Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Older Adults: Week 96 Results
Collecting data on the long-term safety of B/F/TAF regimen in older HIV patients is crucial due to increased co-morbidities and polypharmacy risks. This study presents Week 96 outcomes from an open-label trial, emphasizing the regimen's safety profile and efficacy through secondary endpoints. Baseline characteristics and key inclusion criteria reflect the importance of assessing ART tolerability in the elderly population.
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Switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in adults aged 65 years or older: Week 96 results from an international, phase 3b, open-label trial (GS-US-380-4449) Maggiolo F, Rizzardini G, Molina JM, Pulido F, De Wit S, Vandekerckhove L, Berenguer J, Blair C, Chuck S, Piontkowsky D, Martin H, McNicholl I, Haubrich R, Gallant J
Background Because 50% of people living with HIV (PLWH) are > 50 years old, collecting and evaluating data on long term safety in older patients is important. Older PLWH are at increased risk of co-morbidities and polypharmacy, so ensuring the safety and tolerability of ART in this population is critical with regimens with lower drug-drug interaction potential. Declines in bone mineral density and renal function are or have been associated with aging; establishing the safety of TAF-based regimens in this population is important. B/F/TAF is a small single-tablet regimen with few drug-drug interactions and a high barrier to resistance. Tenofovir alafenamide (TAF) is a prodrug of tenofovir associated with 90% lower tenofovir plasma levels than tenofovir disoproxil fumarate (TDF), resulting in less renal and bone toxicity. 2
Study Design Multicenter, open-label, 96-week single arm HIV-infected Stable ART for 3 months Prior enrollment in E/C/F/TAF study 292-1826 or currently on E/C/F/TAF (or FTC/TDF + 3rd agent) N = 86 B/F/TAF 96 weeks 48 weeks Study sites in Belgium, France, Italy, Spain and the United Kingdom Primary endpoint: HIV RNA < 50 copies/mL at Week 24 by FDA Snapshot algorithm Secondary endpoints: HIV-1 RNA < 50 copies/mL at Weeks 48, 72 and 96 Safety and tolerability of B/F/TAF through 96 weeks 3
Key Inclusion Criteria Age 65 years at screening Currently receiving an antiretroviral regimen of E/C/F/TAF single tablet regimen (or FTC/TDF + 3rd agent if current or past participant in GS-US-292-1826) for 3 months* Documented plasma HIV-1 RNA < 50 copies/mL on current regimen for the last 2 visits preceding the Screening Visit Transient detectable viremia or blips (HIV-1 RNA 50 and < 400 copies/mL) were acceptable Estimated GFR 30 mL/min (Cockcroft-Gault formula) *Study GS-US-292-1826 was an international open label, randomized 48-week study of the efficacy and safety of switching from a TDF-based regimen to E/C/F/TAF in 167 participants 60 years and older 4
Baseline Demographics and Disease Characteristics B/F/TAF N=86 69 (65-80) 13% (11) Median age, years (range) Female, % (n) Race, % (n)* White 99% (82) Black 1% (1) Ethnicity, Hispanic/Latinx, % (n) 14% (12) Median weight (kg) (range) 78 (49-110) Median estimated GFRCG, mL/min (range) 76 (40-130) Mode of Infection, % (n) MSM 46.5% (40) Heterosexual 46.5% (40) * 3 participants did not disclose race 5
Baseline Demographics and Disease Characteristics (cont) B/F/TAF N=86 HIV RNA < 50 copies/mL at baseline, % (n) 98% (84) Median CD4 count, cells/mm3 (range) 676 (132-1385) Baseline Regimen, % (n)* EVG/COBI/FTC/TAF (E/C/F/TAF) 92% (79) RPV/FTC/TDF 5% (4) EFV/FTC/TDF 1% (1) EVG/COBI/FTC/TDF 1% (1) NVP+FTC/TDF 1% (1) * EVG-elvitegravir, COBI-cobicistat, FTC-emtricitabine, TAF-tenofovir alafenamide, RPV-rilpivirine, TDF-tenofovir disoproxil fumarate, NVP-nevirapine 6
Baseline Demographics and Disease Characteristics (cont) B/F/TAF N=86 3.0 (2, 5) Number of chronic non-ARV medications at baseline, median (IQR) Baseline number of chronic medications by organ-system class, % (n) Cardiovascular system 64% (55) Gastrointestinal tract 63% (54) Nervous system 44% (38) Blood and blood forming organs 27% (23) Musculoskeletal system 23% (20) Genitourinary system and sex hormones 21% (18) IQR-interquartile range 7
Virologic Outcomes at Week 96 (Snapshot Analysis) 100 Participants (%) 74 80 60 40 26 20 0 0 HIV-1 RNA <50 c/mL N=64 No Virologic Data HIV-1 RNA 50 c/mL N=0 N=22 No participant had an HIV-1 RNA 50 c/mL Median change in CD4 count was -3 cells/mm3 (IQR: -59, 91) at W96 (n=59) Due to the COVID-19 pandemic, 11 participants did not have data in the W96 window 8
Virologic Outcomes at Week 96 (M=E) 100 100 Participants (%) 80 60 40 20 0 0 HIV-1 RNA <50 c/mL N=68 HIV-1 RNA 50 c/mL N=0 Eleven participants did not have data due to the COVID-19 pandemic and restrictions on clinic/study visits; all were suppressed at their last visit. 9
Virologic Outcomes at Week 96 by FDA Snapshot B/F/TAF N=86 64 (74%) HIV-1 RNA < 50 c/mL HIV-1 RNA 50 c/mL HIV-1 RNA 50 c/mL in W96 Window DC Study Drug Due to Lack of Efficacy DC Study Drug Due to AE and Last Available HIV-1 RNA 50 c/mL DC Study Drug Due to Other Reasons and Last Available HIV-1 RNA 50 c/mL 0 0 0 0 0 No Virologic Data in W96 Window DC Study Drug Due to AE/Death and Last Available HIV-1 RNA < 50 c/mL DC Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 c/mL Missing Data During Window but on Study Drug 22 (26%)* 7 (8%) 2 (2%) 13 (15%) * Eleven participants did not have data due to the COVID-19 pandemic and restrictions on clinic/study visits. 1) abdominal discomfort (grade 2, drug-related), 2) alcohol withdrawal, 3) benzodiazepine withdrawal, 4) depressive disorder, 5) weight increased (grade 3, drug-related) Of the 13 subjects: 2 subjects had Week 96 visit >1 day after the last dose and an HIV-1 RNA <50 c/mL, 11 subjects missed Week 96 and did not have HIV-1 RNA assessments after Week 84 though their Week 84 HIV-1 RNA <50 c/mL 10 c/mL=copies/mL, DC=discontinued
Treatment-Emergent Adverse Events through Week 96 B/F/TAF (n=86) % (n) 4.7% (4) Any Grades 2-4 Study Drug-Related AE Any Grades 3-4 Study Drug-Related AEs Grades 3 or 4 Laboratory Abnormalities Any Study Drug-Related Serious AE 2.3% (2) 13% (11) 0 AEs Leading to Study Drug Discontinuation AEs Leading to Study Drug Discontinuation (drug-related) Death 5.8% (5)* 3.5% (3) 2 There were no renal, bone or hepatic discontinuations *1) abdominal discomfort (grade 2, drug-related), 2) alcohol withdrawal, (grade 3), 3) benzodiazepine withdrawal (grade 2), 4) irritability and sleep disorder (grade 3, drug-related), 5) weight increased (grade 3, drug related) 1) 77 yo male with pre-existing depressive disorder led to suicide via a benzodiazepine overdose (study day 427), 2) 72 yo male developed pneumonia secondary to COVID-19 infection (study day 672); Neither death study drug-related 11
Weight: Median Change from Baseline through Week 96 5 Median (Q1, Q3) change 4 0 0 0 1.0 0.1 0 0 0 0 from Baseline (kg) 3 2 1 0 -1 -2 -3 -4 -5 0 4 12 24 36 48 Week 60 72 84 96 N= 86 86 84 84 82 79 83 81 80 67 Median change in weight at Week 96 was 0.0 kg (IQR -2.3, 2) 12
Renal Biomarker Changes (%) at Week 96 RBP:Cr 65 139.3 2m:Cr 64 72.0 N Baseline (ug/g) Median percent change (Q1, Q3) 250 200 150 100 50 0 -50 -16.4 18.7 8% of participants switched from a TDF-based regimen to B/F/TAF 13 *RBP:Cr, retinol-binding protein/creatinine; 2m:Cr, urine beta-2-microglobulin/creatinine
Estimated Glomerular Filtration Rate: Median Changes from Baseline through Week 96 Median (Q1, Q3) change from 5 0 Baseline (mL/min) -5 -10 -15 -20 0 4 12 24 36 48 60 72 84 96 Week N= 86 84 84 84 82 79 82 78 79 66 eGFRCG decline is consistent with known inhibition of OCT2 creatinine transporter eGFRCg, estimated glomerular filtration rate calculated with Cockcroft-Gault equation 14
Changes in Fasting Lipids at Week 96 B/F/TAF (N=56) Total LDL HDL Triglycerides Total Cholesterol:HDL Cholesterol Cholesterol Cholesterol 35 Median Change from 1 25 Baseline, mg/dL 15 0.5 5 -5 -1 0 -10 -15 -15 -19 -0.2 -25 -0.5 191 117 51 131 Baseline, mg/dL 3.9 Participants on lipid-modifying medication At baseline: 36 (42%) Initiated during study: 6 (7%) 15
Conclusion In this largest, international, Phase 3b study of virologically suppressed adults 65 years, switching to B/F/TAF was shown to be safe, effective and well tolerated through 96 weeks High virologic suppression when accounting for COVID-related study challenges with participant follow-up No virologic failures and no treatment-emergent resistance No renal, bone, or hepatic AEs resulting in discontinuation Few drug-related AEs leading to discontinuation No serious drug-related AEs eGFR decline consistent with known inhibition of OCT2 creatinine transporter Median weight stable Highly efficacious and well tolerated in the setting of co-morbidities and polypharmacy 16
Acknowledgments We extend our thanks to the participants, their partners and families, and all GS-US-380-4449 Investigators F Ajana, A Antinori, J Berenguer, JI Bernardino de la Serna, A Bonjoch, E Cua, S de Wit, A Di Biagio, G Di Perri, C Duvivier, PM Girard, E Lazaro, G Madeddu, F Maggiolo, J Mallolas Masferrer, GM Mateo Garc a, B Menzaghi, JM Molina, P Morlat, C Mussini, J Navarro, E Ong, G Parruti, B Payne, J Perez Stachowski, P Philibert, L Piroth, F Pulido, T Quirino, F Raffi, G Rizzardini, JD Ross, D Salmon-Ceron, L Vandekerckhove, L Waters This study was funded by Gilead Sciences, Inc. 17
