Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine ( Symtuza ) Prepared by: Brian R. Wood, MD David H. Spach, MD Last Updated: December 22, 2019
Darunavir-Cobicistat-Tenofovir Alafenamide-Emtricitabine ( Symtuza) Symtuza [sim toó zah] Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine 800 mg 150 mg 10 mg 200 mg PI Booster NRTI NRTI Source: Image courtesy of Janssen Therapeutics, Division of Janssen Products, LP
Darunavir-Cobicistat-Tenofovir Alafenamide-Emtricitabine ( Symtuza) Single-Tablet Regimen • Single-Tablet Regimen Components : Darunavir: 800 mg Cobicistat: 150 mg Tenofovir alafenamide: 10 mg Emtricitabine: 200 mg • Dosing : 1 pill daily with food • With Renal or Hepatic Impairment - Not recommended if estimated CrCl <30 mL/min - Not recommended with severe hepatic impairment (Child-Pugh C) • Pregnancy : not recommended during pregnancy • Common Adverse Events (≥5%) - Diarrhea (9%), rash (8%), and nausea (6%)
Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine Summary of Key Studies • Phase 2 Trial in Treatment-Naïve Adults - GS-299-0102: DRV-COBI-TAF-FTC versus DRV-COBI + TDF-FTC • Phase 3 Trials in in Treatment-Naïve Adults - AMBER: DRV-COBI-TAF-FTC versus DRV-COBI + TDF-FTC • Phase 3 Trials in Adults with Virologic Suppression - EMERALD: Switch to DRV-COBI-TAF-FTC or stay on PI + TDF-FTC
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Design 0102:Study Design • Background : Randomized, double-blind, placebo controlled, phase 2 study evaluating the efficacy and safety of a single tablet regimen of DRV/COBI/FTC/TAF DRV/COBI/FTC/TAF compared with DRV + COBI (TAF group) + TDF-FTC for treatment-naïve individuals (n = 103) 2x • Inclusion Criteria (n=153) - Age > 18 - Antiretroviral-naïve 1x - CD4 count >50 cells/mm 3 DRV + COBI + TDF-FTC - HIV RNA ≥ 5,000 copies/mL (TDF group) - eGFR ≥ 70 mL/min (n = 50) - Genotypic sensitivity to DRV, TDF, FTC - No hepatitis B or C - Not pregnant - No AIDS-defining condition within 30 days Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Results Week 24 and 48: Virologic Response by FDA Snapshot Analysis, ITT DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 100 HIV RNA < 50 copies/mL (%) 84 77 80 75 74 60 40 20 77/103 37/50 79/103 42/50 0 24 weeks 48 weeks Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Results Week 48: Change in Urinary Markers of Tubular Dysfunction DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 100 Change from Baseline (%) 54 50 9 2.3 0 -50 -42 -100 β -2 microglobulin/Cr RBP/Cr RBP/Cr = retinol binding protein-to-creatinine ratio β -2 microglobulin /Cr = β -2 microglobulin-to-creatinine ratio Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Results Week 48: Change in Bone Mineral Density DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 0 Change from Baseline (%) -1 -0.84 -1.57 -2 -3 -3.62 -4 -3.82 -5 Hip Lumbar spine Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Results Median Change in Fasting Metabolic Assessments at Week 48 DRV/COBI/FTC/TAF DRV/COBI + TDF-FTC TAF group TDF group (n = 103) (n = 50) Total cholesterol, mg/dL 40 5 LDL, mg/dL 26 4 HDL, mg/dL 7 3 TC:HDL 0.0 -0.2 Triglycerides 29 -5 Serum glucose, mg/dL 5 2 Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI- TAF -FTC versus DRV-COBI plus TDF-FTC GS-299-0102: Conclusions Conclusions : “ The tenofovir alafenamide arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide single table regimen. This darunavir-cobicistat-emtricitabine-tenofovir alafenamide single tablet regimen offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with tenofovir alafenamide .” Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC AMBER
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Design AMBER: Study Design • Background : Randomized, double-blind, active- controlled, international, phase 3 study evaluating the efficacy and safety of the single-tablet regimen DRV-COBI-TAF-FTC + DRV-COBI-TAF-FTC compared with DRV-COBI + 2 placebo tabs TDF-FTC for treatment-naïve individuals (n = 362) 1x • Inclusion Criteria (n=725) - Age > 18 - Antiretroviral-naïve 1x - CD4 count >50 cells/mm 3 DRV-COBI + TDF-FTC + - HIV RNA ≥ 1,000 copies/mL placebo tab - eGFR ≥ 70 mL/min (n = 363) - Genotypic sensitivity to DRV, TDF, and FTC - No hepatitis B or C - Not pregnant - No AIDS-defining condition within 30 days Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Results Week 48: Virologic Response by FDA Snapshot Analysis, ITT DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 100 91.7 91.4 90.4 89.8 88.4 HIV RNA < 50 copies/mL (%) 80.0 80 60 40 20 53/59 56/70 331/362 321/363 278/303 265/293 0 ≤100,000 copies/mL Overall >100,000 copies/mL Baseline HIV RNA Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Results Week 48: Change in Serum Creatinine and Estimated GFR DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 15 Mean Change from 10 8.2 Baseline 5.3 4.8 5 2.9 0 -5 -5.9 -10 -9.3 -15 Change in Serum Cr Change in eGFR (Cr) Change in eGFR (Cyst) Cr = creatinine (measured in µmol/L) eGFR = estimated glomerular filtration rate (measured in mL/min/1.73m 2 , calculated using CKD-EPI) Cyst = cystatin C Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Results Week 48: Change in Urinary Markers of Tubular Dysfunction Mean Change in Markers of Proximal Tubulopathy at Week 48 DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC (n = 362) (n = 363) UPCR (mg/g) -22.42 -10.34 UACR (mg/g) -2.45 -0.58 RBP:Cr (μg/g) 16.84 401.12 β2M:Cr (μg/g) -100.58 837.63 UPCR = urine protein to creatinine ratio; UACR = urine albumin to creatinine ratio RBP:Cr = retinol binding protein to creatinine ratio; β 2M:Cr = beta-2-microglobulin to creatinine ratio Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Results Week 48: Percentage Change in Bone Mineral Density DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC 5.0 Change from Baseline (%) 2.5 0.2 0.0 -0.3 -0.7 -2.5 -2.4 -2.7 -3.0 -5.0 Hip Lumbar spine Femoral neck This is from a bone mineral density substudy (n = 113 participants in TAF arm, 99 in control arm) Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Results Median Change in Fasting Lipid Parameters at Week 48 DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC (n = 362) (n = 363) TC (mg/dL) 28.6 10.4 LDL (mg/dL) 17.4 5.0 HDL (mg/dL) 4.3 1.5 TC:HDL ratio 0.2 0.08 Triglycerides (mg/dL) 23.9 14.2 TC = total cholesterol; LDL = low density lipoprotein; HDL = high density lipoprotein Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART AMBER: Conclusions Conclusions : “ Darunavir-cobicistat-emtricitabine-tenofovir alafenamide achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir-cobicistat with emtricitabine-tenofovir DF. Darunavir- cobicistat-emtricitabine-tenofovir alafenamide also demonstrated the bone and renal safety advantages of tenofovir alafenamide in combination with darunavir-cobicistat. ” Source: Eron JJ, et al. AIDS. 2018;32:1431-42.
DRV-COBI-TAF-FTC vs Continue Boosted PI + TDF-FTC EMERALD
DRV-COBI-TAF-FTC vs Continue Boosted PI + TDF-FTC EMERALD: Design EMERALD: Study Design • Background : Randomized, open-label, active- controlled, international, phase 3 study evaluating the efficacy and safety of switching to the single-tablet Switch Group regimen DRV-COBI-TAF-FTC versus continuing a boosted PI + TDF-FTC DRV-COBI-TAF-FTC (n = 763) • Inclusion Criteria (n=1,141) 2x - Age >18 - Antiretroviral-experienced 1x - HIV RNA <50 copies/mL for ≥2 months* Continue Group - No prior virologic failure on a DRV-based regimen Boosted PI + TDF-FTC - Virologic failure on non-DRV-based regimen allowed (n = 378) - Taking a PI plus ritonavir or cobicistat - Regimen stable for ≥ 6 months - eGFR ≥ 50 mL/min - Not pregnant or breastfeeding - No HBV or HCV infection *One HIV RNA 50-200 copies/mL within prior 12 months allowed Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.
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