Switch to D/C/F/TAF EMERALD Study

EMERALD Study: Switch to D/C/F/TAF Design Randomisation * 2 : 1 Open label W48 W96 HIV+ ≥ 18 years On F/TDF + PI/r or/c ≥ 6 months Absence of history of virologic failure on DRV (previous VF allowed) Absence of DRV RAM (if historical genotype available) HIV RNA < 50 c/mL ≥ 2 months (1 blip 50-200 c/mL within past 12 months allowed) eGFR (Cockroft-Gault) ≥ 50 mL/min N = 763 D/C/F/TAF QD D/C/F/TAF Continuation PI/r or /C + F/TDF D/C/F/TAF N = 378 * Randomisation stratified by boosted PI Primary endpoint Proportion of patients with virologic rebound at W48 ; non-inferiority if lower margin of a two-sided 95% CI for the adjusted difference = - 4%, 89% power Virologic rebound: confirmed HIV RNA ≥ 50 c/mL (or single HIV RNA > 50 c/mL at W48), or premature discontinuation, irrespective of reason, with last HIV RNA ≥ 50 c/mL through W48 EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34.; Eron J, IDWeek 2018, Abs. 1768

EMERALD Study: Switch to D/C/F/TAF Baseline characteristics and patient disposition D/C/F/TAF N = 763 Continuation PI/r or/C + F/TDF N = 378 Median age, years 46 45 Female, % 18.3 17.2 Race: white / black / other, % 75 / 20 / 5 75 / 22 / 4 CD4/mm3, median 630 624 On first ARV regimen, % 41.6 42.6 Prior exposure to ≥ 5 ARV, % 59 57 Prior virologic failure, % 15.2 14.1 eGR (Cockroft-Gault), mL/min, median 104.2 103.3 Boosted PI at screening, % DRV / ATV / LPV COBI 70.8 / 21.5 / 7.7 14.0 70.4 / 21.7 / 7.9 17.2 Discontinuation by W48, N (%) For adverse event, N Withdrew consent, N Lost to follow-up, N Non-compliant, N Other reasons, N 34 (4.5) 11 10 5 2 6 20 (5.3) 8 3 EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34.

EMERALD Study: Switch to D/C/F/TAF Cumulative confirmed virologic rebound (HIV RNA ≥ 50 c/mL) through W48 Virologic response at W48 (HIV RNA < 50 c/mL), ITT snapshot Difference : 0.4% (95% CI : - 1.5 to 2.2) 2.5 2.1 20 40 60 80 100 % D/C/F/TAF (N = 763) Continuation PI (N = 378) 94.9 0.8 4.3 93.7 0.5 5.8 HIV RNA < 50 c/mL HIV RNA ≥ 50 c/mL No virologic data 20 40 60 80 100 Difference : 1.2% (95 % CI : - 1.7 to 4.1) % 4 patients with virologic rebound genotyped: 1 in D/C/F/TAF (presence of D67D/N) and 3 in continuation group (E138E/G NNRTI mutation in 1) EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34

No previous ARV failure EMERALD Study: Switch to D/C/F/TAF Virologic rebound rate through W48 according to previous antiretroviral failure Difference: 0% (95% CI: - 2.6 to 2.0) 2.5 20 40 60 80 100 % D/C/F/TAF (N = 647) Continuation PI (N = 325) No previous ARV failure ≥ 1 previous ARV failure Difference: 2.6% (95% CI: - 4.8 to 7.5) 2.6 20 40 60 80 100 % D/C/F/TAF (N = 116) Continuation PI (N = 53) EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34.

Confirmed virologic rebound (HIV RNA ≥ 50 c/mL) EMERALD Study: Switch to D/C/F/TAF Confirmed virologic rebound (HIV RNA ≥ 50 c/mL) HIV RNA < 50 c/mL at W96, ITT snapshot D/C/F/TAF immediate switch D0-W48 (N = 763) D/C/F/TAF immediate switch D0-W96 (N = 763) 3.1 2.5 20 40 60 80 100 % 90.7 94.9 20 40 60 80 100 % Most rebounders (14/24 D/C/F/TAF immediate switch and 2/8 deferrred switch) resuppressed to HIV RNA < 50 c/mL by W96, without treatment change Genotype performed if virologic rebound ≥ 400 c/mL (4 D/C/F/TAF immediate switch and 5 deferred switch): no emergence resistance to NRTI or PI Eron J, IDWeek 2018, Abs. 1768

Mean (SE) % change from baseline in bone mineral density (g/cm2) EMERALD Study: Switch to D/C/F/TAF Mean (SE) % change from baseline in bone mineral density (g/cm2) D/C/F/TAF Continuation PI Hip Lumbar spine 24 48 -1 1 2 204 104 184 193 188 97 Weeks D/C/F/TAF Continuation PI p < 0.0001 No of participants 1.43 (2.34) - 0.26 (2.00) 24 48 -1 1 2 206 107 192 97 101 Weeks D/C/F/TAF Continuation PI p < 0.0001 No of participants 1.49 (3.34) - 0.63 (2.86) Hip BMD change at W48 D/C/F/TAF Continuation PI  ≥ 3% 20.2 4.1  ≥ 5% 4.8 1.0  ≥ 3% 2.1 8.2  ≥ 5% Lumbar BMD change at W48 D/C/F/TAF Continuation PI  ≥ 3% 31.8 8.9  ≥ 5% 15.1 1.0  ≥ 3% 7.8 19.8  ≥ 5% 1.6 EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34

Mean (SE) % change from baseline in bone biomarkers EMERALD Study: Switch to D/C/F/TAF Mean (SE) % change from baseline in bone biomarkers -20 Weeks 2 4 12 24 48 -10 5 p < 0.0001 -30 N = 191 N = 98 Procollagen type N-terminal propeptide -20 Weeks 2 4 12 24 48 -15 -10 -5 5 p < 0.0001 N = 193 N = 103 Alkaline phosphatase -20 Weeks 2 4 12 24 48 -10 p < 0.0001 p = 0.0003 10 20 N = 185 N = 98 C-type collagen sequence Parathyroid hormone Weeks 24 48 -10 -5 5 p = 0.0019 p = 0.0074 10 15 20 N = 186 N = 96 25-hydroxy vitamin D Weeks 24 48 -10 -5 p = 0.074 p = 0.495 10 20 30 N = 154 N = 76 D/C/F/TAF Continuation PI EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34.

EMERALD Study: Switch to D/C/F/TAF Median lipid values TC:HDL-C ratio D/C/F/TAF baseline Continuation PI baseline D/C/F/TAF W48 Continuation PI W48 mg/dL mmol/L 50 100 150 200 1.3 2.6 3.9 5.2 184 205 * 181 186 107 123 * 103 106 47 50 * 48 123 129 128 3.8 4 ** 3.9 ** 1 2 3 4 * p < 0.0001 W48 vs baseline ; **p < 0.001 D/C/F/TAF vs continuation PI EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34

Mean Changes in eGFR (mL/min/1.73 m2) at W48 Between-group comparison EMERALD Study: Switch to D/C/F/TAF Mean Changes in eGFR (mL/min/1.73 m2) at W48 D/C/F/TAF Continuation PI Between-group comparison p eGFRcyst - 0.4 ± 9.6 - 1.9 ± 10.7 0.034 eGFR cr - 1.9 - 0.9 0.092 EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34

Adverse events between D0 and W48, % EMERALD Study: Switch to D/C/F/TAF Adverse events between D0 and W48, % D/C/F/TAF (N = 763) PI/r or PI/C + F/TDF (N = 378) Grade 3-4 adverse event 7 8 Serious adverse event 5 Discontinuation for adverse event Due to renal event 1.4% (N = 11) 0.1% (N = 1 *) 1.3% (N = 5) 0.5% (N = 2 **) Adverse event in ≥ 5% of either group Naso-pharyngitis Upper respiratory tract infection Diarrhea Headache Back pain Vitamin D deficiency Osteopenia 11 8 8 7 7 5 10 10 4 4 6 7 6 Grade 3-4 laboratory abnormalities LDL-cholesterol ≥ 4,9 mmol/L Total-cholesterol ≥ 7.77 mmol/L Phosphate < 0,65 mmol/L Total bilirubin ≥ 2,6 x ULN 7 4 3 < 1 2 1 5 6 * Worsening of pre-existing renal insufficiency ; ** Toxic nephropathy, N = 1 ; tubulopathy, N = 1 EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34

EMERALD Study: Switch to D/C/F/TAF Adverse events, D0-W96(%) D/C/F/TAF (N = 763) PI/b + F/TDF (N = 378) (N = 352) D0-W48 D0-W96 D0-W52 W52-W96 Grade 3-4 adverse events 7.1 12.8 8.2 7.4 Serious adverse events 4.6 8.7 4.8 6.0 Discontinuation for adverse event 1.6 2.2 1.3 2.0 Deaths 0.4 * * 1 metastatic pancreas cancer and 2 myocardial infarction Eron J, IDWeek 2018, Abs. 1768

Changes in renal, lipid and bone parameters at W96 (%) EMERALD Study: Switch to D/C/F/TAF Changes in renal, lipid and bone parameters at W96 (%) D/C/F/TAF (N = 763) PI/b + F/TDF (N = 378) (N = 352) D0-W96 D0-W52 W52-W96 Median change in eGDRCKD-EPI, mL/min/1,73 m2 UPCR UACR RBP:CR B2M:CR - 1.3 - 22.23 - 0.63 - 25.08 - 68.22 - 0.6 - 7.37 0.40 + 19.66 + 20.24 - 0.7 - 12.81 - 0.93 - 39.07 - 110.31 Median change in lipids, mg/dL Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides Total cholesterol/HDL-cholesterol ratio + 22.0 + 17.0 + 3.0 + 7.0 + 0.2 + 1.3 + 1.9 + 4.9 + 0.1 + 15.0 + 3.3 + 8.0 Mean % change in BMD Lumbar spine Total hip Femoral neck + 1.99 + 1.86 + 1.40 - 0.27 - 0.51 + 2.91 + 1.22 + 0.98 Eron J, IDWeek 2018, Abs. 1768

EMERALD Study: Switch to D/C/F/TAF Conclusion Through Week 96, switching from boosted PI + FTC/TDF to D/C/F/TAF resulted in: Low virologic rebound rate cumulative (2.5% at W48, 3.1 % at W96) High virologic suppression rate (94.9% at W48, 91% at W96) Virologic non-response rate of 1% No resistance to any study drug Few serious adverse events and discontinuations due to adverse events (2%) D/C/F/TAF bone, renal and lipid safety were consistent with known profiles of TAF and cobicistat EMERALD Orkin C. Lancet HIV. 2018; 5 :e23-34; Eron J, IDWeek 2018, Abs. 1768