tenofovir alafenamide (taf) - university of...

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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.


Proportion with HIV RNA <50 copies/mL at 48 Weeks


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

*



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


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



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


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


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 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


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


*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

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