Introduction ♦ The single-tablet regimen bictegravir (BIC; B), emtricitabine (FTC; F), and tenofovir alafenamide (TAF; B/F/TAF) is an EACS, US Dept of Health & Human Services, and International Antiviral Society–USA guidelines-recommended regimen, 1-3 with demonstrated safety and efficacy, and a high barrier to resistance ♦ We report long-term (Week 144) results pooled from two Phase 3 studies of treatment-naïve adults living with HIV comparing randomized treatment with B/F/TAF to 1 of 2 recommended dolutegravir (DTG)‒containing regimens: DTG/abacavir (ABC)/lamivudine (3TC) in Study 1489 and DTG + F/TAF in Study 1490 Objectives ♦ To evaluate the safety and efficacy of B/F/TAF and DTG- containing regimens in treatment-naïve adults living with HIV based on a pooled analysis from two Phase 3 studies Methods Results ♦ Differences in HIV-1 RNA <50 copies/mL by FDA Snapshot at Week 144: – Study 1489: -2.6% (95% confidence interval [CI] -8.5%, 3.4%) – Study 1490: -1.9% (-7.8%, 3.9%) ♦ B/F/TAF was noninferior to DTG-containing regimens in each of the individual studies ♦ Per-protocol analysis of HIV-1 RNA <50 copies/mL: – Overall population: B/F/TAF 100% vs DTG/ABC/3TC 99% vs DTG + F/TAF 99% – HIV RNA >100,000 copies/mL at baseline: B/F/TAF 100% vs DTG/ABC/3TC 97% vs DTG + F/TAF 100% – CD4 <200 cells/µL at baseline: B/F/TAF 100% vs DTG/ABC/3TC 92% vs DTG + F/TAF 100% ♦ No treatment-emergent resistance to any components of the regimens was detected in any treatment group ♦ 1 participant with baseline DTG resistance (Q148H + G140S) was randomized to B/F/TAF, suppressed <50 copies/mL at Week 4, and remained suppressed at Week 144 ♦ B/F/TAF had lower rates of study drug-related AEs, nausea, and study drug-related nausea than DTG/ABC/3TC (p <0.001) ♦ An AE of weight increase was reported for B/F/TAF 3%, DTG/ABC/3TC 4%, and DTG + F/TAF 3%, and weight decrease for B/F/TAF 1%, DTG/ABC/3TC 1%, and DTG + F/TAF 3% ♦ Changes in eGFR were consistent with inhibition of tubular creatinine secretion via organic cation transporter-2 by DTG or BIC ♦ There were no D/Cs due to renal AEs in B/F/TAF or DTG + F/TAF group ♦ There was 1 D/C due to renal failure in DTG/ABC/3TC group not attributed to study drug ♦ There were no cases of proximal renal tubulopathy reported in any group ♦ Changes in BMD from baseline were similar between groups ♦ Fasting lipids increased in all groups after treatment initiation ♦ Differences between groups in changes from baseline in fasting lipids were not clinically relevant ♦ Similar percentages of participants in each group received lipid-modifying agents at study entry (B/F/TAF 5.0%, DTG/ABC/3TC 2.2%, and DTG + F/TAF 5.5%) and initiated treatment during the study (B/F/TAF 4.7%, DTG/ABC/3TC 5.1%, and DTG + F/TAF 4.9%) Presented at 17th European AIDS Conference, November 6–9, 2019, Basel, Switzerland © 2019 Gilead Sciences, Inc. All rights reserved. 1:1 1:1 Study 1489 (ClinicalTrials.gov NCT02607930) ■ HLA B*5701 negative ■ Negative for chronic HBV ■ eGFR CG ≥50 mL/min 48 Week 0 n=314 n=315 Study 1490 (NCT02607956) n=320 n=325 Treatment-Naïve Adults 96 2° Endpoint 2° Endpoint 1° Endpoint B/F/TAF qd DTG/ABC/3TC qd DTG/ABC/3TC placebo qd B/F/TAF placebo qd B/F/TAF qd DTG + F/TAF qd DTG + F/TAF placebo qd B/F/TAF placebo qd 144 +96 Open-label B/F/TAF Open-label B/F/TAF ■ Chronic HBV or HCV infection allowed ■ eGFR CG ≥30 mL/min Key inclusion criteria for both: ■ No known resistance to FTC, TAF, ABC, or 3TC ■ HIV-1 RNA ≥500 copies/mL Study Designs eGFR CG , estimated glomerular filtration rate by Cockcroft-Gault equation; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA, human leukocyte antigen. 113 (18%) 42 34 12 6 6 5 5 3 B/F/TAF n=634 Randomized: N=1288 Randomized and not treated: n=9 Reason for D/C, n Lost to follow-up Participant decision Investigator’s discretion AE Pregnancy Death Protocol violation Noncompliance 48 (15%) 16 15 2 5 0 1 3 6 47 (14%) 14 13 2 6 3 4 1 4 n=521 n=267 n=278 Remain on treatment Randomized and not treated: n=5 DTG/ABC/3TC n=315 DTG + F/TAF n=325 Pooled Participant Disposition From Baseline to Week 144 AE, adverse event; D/C, discontinuation. B/F/TAF DTG/ABC/3TC DTG + F/TAF Participants, n n=634 n=315 n=325 Met criteria for resistance testing* 8 6 7 NRTI resistance detected 0 0 0 INSTI resistance detected 0 0 0 Overall Virologic Resistance Results at Week 144 *Performed for participants with confirmed HIV-1 RNA ≥50 copies/mL, with confirmation sample being ≥200 copies/mL or ≥200 copies/mL at last visit, and no resuppression of HIV-1 RNA to <50 copies/mL while on study drug. INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor. Overall B/F/TAF DTG/ABC/3TC DTG + F/TAF All Grades n=634 n=315 n=325 ≥10% of any group Diarrhea 19 18 16 Headache 16 18 18 Nasopharyngitis 14 17 19 Upper respiratory tract infection 14 19 16 Nausea* 11 24 13 Syphilis 11 16 10 Back pain 10 12 12 Fatigue 10 12 11 Insomnia 9 11 7 Oropharyngeal pain 7 11 6 Any drug-related AE* 26 42 29 AEs occurring in ≥5% of any group Nausea* 4 18 5 Headache 5 5 3 Diarrhea 5 4 3 Adverse Events Through Week 144 *p <0.001: B/F/TAF vs DTG/ABC/3TC based on Fisher exact test. Overall 6 deaths reported: • Cardiac arrest during septic shock (Day 28) • Gastric adenocarcinoma (Day 376) • Hypertensive heart disease and congestive heart failure (Day 412) • Suicide (Day 656) • Recreational drug overdose (Day 771) • Sudden cardiac death (Day 1060) 4 deaths reported: • Unknown cause (Day 174) • Pulmonary embolism (Day 266) • Lymphoma (Day 422) • Unknown cause (Day 771) 1 death reported: • Recreational drug overdose (Day 812) B/F/TAF DTG/ABC/3TC DTG + F/TAF n=634 n=315 n=325 n=6 (1%) n=5 (2%) n=6 (2%) Cardiac arrest (Day 28) Nausea and generalized rash (Day 4)* Erythema and pruritus (Day 112) Atypical chest pain (Day 31)* Thrombocytopenia (Day 50)* Depression (Day 420)* Sleep disorder, dyspepsia, tension headache, depressed mood, and Steatorrhea (Day 134)* Lipoatrophy (Day 464)* insomnia (Day 65)* Paranoia (Day 302) Depression (Day 248)* Depression (Day 532)* Abdominal distension (Day 304)* Renal failure (Day 621) Supraventricular tachycardia (Day 597) Depression (Day 337)* Large B-cell lymphoma (Day 1009) Adverse Events Leading to Discontinuation Through Week 144 *Considered study drug-related by investigator. 92 88 82 1 1 <1 7 12 18 93 90 84 3 2 3 4 8 13 0 20 40 60 80 100 Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 HIV-1 RNA <50 Copies/mL HIV-1 RNA ≥50 Copies/mL No HIV-1 RNA Data Participants, % B/F/TAF (n=314) DTG/ABC/3TC (n=315) B/F/TAF (n=320) DTG + F/TAF (n=325) 89 84 82 4 4 5 6 12 13 93 86 84 1 3 3 6 11 13 0 20 40 60 80 100 Participants, % HIV-1 RNA <50 Copies/mL HIV-1 RNA ≥50 Copies/mL No HIV-1 RNA Data Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 Virologic Outcome by FDA Snapshot at Weeks 48, 96 and 144: Full Analysis Set Study 1489 -60 -40 -20 0 20 40 60 80 β2-Microglobulin:Creatinine p=0.41 Retinol Binding Protein:Creatinine p=0.83 Urine Albumin:Creatinine p=0.94 81 μg/g 81 μg/g Baseline Ratios 5.5 mg/g 5.4 mg/g B/F/TAF DTG/ABC/3TC Median % Change From Baseline (Q1, Q3) 108 μg/g 110 μg/g 3 -2 20 15 -26 -34 % Change From Baseline in Quantitative Proteinuria at Week 144: Study 1489 Difference in % change from baseline for each marker tested between treatment groups by Wilcoxon rank sum test; urine protein tests performed for Study 1489 only. B/F/TAF n=304 284 281 264 243 DTG/ABC/3TC n=299 287 283 266 244 -2 -1 0 1 2 0 48 96 144 -2 -1 0 1 2 0 48 96 144 −0.4% +0.0% −1.0% −1.3% p=0.26 p=0.39 Week Week B/F/TAF DTG/ABC/3TC Hip Spine n=300 278 275 258 236 n=297 285 279 265 240 Mean % Chnage From Baseline (95% Cl) % Change in Spine and Hip BMD Through Week 144: Study 1489 Comparison of B/F/TAF vs DTG/ABC/3TC at Week 144 by analysis of variance model; bone mineral density (BMD) measured by dual-energy x-ray absorptiometry in Study 1489 only. Week 144 0 1 2 3 4 5 157 162 161 99 101 99 42 42 43 95 96 95 0 40 80 120 160 200 Median Total Cholesterol:HDL Fasting Lipid Component Total Cholesterol LDL Cholesterol Triglycerides HDL Cholesterol p=0.23 p=0.001 0 -0.3 -0.1 3.4 3.6 +5 +5 +2 +4 +6 +5 +20 +14 +19 p=0.51 p=0.35 p=0.33 p=0.43 p=0.06 p=0.005 p=0.01 p=0.56 +13 +10 +12 3.7 B/F/TAF DTG + F/TAF DTG/ABC/3TC Baseline B/F/TAF DTG + F/TAF DTG/ABC/3TC Median, mg/dL Change From Baseline in Fasting Lipids at Week 144: Overall p-values from 2-sided Wilcoxon rank-sum test to compare changes from baseline between treatment groups. HDL, high-density lipoprotein. B/F/TAF DTG/ABC/3TC DTG + F/TAF ≥5% of Any Overall Group, % n=634 n=315 n=325 Any Grade 3 or 4 lab abnormality 26 25 23 Increased creatine kinase 7 8 4 Increased fasting LDL 4 5 6 Overall Laboratory Abnormalities Through Week 144 LDL, low-density lipoprotein. -2 0 2 4 6 8 10 0 24 48 72 96 120 144 -2 0 2 4 6 8 10 0 24 48 72 96 120 144 Study 1489 Study 1490 Week Week +5.0 kg +3.5 kg +4.1 kg +4.4 kg B/F/TAF DTG/ABC/3TC DTG + F/TAF Median Weight Change, kg (Q1, Q3) Study 1490 Study 1489 B/F/TAF DTG/ABC/3TC B/F/TAF DTG + F/TAF Week 144 n=314 n=315 n=320 n=325 Participants, % ≥5% weight gain 52 48 53 55 ≥10% weight gain 29 25 30 32 Weight loss or no change from baseline 24 26 21 22 Mean weight change from baseline, kg (SD) 5.3 (9.2) 4.3 (7.8) 5.6 (8.3) 5.7 (7.8) Weight Change Through Week 144 Q, quartile; SD, standard deviation. 0 10 -10 -20 0 12 24 36 48 60 72 84 96 108 120 132 144 4 8 -9 mL/min -11 mL/min -11 mL/min B/F/TAF DTG/ABC/3TC DTG + F/TAF Median eGFR CG Change From Baseline, mL/min (Q1, Q3) Week Change From Baseline in eGFR Through Week 144: Overall Differences at Week 144 between B/F/TAF and DTG/ABC/3TC, p=0.13; and B/F/TAF vs DTG + F/TAF, p=0.28; p-values from 2-sided Wilcoxon rank-sum test. 82 3 16 84 3 13 84 3 13 0 20 40 60 80 100 n= 518 634 265 315 273 325 17 634 9 315 10 325 99 634 41 315 42 325 B/F/TAF DTG + F/TAF DTG/ABC/3TC Participants, % HIV-1 RNA <50 Copies/mL HIV-1 RNA ≥50 Copies/mL No Data in Analysis Window Pooled Virologic Outcomes by FDA Snapshot at Week 144 Study 1490 Study 1489 Pooled B/F/TAF B/F/TAF DTG/ABC/3TC B/F/TAF DTG + F/TAF n=634 n=314 n=315 n=320 n=325 Median age, y (range) 32 (18‒71) 31 (18–71) 32 (18‒68) 33 (18–71) 34 (18‒77) Men, % 89 91 90 88 89 Race/ethnicity, % Black or African descent 33 36 36 30 31 Hispanic/Latino 24 23 21 26 25 Median HIV-1 RNA, 4.4 (4.0‒4.9) 4.4 (4.0‒4.9) 4.5 (4.0‒4.9) 4.4 (4.0‒4.9) 4.5 (4.0‒4.8) log 10 copies/mL (IQR) HIV-1 RNA >100,000 copies/mL, % 19 17 16 21 17 Median CD4 cell count, cells/μL (IQR) 442 (293‒590) 443 (299‒590) 450 (324‒608) 440 (289‒591) 441 (297‒597) CD4 count <200 cells/μL, % 13 11 10 14 10 Asymptomatic HIV infection, % 90 91 91 89 89 Median eGFR CG , mL/min (IQR) 122 (104‒143) 126 (108‒146) 123 (107‒144) 120 (101‒142) 121 (103‒145) Baseline Characteristics CD4, cluster of differentiation-4; IQR, interquartile range. Long-term Efficacy and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in ART-Naïve Adults Chloe Orkin, 1 Paul E. Sax, 2 Jose Arribas, 3 Samir Gupta, 4 Claudia Martorell, 5 Jeffrey L. Stephens, 6 Hans-Jürgen Stellbrink, 7 Edwin DeJesus, 8 Franco Maggiolo, 9 Hailin Huang, 10 Rima Acosta, 10 Diana M. Brainard, 10 Sean E. Collins, 10 Hal Martin, 10 on behalf of the Study 1489 and 1490 Investigators 1 Barts Health NHS Trust, London, UK; 2 Brigham and Women’s Hospital, Boston, Massachusetts, USA; 3 Hospital Universitario La Paz, Madrid, Spain; 4 Indiana University School of Medicine, Indianapolis, Indiana, USA; 5 Infectious Disease and The Research Institute, Springfield, Massachusetts; 6 Mercer University School of Medicine, Macon, Georgia, USA; 7 ICH Study Center, Hamburg, Germany; 8 Orlando Immunology Center, Orlando, Florida, USA; 9 ASST Papa Giovanni XXIII, Bergamo, Italy; 10 Gilead Sciences, Inc., Foster City, California, USA PE3/14 Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 800-445-3235 References: 1. EACS European AIDS Clinical Society. Guidelines Version 9.1, October 2018. https://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf; 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Dep of Health and Human Services. https://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL003510.pdf; 3. Saag MS, et al. JAMA 2018;320:379-96. Acknowledgments: We extend our thanks to the participants, their partners and families, and all Study 1489 and 1490 investigators and staff: Study 1489: Albrecht H, Angel J, Antinori A, Arribas Lopez JR, Asmuth DM, Baumgarten A, Bennani Y, Benson P, Berhe M, Bordon J, Brar I, Brinson C, Brunetta J, Charest L, Cindrich R, Clarke A, Clotet B, Cook P, Cotte L, Coulston DR, Crofoot GE, Cruickshank FA, Cunningham D, Daar E, DeJesus E, De Wet JJ, Dietz C, Edelstein H, Estrada Perez V, Fichtenbaum C, Flamm J, Gallant J, Gathe JC, Girard P-M, Grossberg R, Gupta S, Hagins D, Hardy W, Hare CB, Henn S, Henry WK, Hileman C, Hite A, Hsiao CB, Jain M, Johnson M, Kasper K, Kinder CA, Klein D, Koenig E, Lazzarin A, LeBlanc R, LeBouche B, Lucasti C, Maggiolo F, Mallolas Masferrer J, Mayer C, McDonald C, McGowan JP, Meybeck A, Mills A, Miralles Alvarez C, Molina J-M, Moreno Guillen S, Mounzer K, Newman C, Orkin C, Osiyemi O, Palmieri PJ, Para M, Parks DA, Parsons C, Petroll A, Pierone G, Podzamczer D, Polk C, Portilla Sogorb J, Post F, Pozniak A, Prelutsky DJ, Pugliese P, Rachlis A, Ramgopal MN, Rashbaum BS, Richmond GJ, Roman A, Roberts A, Rockstroh J, Ross JD, Ruane PJ, Rubio Garcia R, Saag M, Santana-Bagur JL, Santiago Colon L, Schrader S, Scribner A, Shalit P, Shamblaw DJ, Shon A, Sims J, Slim J, Stellbrink H-J, Stephan C, Tebas P, Thompson MA, Towner WJ, Ustianowski A, Van Dam C, Vanderkerckhove L, Vandercam B, Vanig T, Voskuhl G, Wade BH, Walker D, Waters L, Wilkin A, Wohl DA, Wohlfeiler M, Workowski K, Wurapa A, Yazdanpanah Y, Young B, Zurawski C; Study 1490: Akil B, Albrecht H, Anday N, Angel J, Antinori A, Arastéh K, Arribas Lopez JR, Asmuth DM, Bartczak J, Bellos NC, Benson P, Berenguer J, Berger DS, Berhe M, Bloch M, Brar I, Brinson C, Brunetta J, Colson A, Cook PP, Coulston DR, Cox JJ, Creticos C, Crofoot GE Jr, Cruickshank FA, Cunningham DL, DeJesus E, Dietz C, Dronda F, Esser S, Fichtenbaum C, Flamm J, Florence E, Fox J, Gathe JC Jr, Gupta SK, Hagins DP, Hardy WD, Hassler SK, Hay P, Hsiao C-B, Hsu R, Jäger H, Jain M, Jayaweera DT, Johnson M, Johnson MA, Jordan WC, Kasper K, Kinder CA, Klein D, Koenig E, Lazzarin A, Lehmann C, Lutz T, Maggiolo F, Martorell CT, Mauss S, Mayer CA, McDonald C, McGowan J, McMahon J, Meybeck A, Mills A, Miralles Alvarez C, Mogyoros M, Moore R, Morales-Ramirez JO, Mounzer K, Nahass RG, Oguchi G, Orkin CM, Osiyemi O, Palacios R, Palmieri PJ, Parks D, Peyrani P, Podzamczer D, Portilla Sogorb J, Post FA, Pozniak AL, Prelutsky DJ, Pugliese P, Pulido F, Ramgopal M, Rashbaum B, Reynes J, Richmond GJ, Roberts A, Ross J, Roth N, Ruane PJ, Santiago Colon L, Sax PE, Scarsella AJ, Schembri G, Schmidt M, Scribner A, Shalit P, Sims J III, Sinclair G, Slim J, Sokol-Anderson ML, Stein DK, Stellbrink H-J, Stephan C, Stephens J, Taylor S, Tebas-Medrano P, Thompson MA, Towner WJ, Ustianowski AP, Van Dam C, Vandekerckhove L, Vanig TJ, Wade BH, Walmsley S, Warduglas J, Waters LJ, Wheeler DA, Wiberg K, Wilkin AM, Wohl D, Wohlfeiler MB, Woolley I, Workowski K, Wurapa AK, Yazdanpanah Y. Special thanks to the 1489 and 1490 study teams. These studies were funded by Gilead Sciences, Inc. ♦ At Week 144, B/F/TAF remained noninferior to either DTG-based triple therapy regimen in treatment-naïve participants with high rates of virologic suppression in all treatment arms ♦ There was no treatment-emergent resistance to any of these triple-therapy treatment regimens ♦ B/F/TAF was associated with fewer treatment-related AEs than DTG/ABC/3TC (p <0.001) – Nausea and treatment-related nausea were less common with B/F/TAF vs DTG/ABC/3TC (p <0.001) ♦ Changes from baseline in BMD and renal markers for B/F/TAF were similar to DTG/ABC/3TC – There were no cases of proximal renal tubulopathy in any treatment arm – No participant discontinued B/F/TAF due to renal or bone-related AEs ♦ There were no clinically relevant differences between arms in median changes from baseline in fasting lipids and no differences in proportions initiating lipid-lowering medications ♦ This 3-year long-term follow-up demonstrates treatment with B/F/TAF was effective, and may offer better safety and tolerability over other guideline-recommended regimens Conclusions Study 1490
