Switch from TDF to TAF GS-US-292-0109 Study GS-US-311-1089 Study ARV-trial.com Switch from TDF to TAF GS-US-292-0109 Study GS-US-311-1089 Study GS-US-366-1216 Study GS-US-366-1160 Study

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Design Randomisation 1 : 1 Double blind W48 W96 HIV+ ≥ 18 years On RPV/FTC/TDF > 6 months HIV RNA < 50 c/mL ≥ 6 months eGFR (Cockroft-Gault) > 50 mL/min No resistance to RPV, FTC or TDF N = 316 RPV/FTC/TAF 25/200/25 mg QD + RPV/FTC/TDF placebo RPV/FTC/TDF 25/200/300 mg QD + RPV/FTC/TAF placebo N = 316 Endpoints Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (ITT, snapshot) ; non-inferiority if lower margin of a two-sided 95.001% CI for the difference = - 8%, 85% power Secondary: percentage change for hip and spine bone mineral density between treatment groups ; 90% power to detect a 1.38% difference (non- inferiority margin) ; multiple adjustments to test for superiority GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Baseline characteristics and outcome RPV/FTC/TAF N = 316 RPV/FTC/TDF N = 314 Median age, years 46 44 Female, % 13 8 Race: white / black / other, % 75 / 21 / 4 75 / 17 / 8 CD4/mm3, median 673 668 HIV RNA < 50 c/mL, % 97 99 eGR (Cockroft-Gault), mL/min, median 103.5 99.7 Proteinuria: grade 1 / grade 2, % 10 / 0 9 / < 1 Discontinuation by W48, N (%) Adverse event Death Pregnancy Investigator decision Consent withdrawal Lost to follow-up Protocol violation 18 (5.7%) 4 1 2 6 18 (5.8%) 3 GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204 3

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Virologic outcome at W48 (ITT, snapshot) Difference (95% CI) = - 0.3% (- 4.2 to 3.7) 93.7 0.6 5.7 93.9 6.1 20 40 60 80 100 Success HIV RNA< 50 c/mL Virologic failure No virologic data % 313 * 316 RPV/FTC/TAF RPV/FTC/TDF Other efficacy results at W48 Per protocol analysis (HIV RNA < 50 c/mL) 99.3% RPV/FTC/TAF 100% RPV/FTC/TDF Virologic success was similar between treatment groups for the subgroups of age, sex, race, geographic region, and study drug adherence Mean changes in CD4/mm3 + 9 RPV/FTC/TAF - 1 RPV/FTC/TDF * 1 patient excluded from full-analysis set (was taking EFV/FTC/TDF) GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Resistance analysis Genotype and Phenotype testing if confirmed HIV RNA ≥ 50 c/mL and confirmatory sample ≥ 400 c/mL, or HIV RNA ≥ 400 c/mL at W48 or at the last visit on study drug 1 patient in the RPV/FTC/TAF group: re-emergence of archived mutations M41K, E44D, D67N, V118I, L210W, T215Y; no new mutations (did not re- suppress) 1 patient in the RPV/FTC/TDF group: no resistance detected, was re- suppressed on continued therapy Historical genotypes: resistance mutations to study drug in 3 participants 3 patients in the TAF group: M184V (N = 2), E138A, K101E + E138K 1 discontinued at W4 with HIV RNA < 50 c/mL, 3 with HIV RNA < 50 c/mL at W48 3 patients in the TDF group: M184V, E138A (N = 2) All 3 with HIV RNA < 50 c/mL at W48 GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Adverse events, % RPV/FTC/TAF N = 316 RPV/FTC/TDF N = 314 Adverse events related to study drug 6 12 Serious adverse event related to study drug 4 Adverse event leading to discontinuation 1 * 1 ** Most common adverse events (≥ 5% of patients) Upper respiratory tract infection Diarrhea Nasopharyngitis Headache Bronchitis Sinusitis 9 7 5 8 * Gastroesophageal reflux disease (N = 1), hiatus hernia and ulcerative oesophagitis (N = 1), fatigue (N = 1), leading to discontinuation), suicidal depression (N = 1) ** Drug hypersensitivity (N = 1), leading to discontinuation), increased ALT and AST (N = 1), chronic myeloid leukaemia (N = 1) GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Change in renal biomarkers at W48 - 18.8 - 7.8 - 18.0 - 29.0 7.3 16.8 21.5 12.0 - 50 40 30 20 10 P/Cr Alb/Cr RBP/Cr b2MG/Cr Cr: creatininuria ; P: proteinuria ; Alb: albuminuria ; RBP : retinol binding protein ; b2MG : béta-2 microglobinuria Urine protein to creatinine ratio (% median change) * p < 0.001 * F/TAF F/TDF Median change in eGFR: + 4.5 mg/dL on RPV/FTC/TAF vs + 0.7 mg/dL on RPV/FTC/TDF (p = 0.0024) No discontinuation for study-drug renal adverse event in either group No reported cases of proximal renal tubulopathy or Fanconi syndrome in either group GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Mean % change in bone mineral density through W48 (%, 95% CI) Hip Lumbar spine 3 1.61 2 1.04 1 p < 0.0001 p < 0.0001 0.08 RPV/FTC/TAF -1 - 0.25 RPV/FTC/TDF -2 Baseline W24 W48 Baseline W24 W48 Number assessed RPV/FTC/TAF RPV/FTC/TDF 184 173 175 171 168 165 187 176 178 174 172 168 ≥ 3 % BMD increase at W48 RPV/FTC/TAF 16% EFV/FTC/TDF 4% 27% 11% p < 0.001 GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Fasting lipids changes at W48 Increases in total cholesterol, direct LDL, HDL and triglycerides in the RPV/FTC/TAF group Stable in the RPV/FTC/TDF group Change in total cholesterol:HDL-cholesterol ratio: similar in both groups Introduction of lipid-lowering agent between baseline and W48: 4% in the RPV/FTC/TAF group vs 1% in the RPV/FTC/TDF group (p = 0.067) GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204

GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF ARV-trial.com GS-US-366-1216 Study: Switch RPV/FTC/TDF to RPV/FTC/TAF Conclusion Overall, virally suppressed, HIV-1 infected participants who switched to rilpivirine, emtricitabine, and tenofovir alafenamide maintained viral suppression at 48 weeks with low rates of virological failure, good tolerability, and improvements in measures of bone and renal safety compared with rilpivirine, emtricitabine, and tenofovir disoproxil fumarate GS-US-366-1216 Orkin C. Lancet HIV 2017 ; 4:e195-204