Brian R. Wood, MD David H. Spach, MD Last Updated: December 22, - - PowerPoint PPT Presentation

▶
brian r wood md
SMART_READER_LITE
LIVE PREVIEW

Brian R. Wood, MD David H. Spach, MD Last Updated: December 22, - - PowerPoint PPT Presentation

Apr 03, 2024 395 likes •703 views

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 to zah]

slide-1
SLIDE 1

Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine (Symtuza) Prepared by: Brian R. Wood, MD David H. Spach, MD

Last Updated: December 22, 2019

slide-2
SLIDE 2

Darunavir-Cobicistat-Tenofovir Alafenamide-Emtricitabine (Symtuza)

Source: Image courtesy of Janssen Therapeutics, Division of Janssen Products, LP

Booster NRTI NRTI

Symtuza

[sim toó zah]

Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine

PI

10 mg 200 mg 800 mg 150 mg

slide-3
SLIDE 3

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%)
slide-4
SLIDE 4
  • 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

Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine Summary of Key Studies

slide-5
SLIDE 5

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102

slide-6
SLIDE 6

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102: Design

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

DRV/COBI/FTC/TAF (TAF group)

(n = 103)

DRV + COBI + TDF-FTC (TDF group)

(n = 50)

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 compared with DRV + COBI + TDF-FTC for treatment-naïve individuals

  • Inclusion Criteria (n=153)
  • Age > 18
  • Antiretroviral-naïve
  • CD4 count >50 cells/mm3
  • HIV RNA ≥ 5,000 copies/mL
  • eGFR ≥ 70 mL/min
  • Genotypic sensitivity to DRV, TDF, FTC
  • No hepatitis B or C
  • Not pregnant
  • No AIDS-defining condition within 30 days

1x 2x

slide-7
SLIDE 7

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

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

75 77 74 84

20 40 60 80 100

24 weeks 48 weeks HIV RNA < 50 copies/mL (%) DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

77/103 37/50 79/103 42/50

slide-8
SLIDE 8

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102: Results

Week 48: Change in Urinary Markers of Tubular Dysfunction

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

9

  • 42

54 2.3

  • 100
  • 50

50 100 RBP/Cr β-2 microglobulin/Cr Change from Baseline (%) DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

RBP/Cr = retinol binding protein-to-creatinine ratio β-2 microglobulin/Cr = β-2 microglobulin-to-creatinine ratio

slide-9
SLIDE 9

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102: Results

Week 48: Change in Bone Mineral Density

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

  • 0.84
  • 1.57
  • 3.82
  • 3.62
  • 5
  • 4
  • 3
  • 2
  • 1

Hip Lumbar spine Change from Baseline (%) DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

slide-10
SLIDE 10

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102: Results

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

Median Change in Fasting Metabolic Assessments at Week 48 DRV/COBI/FTC/TAF TAF group

(n = 103)

DRV/COBI + TDF-FTC TDF group

(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

slide-11
SLIDE 11

DRV-COBI-TAF-FTC versus DRV-COBI plus TDF-FTC

GS-299-0102: Conclusions

Source: Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-45.

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.”

slide-12
SLIDE 12

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC

AMBER

slide-13
SLIDE 13

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Design

Source: Eron JJ, et al. AIDS. 2018;32:1431-42.

DRV-COBI-TAF-FTC + 2 placebo tabs

(n = 362)

DRV-COBI + TDF-FTC + placebo tab

(n = 363)

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 compared with DRV-COBI + TDF-FTC for treatment-naïve individuals

  • Inclusion Criteria (n=725)
  • Age > 18
  • Antiretroviral-naïve
  • CD4 count >50 cells/mm3
  • HIV RNA ≥ 1,000 copies/mL
  • eGFR ≥ 70 mL/min
  • Genotypic sensitivity to DRV, TDF, and FTC
  • No hepatitis B or C
  • Not pregnant
  • No AIDS-defining condition within 30 days

1x 1x

slide-14
SLIDE 14

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Results

Week 48: Virologic Response by FDA Snapshot Analysis, ITT

Source: Eron JJ, et al. AIDS. 2018;32:1431-42. 91.4 91.7 89.8 88.4 90.4 80.0

20 40 60 80 100 Overall ≤100,000 copies/mL >100,000 copies/mL HIV RNA < 50 copies/mL (%)

Baseline HIV RNA

DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

331/362 321/363 278/303 265/293 53/59 56/70

slide-15
SLIDE 15

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Results

Week 48: Change in Serum Creatinine and Estimated GFR

Source: Eron JJ, et al. AIDS. 2018;32:1431-42.

4.8

  • 5.9

5.3 8.2

  • 9.3

2.9

  • 15
  • 10
  • 5

5 10 15 Change in Serum Cr Change in eGFR (Cr) Change in eGFR (Cyst)

Mean Change from Baseline

DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

Cr = creatinine (measured in µmol/L) eGFR = estimated glomerular filtration rate (measured in mL/min/1.73m2, calculated using CKD-EPI) Cyst = cystatin C

slide-16
SLIDE 16

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Results

Week 48: Change in Urinary Markers of Tubular Dysfunction

Source: Eron JJ, et al. AIDS. 2018;32:1431-42. UPCR = urine protein to creatinine ratio; UACR = urine albumin to creatinine ratio RBP:Cr = retinol binding protein to creatinine ratio; β2M:Cr = beta-2-microglobulin to creatinine ratio

Mean Change in Markers of Proximal Tubulopathy at Week 48 DRV-COBI-TAF-FTC

(n = 362)

DRV-COBI + TDF-FTC

(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

slide-17
SLIDE 17

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Results

Week 48: Percentage Change in Bone Mineral Density

Source: Eron JJ, et al. AIDS. 2018;32:1431-42.

0.2

  • 0.7
  • 0.3
  • 2.7
  • 2.4
  • 3.0
  • 5.0
  • 2.5

0.0 2.5 5.0 Hip Lumbar spine Femoral neck Change from Baseline (%) DRV-COBI-TAF-FTC DRV-COBI + TDF-FTC

This is from a bone mineral density substudy (n = 113 participants in TAF arm, 99 in control arm)

slide-18
SLIDE 18

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Results

Source: Eron JJ, et al. AIDS. 2018;32:1431-42.

Median Change in Fasting Lipid Parameters at Week 48 DRV-COBI-TAF-FTC

(n = 362)

DRV-COBI + TDF-FTC

(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

slide-19
SLIDE 19

DRV-COBI-TAF-FTC vs DRV-COBI + TDF-FTC as Initial ART

AMBER: Conclusions

Source: Eron JJ, et al. AIDS. 2018;32:1431-42.

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.”

slide-20
SLIDE 20

DRV-COBI-TAF-FTC vs Continue Boosted PI + TDF-FTC

EMERALD

slide-21
SLIDE 21

DRV-COBI-TAF-FTC vs Continue Boosted PI + TDF-FTC

EMERALD: Design

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

Switch Group DRV-COBI-TAF-FTC

(n = 763)

Continue Group Boosted PI + TDF-FTC

(n = 378)

EMERALD: Study Design

  • Background: Randomized, open-label, active-

controlled, international, phase 3 study evaluating the efficacy and safety of switching to the single-tablet regimen DRV-COBI-TAF-FTC versus continuing a boosted PI + TDF-FTC

  • Inclusion Criteria (n=1,141)
  • Age >18
  • Antiretroviral-experienced
  • HIV RNA <50 copies/mL for ≥2 months*
  • No prior virologic failure on a DRV-based regimen
  • Virologic failure on non-DRV-based regimen allowed
  • 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

1x 2x

*One HIV RNA 50-200 copies/mL within prior 12 months allowed

slide-22
SLIDE 22

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Baseline Characteristics

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

EMERALD Study: Baseline Characteristics

DRV-COBI-TAF-FTC Switch Group

(n = 763)

Boosted PI + TDF-FTC Continue Group

(n = 378)

CD4 Count (cells/mL) 630 624 Time since HIV diagnosis (years) 9.3 8.9 Time since first ART (years) 6.2 5.8 Previous use of >5 ARV’s 59 58 Previous virologic failure 15 14 Boosted darunavir at screening (%) 70 70 Boosted atazanavir at screening (%) 22 22 Boosted lopinavir at screening (%) 8 8

slide-23
SLIDE 23

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Week 48: Virologic Response by FDA Snapshot Analysis, ITT

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

94.9 93.7 20 40 60 80 100 HIV RNA < 50 copies/mL (%) Switch to DRV-COBI-TAF-FTC Continue Boosted PI + TDF-FTC

724/763 354/378

slide-24
SLIDE 24

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Week 48: Virologic Outcomes

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34. 724/763 354/378

EMERALD Study Virologic Outcomes

DRV-COBI-TAF-FTC Switch Group

(n = 763)

Boosted PI + TDF-FTC Continue Group

(n = 378)

Virologic rebound rate through 48 weeks* 2.5% 2.1% HIV RNA <50 copies/mL at 48 weeks 94.9% 93.7% HIV RNA >50 copies/mL at 48 weeks 0.8% 0.5% No virologic data at 48 weeks 4.3% 5.8%

*HIV RNA >50 copies/mL or premature discontinuation with last HIV RNA >50 copies/mL

slide-25
SLIDE 25

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Week 48: Change in Serum Creatinine and Estimated GFR

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

1.3

  • 1.9
  • 0.4

0.6

  • 0.9
  • 1.9
  • 3.0
  • 2.0
  • 1.0

0.0 1.0 2.0 3.0 Change in Serum Cr Change in eGFR (Cr) Change in eGFR (Cyst) Mean Change from Baseline DRV-COBI-TAF-FTC Continue Boosted PI + TDF-FTC

Cr = creatinine (measured in µmol/L) eGFR = estimated glomerular filtration rate (measured in mL/min/1.73 m2, calculated using CKD-EPI) Cyst = cystatin C

slide-26
SLIDE 26

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Week 48: Change in Urinary Markers of Tubular Dysfunction

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34. UPCR = urine protein to creatinine ratio; UACR = urine albumin to creatinine ratio RBP:Cr = retinol binding protein to creatinine ratio; β2M:Cr = beta-2-microglobulin to creatinine ratio

Mean Change in Markers of Proximal Tubulopathy at Week 48 DRV-COBI-FTC-TAF Switch Group

(n = 763)

Boosted PI + TDF-FTC Continue Group

(n = 378)

UPCR (mg/g)

  • 33.9
  • 6.43

UACR (mg/g)

  • 3.2

1.3 RBP:Cr (mg/g)

  • 630.5

1037.1 β2M:Cr (mg/g)

  • 1454.7

1371.3

slide-27
SLIDE 27

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Week 48: Change in Bone Mineral Density

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

1.4 1.5 0.7

  • 0.3
  • 0.6
  • 0.5
  • 5.0
  • 2.5

0.0 2.5 5.0 Hip Lumbar spine Femoral neck Change from Baseline (%) Switch to DRV-COBI-TAF-FTC Continue Boosted PI + TDF-FTC

This is from a bone mineral density substudy (n = 209 participants in switch arm, 108 in control arm)

slide-28
SLIDE 28

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Results

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

Median Change in Fasting Lipid Parameters at Week 48 DRV-COBI-FTC-TAF (Switch Group)

(n = 763)

Boosted PI + TDF-FTC (Control Group)

(n = 378)

TC (mg/dL) 19.7 1.3 LDL (mg/dL) 15.7 1.9 HDL (mg/dL) 3.0

  • 1.0

TC:HDL ratio 0.2 0.1 Triglycerides (mg/dL) 6.0 5.0

TC = total cholesterol; LDL = low density lipoprotein; HDL = high density lipoprotein

slide-29
SLIDE 29

DRV-COBI-TAF-FTC vs Continue a Boosted PI + TDF-FTC

EMERALD: Conclusions

Source: Orkin C, et al. Lancet HIV. 2018;5:e23-e34.

Conclusions: “Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression.”

slide-30
SLIDE 30

Acknowledgment

The National HIV Curriculum is an AIDS Education and Training Center (AETC) Program supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) as part of an award totaling $800,000 with 0% financed with non-governmental sources. This project is led by the University of Washington’s Infectious Diseases Education and Assessment (IDEA) Program.

The content in this presentation are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS, or the U.S. Government.