3.7% (0.4 to 7.0) 93 89 5 9 2 * One patient in the TAF group with virologic failure (W8) had genotypic resistance : M184I/M. The patient resuppressed 4 weeks later without a change of regimen GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52 ; DeJesus E. ASM Microbe 2016, Abs. LB-087

GS-US-292-0109 Study: Switch TDF to TAF HIV-1 RNA < 50 c/mL at W48 by prior treatment regimen, % E/C/F/TAF TDF-based regimens 97 93 96 90 92 98 100 80 60 40 20 p < 0.001 p = NS p = 0.02 Primary Endpoint 0.5 to 12.3 0.9 to 9.2 -1.9 to 3.9 1.6 to 6.7 95% CI = 959 477 306 153 251 125 402 199 All prior regimens Prior EFV/FTC/TDF Prior boosted ATV + FTC/TDF E/C/F/TDF GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Differences in patients with HIV-1 RNA < 50 c/mL at W96 by subgroup, % (95% CI) Overall Age, years Sex Race Adherence < 50 > 50 Male Female Black Nonblack < 95% > 95% E/C/F/TAF TDF-based regimens -12 -6 12 GS-US-292-0109 DeJesus E. ASM Microbe 2016, Abs. LB-087

GS-US-292-0109 Study: Switch TDF to TAF Changes in bone mineral density from baseline to W48 E/C/F/TAF TDF-based regimens Difference in least square means (95% CI) Hip BMD change (N) 869 428 T-score mean change from baseline 0.11 - 0.02 0.13 (0.10 – 0.15) ; p < 0.0001 Percent change from baseline 1.47% - 0.34% 1.81 (1.49 – 2.13) ; p < 0.0001 0 to 3% increase in BMD > 3% increase 56% 21% 38% 8% p < 0.0001 Spine BMD change (N) 881 436 0.17 0.19 (0.16 – 0.23) ; p < 0.0001 1.56% - 0.44% 2.00 (1.55 – 2.45) ; p < 0.0001 41% 33% 34% 13% GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Changes in bone mineral density from baseline to W48 in patients previously on ATV + r + FTC/TDF E/C/F/TAF ATV + r + FTC/TDF Hip BMD mean change (N) 41 13 During 144 weeks of prior ATV + r + FTC/TDF - 4.58% Percent change from baseline to W48 + 1.35% - 0.77% Spine BMD mean change (N) 42 16 - 3.1% + 2.83% - 0.74% GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Median % change in BMD (Q1, Q3) on DXA E/C/F/TAF TDF-based regimens Baseline Week 24 Week 96 -2.5 -0.5 0.5 1.5 2.5 4.5 2.0 Week 48 -1.5 3.5 -0.3 p < 0,001 Spine BMD All Patients (N=1369) Baseline Week 24 Week 96 -2.5 -0.5 0.5 1.5 2.5 4.5 2.1 Week 48 -1.5 3.5 -0.6 p < 0,001 Hip BMD All Patients (N=1354) Regardless of prior treatment regimen, differences between arms were statistically significant for spine and hip BMD GS-US-292-0109 DeJesus E. ASM Microbes 2016, Abs. LB-087

GS-US-292-0109 Study: Switch TDF to TAF Change in Osteopenia/Osteoporosis Diagnosis (defined by T-Score) Spine Normal Osteopenia Osteoporosis Baseline Week 48 E/C/F/TAF N = 912 TDF-Based Regimen N = 457 Hip E/C/F/TAF N = 902 TDF-Based Regimen N = 452 % 100 80 60 40 20 5.8 4.8 7.2 7.6 0.7 1.3 2.1 36 32 35 37 31 26 59 64 57 56 69 73 67 66 Differences between E/C/F/TAF and TDF-based regimens were statistically significant (p < 0.001) GS-US-292-0109 Mills A. IAS 2015, Abs. TUAB0102; Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Serum creatinine and eGFR changes from baseline to W48 E/C/F/TAF EFV/FTC/TDF (unboosted regimen) Other TDF-based regimens Mean serum creatinine change, mmol/L - 0.4 - + 2.9 + 9.2 + 1.77 Median eGFR (Cockroft-Gault), mL/min + 1.2 - 3.7 Median changes in markers of renal function from baseline to W48 E/C/F/TAF TDF-Based regimens p Fractional excretion of phosphate + 0.2 + 0.7 0.054 Fractional excretion of uric acid - 0.8 + 0.3 < 0.001 TmP/GFR *, mg/dL - 0.1 0.63 * TmP/GFR: ratio of tubular maximum reabsorption of phosphate (TmP) to GFR GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Renal Safety Results (Median % change in proteinuria at W48) E/C/F/TAF TDF-based regimens Each difference between treatment arms was statistically significant (p < 0.001) RBP:Cr β-2-m:Cr UPCR UACR Tubular Proteinuria 30 20 10 -10 -20 -30 -40 -50 -20.9 9.6 -17.9 8.5 -33.4 18.1 -52.3 18.7 -60 UPCR: urine protein:creatinine ratio ; UACR: urine albumin:creatinine ratio ; RBP, retinol-binding protein ; β-2-m: beta-2 microglobulin GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Adverse events, N (%) (W48) E/C/F/TAF N = 959 TDF-based regimens N = 477 Study-drug related adverse event 21% 16% Grade 3 or 4 adverse event 9% 11% Serious adverse event 65 (7%) 35 (7%) Study drug-related serious adverse event 2 (< 1%) Premature study drug discontinuation for kidney-related adverse event for jaundice 9 (0.94%) * 2 12 (2.52%) ** 5 (1 Fanconi) 3 (all on boosted ATV) * Panic attack; apathy, amnesia, speech disorder; Reiter’s syndrome; nausea, vomiting, and headache; suicide attempt; leg swelling and impaired concentration; depression; acute renal failure (after cancer chemotherapy: sepsis and multisystem organ failure); tubulo-interstitial nephritis (recurrent hematuria with subsequent diagnosis of Hodgkin lymphoma) ** Abnormal dreams; depression, insomnia, and irritability; depression, insomnia, and nightmares; elevated bilirubin; jaundice (N = 2); memory impairment; chronic kidney disease; elevated serum creatinine (N = 2); Fanconi’s syndrome and mild jaundice; renal colic No discontinuation for adverse event in both groups between W48 and W96 GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Most-common drug-related adverse event, % (W48) E/C/F/TAF N = 959 TDF-based regimens N = 477 Upper respiratory tract infection 16 11 Diarrhea 10 9 Nasopharyngitis 8 Headache 7 4 Cough 5 Syphilis 6 Insomnia Arthralgia Bronchitis Depression Osteopenia Back pain Nausea 3 Sinusitis GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Grade 2-4 laboratory abnormalities (W48) E/C/F/TAF N = 959 TDF-based regimens N = 477 Any abnormality 25% 31% Creatine kinase 10% AST 5% 7% ALT Neutropenia 4% 3% Hypophosphatemia 2% Hyperuricemia 1% Alkaline phosphatase < 1% Leukopenia Platelets Total bilirubin 24% Hemoglobin Creatinine GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF Fasting Lipids (mg/dL, median), baseline and W48 Total Cholesterol LDL HDL Triglycerides TC:HDL Ratio p < 0.001 p < 0.001 p = 0.003 p < 0.001 p = 0.004 E/C/F/TAF Baseline Week 48 TDF-Based Regimens 202 183 125 114 52 112 3.6 131 3.8 181 116 49 120 50 100 150 200 250 1 2 3 4 5 Participants initiating lipid-modifying medications: E/C/F/TAF: 8% ; TDF-based regimens: 6% GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52

GS-US-292-0109 Study: Switch TDF to TAF ARV-trial.com GS-US-292-0109 Study: Switch TDF to TAF Conclusion Switching virologically suppressed patients to TAF regimen (EVG 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and TAF 10 mg) was non inferior to the to 3 TDF-containing regimens at week 48 and week 96 It was also superior to continuing with the TDF-containing regimens. Switching to the TAF group showed several important safety advantages of TAF over any of the TDF-containing regimens : Improvements in hip and spine bone mineral density Improvements in renal function Decreases in serum creatinine in patients switched from a boosted regimen Decreases in dipstick proteinuria, in quantitative tests of total urine protein, and total urine albumin, in specific proximal tubular proteins Improvements in proximal renal tubular function (fractional excretion of uric acid, fractional excretion of phosphate, and renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate Slightly higher lipid concentrations with TAF than with TDF-based regimens GS-US-292-0109 Mills A. Lancet Infec Dis 2016;16:43-52 17