Transcript id_week_review_2015... - University of Washington

Frontier AIDS Education and Training Center
ID Week Review 2015
Brian R. Wood, MD
Assistant Professor of Medicine, University of Washington
Medical Director, Frontier AETC ECHO
October 2015
This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice
related to any specific patient.
ID Week Review 2015
1) Switching from TDF to TAF
2) Simplifying salvage therapy to E/C/F/TAF + DRV
Abbreviations:
• TDF: tenofovir disoproxil fumarate
• TAF: tenofovir alafenamide
• E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
• E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
• ATV/booster: boosted atazanavir
• DRV: darunavir
• RPV: rilpivirine
Tenofovir disoproxil fumarate (TDF) vs.
Tenofovir alafenamide (TAF)
Gut
TDF
Plasma
TDF
Lymphoid Cells
TFV
TFV
P
Cathepsin A
TFV-MP
TAF
TAF
P
TAF
TFV-DP
91% lower plasma TFV
levels with TAF
Active drug
TDF = tenofovir disoproxil fumarate; TFV = tenofovir; MP = monophosphate; DP = diphosphate
Switching from TDF to TAF
GS-109: Switching from TDF to TAF
Study Design
Protocol
- Randomized, open-label study
- HIV-infected adults with HIV RNA <50
copies/mL for >48 weeks on a TDFcontaining regimen (their 1st regimen)
Switch to E/C/F/TAF
(n = 959)
- eGFR >50 mL/min
- Total N = 1,436
- 601 TDF/FTC + ATV/booster
- 376 TDF/FTC/EFV
- 459 E/C/F/TDF
Continue current TDF-based
regimen
- Randomized 2:1
*Primary endpoint: HIV RNA <50 copies/mL at 48 weeks
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
(n = 477)
GS-109: Switch from TDF to TAF
48 Week Data: Proportion with HIV RNA <50 copies/mL
E/C/F/TAF
Prior TDF Regimen
% HIV RNA <50 copies/mL
100
97
93
96
97
90
92
P<0.001
P=0.02
P=0.02
All prior regimens
Prior
TDF/FTC/EFV
80
98 97
P=NS
60
40
20
0
Prior TDF/FTC + Prior E/C/F/TDF
ATV/booster
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
GS-109: Switch from TDF to TAF
Median % Change from
Baseline to Week 48
E/C/F/TAF
(N=306)
E/C/F/TDF
(N=153)
P Value
Urine protein:creatinine
-16.2
+13.7
<0.001
Urine albumin:creatinine
-17.7
+7.7
<0.001
Retinol binding protein:creatinine
-28.6
+27.4
<0.001
Beta-2-microglobulin:creatinine
-43.3
+20.8
<0.001
Hip bone mineral density
+1.15
-0.24
<0.001
Spine bone mineral density
+1.33
-0.50
<0.001
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
GS-109: Switch from TDF to TAF
Median Change from Baseline
to Week 48
E/C/F/TAF
(N=306)
E/C/F/TDF
(N=153)
P Value
Total cholesterol
+21
+2
<0.001
LDL
+13
-5
<0.001
HDL
+3
-1
0.01
Triglycerides
+23
-7
<0.001
Total cholesterol:HDL ratio
+0.3
+0.1
0.41
Proportion who initiated a lipid-modifying agent: 7.8% TAF arm, 6.5% TDF arm
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
GS-109: Switch from TDF to TAF
Conclusion: “At Week 48, patients who switched from E/C/F/TDF to E/C/F/TAF
remained on treatment and maintained high virologic control, had significantly
improved hip/spine BMD, serum creatinine, and had significantly less general
proteinuria and specific proximal tubular proteinuria than those remaining on
E/C/F/TDF. Longer term data are needed to understand the clinical relevance of
lipid changes in the TAF arm.”
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
Simplifying Salvage Therapy to
E/C/F/TAF + DRV
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Study Design
Protocol
- N = 136 HIV-infected adults
- Randomized, open-label study
Simplify to E/C/F/TAF + DRV
- HIV RNA <50 copies/ml for >4 months
on a DRV-containing regimen
- >2 prior episodes of virologic failure
and >2-class drug resistance
(n = 89)
Continue current ART
- No DRV RAM’s, no INSTI resistance,
<3 TAM’s, no Q151M or T69ins
(n = 46)
- eGFR >50 mL/min
- Randomized 2:1
*Abbreviations: DRV = darunavir, RAM = resistance associated mutation, INSTI = integrase strand transfer
inhibitor, TAM’s = thymidine analogue mutations
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Simplifying Salvage Therapy to E/C/F/TAF + DRV
E/C/F/TAF + DRV
(N=89)
Baseline Regimen
(N=46)
Median age, years
49
47
Male
82
61
Black (or African descent)
39
57
Median CD4 count, cells/mL
519
518
Median eGFR, mL/min (Cockroft-Gault)
99
100
Median # pills per day in ART regimen
5
5
>6 pills per day in ART regimen, %
40
37
At least BID dosing, %
65
65
Tenofovir, %
61
54
Raltegravir, %
56
50
2 class / 3 class resistance, %
70 / 26
74 / 20
M184V/I / K65R, %
85 / 20
78 / 30
NNRTI resistance / PI resistance
89 / 38
87 / 28
Characteristics
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Simplifying Salvage Therapy to E/C/F/TAF + DRV
• Concern for lower levels of elvitegravir and darunavir when
co-administered with cobicistat
• Pharmacokinetic substudy in 15 participants
• Plasma collected over 24-hour period between weeks 2-8
• Post-dose steady state concentrations of TAF, TFV,
darunavir, and elvitegravir maintained
• Trough concentrations 10-20x higher than inhibitory
concentrations
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Simplifying Salvage Therapy to E/C/F/TAF + DRV
E/C/F/TAF + DRV
Baseline regimen
100
97
% HIV RNA threshold
91
94
90
80
76
60
72
P=0.23
P=0.004
P=0.012
Week 24 (<50 copies/mL)
Week 48 (<50 copies/mL)
Week 48 (<20 copies/mL)
40
20
0
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Simplifying Salvage Therapy to E/C/F/TAF + DRV
E/C/F/TAF +
DRV (N=89)
Baseline
Regimen
(N=46)
P Value
eGFR
+7.4
+3.9
0.18
Urine protein:creatinine
-27
+5
<0.001
Retinol binding protein:creatinine
-17
+14
<0.001
Beta-2-microglobulin:creatinine
-29
+13
<0.001
Median % Change from
Baseline to Week 48
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Conclusion: “For treatment-experienced individuals with >2 class resistance
on complex, high-pill burden regimens, switching to E/C/F/TAF + DRV provides a
simple, once-daily, two-pill option with superior efficacy and comparable
tolerability.”
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.
Update on FDA New Drug Applications for TAF
• E/C/F/TAF: target FDA action date Nov 5, 2015
• TAF/FTC/RPV: to be reviewed by FDA around Jan 2016
• TAF/FTC (2 doses): target action date April 7, 2016
• DRV/C/F/TAF: to be determined…
Source: Gilead Sciences, Inc. Press Release, July 2015.