This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice
related to any specific patient.
Frontier AIDS Education and Training Center
Tenofovir Alafenamide (TAF)
Brian R. Wood, MD
Assistant Professor of Medicine, University of Washington
Medical Director, Frontier AETC ECHO
January 28, 2016
Tenofovir Alafenamide (TAF)
1) What is TAF?
2) Summary of clinical trials, approval and indications to date
3) Review of key clinical trial data
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: atazanavir, DRV: darunavir
• RPV: rilpivirine, EFV: efavirenz
• COBI: cobicistat
What is tenofovir alafenamide (TAF)?
Tenofovir disoproxil fumarate (TDF) vs.
Tenofovir alafenamide (TAF)
Lymphoid CellsGut Plasma
TFV
TFV-MP
TFV-DP
TDF = tenofovir disoproxil fumarate; TFV = tenofovir; MP = monophosphate; DP = diphosphate
TDF TDF
P
P
TFV
Active drug
TAF TAFTAF
Cathepsin A
91% lower plasma TFV
levels with TAF
Summary of Clinical Trials, Approval and
Indications to Date
Summary of Key Tenofovir Alafenamide (TAF) Studies
• Phase 3 Trials of E/C/F/TAF for HIV Treatment:
- GS 104/111: E/C/F/TAF vs. E/C/F/TDF in treatment-naïve
- GS 109: Switch to E/C/F/TAF from standard TDF-containing ART
- GS 112: Switch to E/C/F/TAF in setting of renal impairment
- Switch to E/C/F/TAF + DRV to replace salvage ART
• Ongoing Phase 3 HIV Treatment Trials
- Switch to FTC/TAF from FTC/TDF (both with standard 3rd agent)
- Switch to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF
- DRV/COBI/FTC/TAF in treatment-naïve or experienced
- GS-9883/FTC/TAF in treatment-naïve or experienced
• Phase 3 Hepatitis B (HBV) Treatment Trials
- GS 108/110: TAF vs. TDF for HBV monoinfection
- Switch to E/C/F/TAF for HIV-HBV coinfection
Approved Formulations and Indications to Date
• E/C/F/TAF (Genvoya) approved Nov. 5, 2015
• Indications:
1) Initial regimen for treatment-naïve individuals
2) To replace current regimen for those with HIV RNA <50
copies/mL on a stable regimen for at least 6 months with no
history of treatment failure and no resistance to the individual
components
Source: Genvoya Package Insert, gilead.com
Review of Key Clinical Trial Data
GS104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART
GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART
E/C/F/TAF + Placebo(n = 866)
E/CF/TDF + Placebo(n = 867)
Study Design
Protocol
- 2 double-blind RCT’s
- Treatment-naïve HIV-1 infected adults
with CrCl >50 mL/min
- 178 outpatient centers, 16 countries
- Randomized 1:1 to each study arm
- Outcomes: proportion with HIV RNA
<50 copies/mL at 48 weeks and pre-
specified renal and bone changes
- Results stratified by pre-treatment HIV
RNA level and CD4, as well as age,
race, and gender
Source: Sax PE et al. Lancet 2015; 385: 2606–15.
GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART
Proportion with HIV RNA <50 copies/mL at 48 Weeks
Source: Sax PE et al. Lancet 2015; 385: 2606–15.
92.0 94.087.090.0 91.0 89.0
0
20
40
60
80
100
Overall HIV RNA ≤ 100,000 HIV RNA > 100,000
%H
IV R
NA
<50 c
op
ies/m
l
Baseline HIV RNA Level
E/C/F/TAF E/C/F/TDF
*Statistically significant difference
*
GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART
Source: Sax PE et al. Lancet 2015; 385: 2606–15.
Median % Change from
Baseline to Week 48E/C/F/TAF E/C/F/TDF P Value
Estimated GFR (mL/min) -6.4 -11.2 <0.001
Urine protein:creatinine -3 +20 <0.0001
Urine albumin:creatinine -5 +7 <0.0001
Retinol binding protein:creatinine +9 +51 <0.0001
β-2-microglobulin:creatinine -32 +24 <0.0001
Hip bone mineral density -0.66 -2.95 <0.0001
Spine bone mineral density -1.30 -2.86 <0.0001
GS-104/111: E/C/F/TAF vs. E/C/F/TDF for Initial ART
Median Change from Baseline
to Week 48
E/C/F/TAF
(N=306)
E/C/F/TDF
(N=153)P Value
Total cholesterol +29 +14 <0.001
LDL +14 +5 <0.001
HDL +8 +4 <0.001
Triglycerides +19 +8 0.027
Total cholesterol:HDL ratio +0.1 +0.1 0.84
Proportion who initiated a lipid-modifying agent: 2.9% TAF arm, 3.6% TDF arm
Source: Sax PE et al. Lancet 2015; 385: 2606–15.
Review of Key Clinical Trial Data
GS 109: Switching from TDF to TAF
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 weeks
Source: Mills A et al. Lancet Infect Dis. 2016 Jan;16(1):43-52.
GS-109: Switch from TDF to TAF
48 Week Data: Proportion with HIV RNA <50 copies/mL
Source: Mills A et al. Lancet Infect Dis. 2016 Jan;16(1):43-52.
97 96 97 9893 90 92
97
0
20
40
60
80
100
All prior regimens PriorTDF/FTC/EFV
Prior TDF/FTC +ATV/booster
Prior E/C/F/TDF
% H
IV R
NA
<50 c
op
ies/m
L
E/C/F/TAF Prior TDF Regimen
P<0.001 P=0.02 P=0.02 P=NS
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
Serum creatinine (mean, mg/dL) -0.01 +0.03 <0.001
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
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.
Review of Key Clinical Trial Data
GS 112: Switching to E/C/F/TAF in Setting of
Renal Impairment
GS 112: Switching to E/C/F/TAF in Renal Impairment
Switch to E/C/F/TAF(n = 242)
Study Design
Protocol
- Single arm, open-label safety and
efficacy trial
- HIV-infected adults with HIV RNA <50
copies/mL for at least 6 months
- eGFR stable at 30-69 mL/min (no
change in renal function or medical
management of renal disease for at
least 3 months)
*Primary endpoint: change from baseline in eGFR measured in various ways
Source: Pozniak A et al. J Acquir Immune Defic Syndr. 2015 Nov 30. [Epub ahead of print]
GS 112: Switching to E/C/F/TAF in Renal
Impairment
Baseline CharacteristicseGFR <50
(n=80)
eGFR >50
(n=162)
Total
(n=242)
Median age 59 58 58
Age >65 (%) 31 23 26
Female (%) 26 18 21
Black or African descent (%) 18 19 18
CD4 count (median) 622 635 632
Pre-switch TDF use (%) 58 69 65
Hypertension (%) 50 34 39
Diabetes (%) 15 13 14
Median eGFR (CG, mL/min) 43 60 56
Median eGFR (CKD-epi, mL/min) 45 58 54
Significant proteinuria (%) 56 35 42
Significant albuminuria (%) 64 42 49
Source: Pozniak A et al. J Acquir Immune Defic Syndr. 2015 Nov 30. [Epub ahead of print]
GS 112: Switching to E/C/F/TAF in Renal
Impairment
Week 48 Change from
Baseline
Total
(n=242)
eGFR <50
(n=80)
eGFR >50
(n=162)
TDF-
Containing
(n=158)
Non-TDF-
Containing
(n=84)
eGFR (CG, mL/min) -0.6 +0.6 -1.4 +0.2 -1.8
eGFR (CKD-EPI, mL/min) -1.8 +1.4 -3.1 -1.5 -2.7
Urine protein:Cr ratio -76 -111* 0
Urine albumin:Cr ratio -19 -31* -4
RBP:Cr ratio -635 -1,374* -31
β-2 microglobulin:Cr ratio -1,349 -3,270* -178
Source: Pozniak A et al. J Acquir Immune Defic Syndr. 2015 Nov 30. [Epub ahead of print]
*Statistically significant change
SUMMARY
• TAF consistently demonstrates high virological efficacy with
improvements in proximal tubulopathy and bone mineral density
markers compared to TDF; lipids increase though that is of
unclear clinical significance
• Glass half full perspective: this is a promising advance in ART
and offers significant improvements over TDF that will lead to
fewer long-term adverse events, especially as our patients age
• Glass half empty perspective: follow-up time is limited and does
not include clinically significant events (like fractures) and, as
with TDF, it will take years to know if TAF causes clinically
significant renal impairment or not