Switch to EVG/c/FTC/TDF Strategy in HIV Study

Switch to EVG/c/FTC/TDF STRATEGY-PI Study STRATEGY-NNRTI Study

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Design Randomisation* 2 : 1 Open-label W48 W96 HIV+ 18 years On FTC + TDF + NNRTI HIV RNA < 50 c/mL > 6 months No virologic failure Genotype testing before ART with no resistance to study drugs Integrase inhibitor na ve eGFR > 70 mL/mim N = 292 Switch to EVG/c/FTC/TDF N = 147 Continue NNRTI + FTC + TDF * Randomisation stratified by EFV use at screening Endpoints Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (mITT, snapshot) ; non-inferiority if lower margin of a two-sided 95% CI for the difference = -12%, 85% power. If non-inferiority and lower margin > 0, assessment for superiority Secondary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (TLOVR algorithm), CD4, safety, tolerability to W96 Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Baseline characteristics and patient disposition EVG/c/FTC/TDF N = 291 43 8% 5 90% NNRTI + FTC + TDF N = 143 39 6% 5 91% Median age, years Female Time since HIV diagnosis, median years On first ARV regimen NNRTI at randomisation Efavirenz (coformulated EFV/FTC/TDF) Nevirapine Rilpivirine Etravirine CD4 cell count (/mm3), median Hepatitis B / hepatitis C coinfection Discontinuation by W48 80% (76%) 16% 3% 1% 561 2% / 4% 22 74% (70%) 19% 7% 0 562 2% / 1% 18 Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Virologic outcome at W48 (mITT, snapshot) EVG/c/FTC/TDF NNRTI + FTC + TDF HIV RNA < 50 c/mL HIV RNA 50 c/mL No virologic data % 93 100 88 80 60 40 11 20 6 1 1 0 N = 3 N = 1 Difference (95% CI) = 5.3% (-0.5 to 12.0) Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c HIV RNA < 50 c/mL Sensitivity and secondary analysis EGV/c/FTC/TDF NNRTI + FTC + TDF Per-proctol 99% 99% Difference: 0.1% (95% CI: - 2.1 to 3.5) ITT-TLOVR 92% 87% Difference: 5.0% (95% CI: -1.1 to 12.1) One participant in each group met the criteria for resistance testing (HIV RNA > 400 c/mL at virologic failure or early discontinuation) No emergence of resistance Both remained on study treatment and achieved HIV RNA < 50 c/mL after W48 Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Virologic sucess overall and by subgroup at W48 (mITT) n/N 271/290 126/143 Overall 107/114 62/74 Age < 40 years 164/176 64/69 Age > 40 years 251/267 119/134 Male 20/23 7/9 Female 216/230 99/109 White 55/60 27/34 Non-white 214/231 91/106 Efavirenz 57/59 35/37 Non-efavirenz On first regimen at baseline On second regimen at baseline 245/262 114/130 25/27 11/12 0 10 20 30 Virological success (%) 40 50 60 70 80 90 100 -20 -10 0 10 20 30 40 50 Difference (%) Favours switching Favours not switching No-switch group Switch group Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Adverse events and grade 3-4 laboratory abnormalities EVG/c/FTC/TDF NNRTI + FTC + TDF Any adverse event, 81% 75% Grade 3 or 4 AE 7% 6% Serious adverse event 5% 4% Discontinuation because of AE N = 6 (2%)* N = 1 (1%)** Death N = 1 0 AE occurring more frequently in one group 14% 23% Headache (p = 0.03) 3% 1% Nausea (p = 0.05) 2% 6% Cough (p= 0.04) 2% 1% Fatigue (p = 0.02) 2% 1% * neuromuscular symptoms, suicide, dysgueusia, prurigo, Fanconi syndrome, increased creatinine ** altered mood Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Other safety data Incidence and prevalence of headache and nausea became similar between groups by week 12 Grade 3-4 laboratory abnormalities : 10% in the switch group vs 14% in the no-switch group Creatinine increase in switch group at week 4, stabilizing up to week 48 (median +11 mol/L) Small decrease in HDL-cholesterol in the switch group vs no change in the no-switch group In the subgroup switched form EFV + FTC + TDF to EVG/c/FTC/TDF Improvement in lipids HIV Symptom Index : improvement of CNS symptoms Higher treatment satisfaction score at W4 and W24 Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI

STRATEGY-NNRTI Study: Switch NNRTI to EVG/c Conclusion Coformulated EVG/c/FTC/TDF is non-inferior to continuing an existing regimen of NNRTI plus FTC and TDF in virologically suppressed, HIV- infected adults with no history of virological failure or resistance to FTC or TDF. Low frequency of virologic failure and absence of emergent resistance in the group switched to EVG/c/FTC/TDF Rare discontinuations because of adverse events Fatigue, cough, headache and nausea were more frequent in the switch group ; Rates of CNS symptoms decreased in patients switched from EFV Increase in creatinine similar to that of phase 3 of EGV/c/FTC/TDF Moderate improvement in lipids in patients switched from EFV EVG/c/FTC/TDF is a switch option in virologically suppressed patients with no history of virological failure on an NNRTI regimen, when its continuation is not suitable Pozniak A. Lancet Infect Dis 2014;14:590-9 STRATEGY-NNRTI