Brian R Wood MD Assistant Professor of Medicine University of Washington Medical Director Frontier AETC ECHO October 2015 ID Week Review 2015 1 Switching from TDF to TAF 2 Simplifying salvage therapy to ECFTAF DRV ID: 619715
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Slide1
ID Week Review 2015
Brian R. Wood, MDAssistant Professor of Medicine, University of WashingtonMedical Director, Frontier AETC ECHO
October 2015Slide2
ID Week Review 2015
1) Switching from TDF to TAF2) Simplifying salvage therapy to E/C/F/TAF + DRVAbbreviations:TDF: tenofovir disoproxil fumarateTAF: tenofovir alafenamideE/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarateE/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
ATV/booster: boosted atazanavir
DRV: darunavir
RPV: rilpivirineSlide3
Tenofovir d
isoproxil fumarate (TDF) vs. Tenofovir alafenamide (TAF)
Lymphoid Cells
Gut
Plasma
TFV
TFV-MP
TFV-DP
TDF = tenofovir disoproxil fumarate; TFV = tenofovir; MP = monophosphate; DP = diphosphate
TDF
TDF
P
P
TFV
Active drug
TAF
TAF
TAF
Cathepsin A
91% lower plasma TFV levels with TAFSlide4
Switching from TDF to TAF Slide5
GS-109: Switching from TDF to TAF
Switch to E/C/F/TAF (n = 959)
Continue current TDF-based
regimen
(n = 477)
Study Design
Protocol
-
Randomized, open-label
study
- HIV-infected adults with HIV RNA <50
copies/mL for
>
48
weeks on a
TDF-containing regimen (their 1st regimen)- eGFR >50 mL/min- Total N = 1,436 - 601 TDF/FTC + ATV/booster - 376 TDF/FTC/EFV - 459 E/C/F/TDF- Randomized 2:1
*Primary endpoint: HIV RNA <50 copies/mL at 48 weeksSource
: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.Slide6
GS-109: Switch from TDF to TAF
48 Week Data: Proportion with HIV RNA <50 copies/mLSource: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
P<0.001
P=0.02
P=0.02
P=NSSlide7
GS-109: Switch from TDF to TAF
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
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
<0.001Slide8
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
.Slide9
Source: Thompson M et al. ID Week, Oct 2015, San Diego. Abstract 725.
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.
”
GS-109: Switch from TDF to TAFSlide10
Simplifying Salvage Therapy to E/C/F/TAF + DRVSlide11
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Simplify to E/C/F/TAF + DRV(n = 89)
Continue current ART
(n = 46)
Study Design
Protocol
-
N = 136 HIV-infected adults
-
Randomized, open-label
study
- HIV RNA <50 copies/ml for
>
4 months on a DRV-containing regimen
-
>2 prior episodes of virologic failure and >2-class drug resistance- No DRV RAM’s, no INSTI resistance, <3 TAM’s, no Q151M or T69ins- 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.Slide12
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Characteristics
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
Source:
Huhn G et al
. ID Week, Oct 2015. San Diego. Abstract 726.Slide13
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Concern for lower levels of elvitegravir and darunavir when co-administered with cobicistatPharmacokinetic substudy in 15 participantsPlasma collected over 24-hour period between weeks 2-8Post-dose steady state concentrations of TAF, TFV, darunavir, and elvitegravir maintainedTrough concentrations 10-20x higher than inhibitory concentrationsSource: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.Slide14
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Source:
Source:
Huhn G et al
. ID Week, Oct 2015. San Diego. Abstract 726.
P=0.23
P=0.012
P=0.004Slide15
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Median % Change from Baseline to Week 48
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
Source:
Huhn G et al
. ID Week, Oct 2015. San Diego. Abstract 726.Slide16
Simplifying Salvage Therapy to E/C/F/TAF + DRV
Source: Huhn G et al. ID Week, Oct 2015. San Diego. Abstract 726.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
.
”Slide17
Update on FDA New Drug Applications for TAF
E/C/F/TAF: target FDA action date Nov 5, 2015TAF/FTC/RPV: to be reviewed by FDA around Jan 2016TAF/FTC (2 doses): target action date April 7, 2016DRV/C/F/TAF: to be determined…Source: Gilead Sciences, Inc. Press Release, July 2015.