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Didactic Series

Tenofovir Alafenamide (TAF) in HIV & HBV

Christian B. Ramers, MD, MPH, AAHIVS Family Health Centers of San Diego

8/11/16

This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number and title for grant amount (# U1OHA29292-01-01, Regional AIDS Education and Training Centers, PAETC award

$3,018,761). This information or content and conclusions are those of the author and should not be construed as the official position or policy of, not should any endorsements be inferred by HRSA, HHS or the U.S. Government.

Disclosures

Speaker’s Bureau: Janssen, Gilead, AbbVie, Bristol-Myers Squibb, Clinical Care Options

Scientific Advisor: Gilead, Janssen, Bristol-Myers Squibb

Grant/Research/Contracted Support: California Dept of Public Health, CDC/HRSA, NWAETC, Pacific AETC, HealthHIV, UNM Project ECHO, Gilead Sciences

**Mention will be made of therapeutic combinations not fully evaluated/approved by the FDA (‘off-label’ combinations)**

3

Learning Objectives

1) Describe Basic Pharmacology of TAF and how it compares to TDF

2) Review clinical trials efficacy and safety data of TAF combination in HIV

3) Discuss *off label* use of TAF in HIV/HBV co-infection switch studies

4) Review recent TAF HBV mono-infection data

BASIC PHARMACOLOGY AND MECHANISM OF ACTION

Tenofovir Alafenamide – (TAF)

4

Key Clinical Question: How do pharmacology of TAF and TDF differ?

How do these differences lead to differences in toxicities?

5 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION. 5 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.

TFV

TARGET CELL (Hepatocyte or CD4+ T-Cell) TFV

OAT 1 & 3

OAT 1 & 3

RENAL TUBULAR

CELL

TFV

RENAL TUBULAR

CELL

PLASMA

~90% LOWER PLASMA TFV

ESTER

N

N

N

N

NH2

OPO

OO

O

O

O

OO

O

AMIDATE

ON

NNNH2

NPO

O

HNO

O

N

N

N

N

NH2

OPO

HOOH

DIANION

TDF (tenofovir disoproxil fumarate) 300 mg

TAF (tenofovir

alafenamide) 25 mg

TFV (tenofovir)

Bi

longer plasma half-life † - greater plasma stability

short plasma half-life†

TFV HBV

GI TRACT

TAF – A Novel Prodrug of Tenofovir

Mechanism of Action

5

TFV-DP

† T1/2 based on in vitro plasma data - TDF = 0.4 minutes, TAF = 90 minutes. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. Babusis D, et al. Mol Pharm 2013;10(2):459-66. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. Sax P, et al. Lancet 2015. Jun 27;385(9987):2606-15. Agarwal K et al. J Hepatology 2015; 62: 533-540; Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12

HIV

BRUSH BORDER

TAF 10-Day Dose Ranging Trial

Study 120-0104

Median Change From Baseline in HIV-1 RNA With TAF vs. TDF 300 mg

Ruane P, et al. JAIDS 2013;63:449-455.

Med

ian

Cha

nge

From

Bas

elin

e H

IV-1

RN

A (lo

g 10 c

opie

s/m

L) 0.5

0.0

-0.5

-1.0

-1.5

-2.0 7 14 21

TDF 300mg (N =6)

Dosing period (10 Days)

Placebo (N =7)

TAF 8mg (N =9) TAF 25mg (N =8)

TAF 40mg (N =8)

TAF 25 mg vs 10 mg – impact of P-gp • Intestinal P-gp transporter

pumps drugs (eg, TAF and TDF) back into the intestinal lumen

• Cobicistat inhibits intestinal P-gp transporter allowing more TAF absorption

• This interaction allows for TAF dose to be reduced from 25 mg to 10 mg for GENVOYA with similar exposure to TAF

Intestinal P-gp Inhibition

P-gp, permeability glycoprotein 1.

1. Van Gelder et al. Drug Metab Dispos. 2002, 30(8):924-930. 2. Tong et al. Antimicrob Agents Chemother. 2007, 51(10):5409-5413. 3. Babusis et al. Mol Pharmaceutics. 2013, 10:459-466 4. Lepist E, et al. Antimicrob Agents Chemother 2012;56(10):5409-13.

Plasma Absorption

Intestinal Cell

TAF

TAF TAF

TAF

GI Tract

P-gp

COBI RTV

TDF and TAF are substrates of intestinal P-gp transporters

Intestinal metabolism of drugs and their efflux back into the intestinal lumen may be barriers to absorption.

25 mg 10 mg

Cobicistat

Ritonavir

CLINICAL TRIALS IN HIV MONO-INFECTION


8

Key Clinical Questions: Is TAF as effective as TDF at achieving HIV suppression?

Are there any safety benefits of TAF over TDF?

Study Design

Studies 104 and 111: ART-Naïve Adults, Week 48 Combined Analysis

Two Separate Phase 3, International, randomized, double-blind, active-controlled studies

Primary Endpoint Non-inferiority (12% margin) of E/C/F/TAF to Stribild based on HIV-1 RNA <50 copies/mL* at Week 48 by FDA Snapshot analysis†

Secondary Endpoints Efficacy, safety** and tolerability observed through Week 96, Week 144

ClinicalTrials.gov Identifier: NCT01780506 and NCT01797445

Treatment Naïve Patients Study 102 and 103

Secondary Endpoints

Tx-Naïve Adults

HIV-1 RNA ≥ 1000 c/mL eGFR ≥ 50 mL/min

Primary Endpoint

Week 48 Week 96

Stratification by • HIV-1 RNA ≤ />100,000 c/mL • CD4 cell count • Geographic region

1:1

Week 144

E/C/F/TAF QD

E/C/F/TAF Placebo QD

Stribild Placebo QD

Stribild QD (STB)

N =866

N =867

*Taqman 2.0 assay †Combined efficacy analysis was pre-specified. **SCr, proteinuria, hip and spine BMD were pre-specified week 48 safety endpoints. Study 104 (North America, EU, Asia) and Study 111 (North America, EU, Latin America)

1. Wohl D, et al. CROI 2015. Seattle, WA. Oral #113LB 2. Sax P, et al. CROI 2015. Seattle, WA. Oral #143LB

E/C/F/TAF: elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg STB: elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir DF 300 mg

Virologic/Immunologic Efficacy

• E/C/F/TAF was non-inferior to Stribild at Week 48 in each study – 93% E/C/F/TAF vs 92% Stribild (Study 104) – 92% E/C/F/TAF vs 89% Stribild (Study 111)

• Increase in CD4 count (cells/μL) at Week 48 – E/C/F/TAF: +211 vs Stribild: +181 (P=0.024)


Favors E/C/F/TAF

0

4.7% ‒0.7%

2.0%

HIV

-1 R

NA

<50

c/m

L, %

92

4 4

90

4 6 0

20

40

60

80

100

VirologicSuccess

VirologicFailure

No VirologicData

E/C/F/TAF (n=866)Stribild (n=867)

Treatment Difference (95% CI) Virologic Outcome

‒12% +12%

Favors Stribild

Wohl D, et al. CROI 2015. Seattle, WA. Oral #113LB

CD4 Cell Count

E/C/F/TAF (n=866) Stribild (n=867)

86 93 89 91

96 112

104 117

703 753

680 750

<200 ≥200

CD4 (cells/μL)

94 87 91 89

610 672

171 196

174 195

629 670

≤100,000 >100,000

HIV-1 RNA (c/mL)

Viral Load

Viro

logi

c S

ucce

ss, %

92 90

0

20

40

60

80

100

800 866

784 867

Overall

Efficacy by Baseline HIV-1 RNA and CD4


High rates of virologic success across low & high BL VL and CD4 cell count Wohl D, et al. CROI 2015. Seattle, WA. Oral #113LB

Week 48 BMD Changes

E/C/F/TAF, n=845

Stribild, n=850

797

816

784

773

836

848

789

815

780

767

-4

-2

0

2

-6

2

-2

-4

-6

0

‒0.66%

P<0.001*

‒2.95%

‒1.30%

P<0.001*

‒2.86%

Hip Spine

Med

ian

chan

ge fr

om

base

line

(Q1,

Q3)

, %

24 48

Weeks

0 24 48

Weeks

0


Significantly less decrease in spine and hip BMD in the E/C/F/TAF group at Week 48

Sax P, et al. CROI 2015. Seattle, WA. Oral #143LB

*Comparison of E/C/F/TAF vs Stribild at Week 48

0 1 2 2 4 3 6 4 8

0

1 0

2 0E /C /F /T A F

S t r ib i ld

T im e (W e e k s )

-10

-20

-30

-6.6

-11.2 P<0.001

Med

ian

Cha

nge

from

BL

in

eG

FRC

G, (

Q1,

Q3)

Less GFR decline with E/C/F/TAF compared to Stribild (p<0.001)

Pattern of early decline (2 wks) then stable eGFR is consistent with cobicistat inhibition of tubular secretion of creatinine



Week 48 eGFR Changes

-23

-57

-34

ß-2- µglobulin:Cr

-3 -5

9

-32

20 7

51

24

-50

-25

0

25

50

75

168 133 76

Retinol Binding Protein:Cr

Changes (%) in Proteinuria at Week 48

Med

ian

chan

ge fr

om B

L (Q

1, Q

3), %

Protein:Cr (UPCR)

Albumin:Cr (UACR)

E/C/F/TAF

Stribild

P<0.001 for all

Urine [Protein]:Creatinine Ratio

64 μg/g 67 μg/g 101 μg/g 103 μg/g


43 36

49

4

-35 -33

-23

62

-27

3


TUBULAR MARKERS

Retinol Binding Protein & β-2 μglobulin

TDF: TAF: &

5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g

GLOMERULAR MARKERS

Proteinuria and Albuminuria

TDF: TAF: minimal

-3 -5

9

-32

20 7

51

24

-50

-25

0

25

50

75

168 133 76

Protein:Cr (UPCR)

Albumin:Cr (UACR)

Retinol Binding Protein:Cr ß-2- µglobulin:Cr

43 36

49

4

-35 -33

-23

-57

-23

62

-27

3

-34

Med

ian

chan

ge fr

om B

L (Q

1, Q

3), %

GLOMERULAR & TUBULAR MARKERS

Proteinuria and Albuminuria*

TDF: TAF:

Baseline ratios

44 mg/g 44 mg/g

Significantly less proteinuria with E/C/F/TAF vs. Stribild

CLINICAL TRIALS IN HIV/HBV CO-INFECTION


15

Key Clinical Question: Can TAF maintain suppression of HBV in context of

HIV/HBV co-infection?

HBV and HIV have Nuclear Reservoirs

aHBV cccDNA (covalently closed circular DNA): accumulates in hepatocyte nuclei, acting as a template for viral messenger RNA (mRNA) transcription. bHIV proviral DNA: integrates into the chromatin of infected cells, acting as the template for the transcription of viral genes. Soriano V, et al. J Antimicrob Chemother. 2008;62:1-4.

Nucleus Host Cell Host DNA

HCV

viral RNA cccDNAa

HBV

proviral DNAb

HIV

DHHS Guidelines: Recommendations for HIV/HBV-coinfected Patients

• Regimen should include activity against HIV and HBV

• Earlier initiation of treatment for HIV infection in HBV pts may reduce the risk of liver-disease progression

• Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage due to reactivation of HBV

• If ART needs to be modified, antiviral drugs active against HBV should be continued with the new HIV ART regimen

• Patients should be advised against self-discontinuation and carefully monitored during treatment

17 DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. April 2015.

Study Design Phase 3, 48-week, multicentered, single-arm, open label study

• Efficacy Endpoint Proportion with HIV RNA <50 copies/mL (Snapshot) and HBV DNA <29 IU/mL (missing=failure) at W24 and W48

• Safety Endpoints Safety and tolerability through W24 and W48, ALT normalization,

HBsAg to HBsAb and HBeAg to HBeAb seroconversion, and changes in liver fibrosis stage**

ClinicalTrials.gov Identifier: NCT02071082

Treatment Naïve Patients Study 102 and 103

Key inclusion criteria †HIV-1 RNA <50 c/mL for ≥6 months ‡ HBV DNA ≤9 log10 (+HBsAg for ≥6 months)

N = 72*

*Two subjects were ineligible for enrollment because they did not meet the definition of chronic HBV infection (discovered after study enrollment). Therefore, the full safety analysis set included all 74 subjects, but the final efficacy analysis set excluded these two subjects, leading to a final efficacy analysis set of 72 subjects. **By FibroTest.

Secondary Endpoint Primary Endpoint Week 24 Week 48

E/C/F/TAF QD

Study 1249: HIV/HBV Co-infected Adults on E/C/F/TAF

HIV Suppressed† &

HBV-Infected‡ Adults eGFR ≥50 mL/min

18

Gallant J, et al. IAS 2015, Vancouver, Canada. Poster # WELBPE13

Summary of Efficacy and Safety Endpoints

Switch to E/C/F/TAF in HIV/HBV co-infected patients demonstrated robust HIV and HBV suppression with favourable effects on liver safety

endpoints 19



100

86

62

92 92

58†

0

20

40

60

80

100

HIV-1 RNA <50c/mL HBV DNA<29 IU/mL Fibrosis (mod/severe)

Patie

nts

(%)

3 7

50*

sAg Loss eAg Loss ALTNormalization

Baseline Week 48

*4/8 patients with available ALT data at W48 †35/60 patients with paired baseline and W48 data

BACKGROUND EPIDEMIOLOGY AND NATURAL HISTORY

Hepatitis B Virus Infection

20

Global HBV Epidemiology

Ott JJ Stevens GA, Groeger J Wiersma ST. Global Epidemiology of HBV: new estimates. Vaccine 2012; 30(12):2212-2219

US HBV Epidemiology

0

5000

10000

15000

20000

25000

30000

Rep

orte

d N

umbe

r of C

ases

80 82 84 86 88 90 92 94 96 98 00 02 04 06 08 10 12 13 Year

CDC. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview.

Infant Immunization Recommended

Vaccine Licensed

HBsAg Screening of Pregnant Women Recommended

OSHA Rule Enacted

Adolescent Immunization Recommended

IVDA & sexual transmission

23

HBV Natural History: traditional

Lok AS. Gastroenterol. 2007; 1586

24

HBV Anti-Viral Therapy

www.hepwebstudy.org

CLINICAL TRIALS IN HBV MONO-INFECTION


25

Key Clinical Questions: Given pharmacokinetic differences, can TAF maintain

suppression of HBV as well as TDF? Does TAF offer any advantages in terms of renal/bone toxicity?

TAF HBV Phase 3 Program

Two phase 3, randomized, double-blind studies Inclusion criteria

− HBV DNA ≥20,000 IU/mL; ALT >60 U/L (males), >38 U/L (females) Primary endpoint (non inferiority margin of 10%):

– HBV DNA <29 IU/mL at Week 48 Key secondary safety endpoints

– Bone mineral density and renal parameters at Week 48

26

Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF

†Amendment to extend double-blind to Week 144 and open-label phase to Week 384 (Year 8) is currently underway

*Non-inferiority margin of 10%

Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12

Primary Endpoint*

Baseline Wk 144† Wk 96

TAF 25mg

TDF 300mg

Open-label R

ando

miz

ed 2

:1

Wk 48

Double-blind

TAF 25 mg

Study 108 HBeAg- (N=425)

Study 110 HBeAg+ (N=873)

Study 110 (HBeAg+) (N=873)

TAF n=581

TDF n=292

38 (18‒69) 38 (18‒68) 371 (64) 189 (65) 482 (83) 232 (79) 24 (4) 24 (4)

151 (26) 77 (26) 287 (49) 145 (50) 7.6 (1.3) 7.6 (1.4)

272 (47) 142 (49)

85 (61, 139) 86 (57, 137) 45/566 (8) 22/282 (8)

Study 108 (HBeAg-) (N=425)

TAF n=285

TDF n=140

Mean age, y (range) 45 (19‒80) 48 (25‒72)* Male, n (%) 173 (61) 86 (61) Asian, n (%) 205 (72) 101 (72) Mean BMI, kg/m2 (SD) 25 (4) 25 (4) Treatment experienced, n (%) 60 (21) 31 (22) East Asia region†, n (%) 114 (40) 64 (46) Mean HBV DNA, log10 IU/mL (SD) 5.7 (1.34) 5.8 (1.32)

Elevated HBV DNA, n (%) HBeAg- (≥7 log10 IU/mL) HBeAg+ (≥8 log10 IU/mL)

55 (19) 24 (17)

Median ALT, U/L (Q1, Q3) 67 (44, 102) 67 (47, 102) FibroTest score ≥0.75, n/n (%) 31/280 (11) 20/139 (14)

Demographics


*P=0.011 †East Asia region denotes Hong Kong, Japan, Singapore (Study 110 only), South Korea, and Taiwan Q, quartile; SD, standard deviation Buti EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12

• Non-inferior rates of virologic suppression with TAF and TDF at Week 48

• No resistance detected in either treatment group

HBV DNA Response at 48 Weeks

Buti, EASL 2016, Oral GS06

Log10 HBV DNA Change

TAF

TDF

Study 108: HBeAg- Phase 3 CHB Study: TAF vs TDF

0 8 1 6 2 4 3 2 4 0 4 80

2 0

4 0

6 0

8 0

1 0 0

S tu d y W e e k

Pa

tie

nts

, %

(9

5%

CI)

0 8 1 6 2 4 3 2 4 0 4 8-5

-4

-3

-2

-1

0

S tu d y W e e k L

og

10

HB

V D

NA

Ch

an

ge

IU/m

L,

Me

an

(9

5%

C

I)

HBV DNA <29 IU/mL (%)

TAF: 94% (Wk 48)

TDF: 93% (Wk 48)

Stu

dy 1

08

(HB

eAg-

subj

ects

)

Treatment difference +1.8% (-3.6, +7.2); p=0.47

HBV DNA Response at 48 Weeks

Chan, EASL 2016, Oral GS12

Log10 HBV DNA Change

0 8 1 6 2 4 3 2 4 0 4 8-7

-6

-5

-4

-3

-2

-1

0

S tu d y W e e k

Me

an

IU

/mL

(9

5%

CI)

TAF

TDF

Study 110: HBeAg+ Phase 3 CHB Study: TAF vs TDF

Similar and non-inferior rates of virologic suppression with TAF and TDF at Week 48

No resistance detected in either treatment group

0 8 16 24 32 40 480

20

40

60

80

100

Study Week

Pro

po

rtio

n o

f P

atie

nts

, %

HBV DNA <29 IU/mL (%)

Stu

dy 1

10

(HB

eAg+

sub

ject

s)

TAF: 64% (Wk 48)

TDF: 67% (Wk 48)

Treatment difference -3.6% (-9.8, +2.6); p=0.25

0 8 1 6 2 4 3 2 4 0 4 80

2 0

4 0

6 0

8 0

1 0 0

S tu d y W e e k

Pro

por

tion

of P

atie

nts

, %

0 8 1 6 2 4 3 2 4 0 4 80

2 0

4 0

6 0

8 0

1 0 0

S tu d y W e e k

Pro

por

tion

of P

atie

nts

, % T A F

T D F

0 8 1 6 2 4 3 2 4 0 4 80

2 0

4 0

6 0

8 0

1 0 0

S tu d y W e e k

Pro

po

rtio

n o

f P

atie

nts

, %

0 8 1 6 2 4 3 2 4 0 4 80

2 0

4 0

6 0

8 0

1 0 0

S tu d y W e e k

Pro

po

rtio

n o

f P

atie

nts

, %

Central Laboratory AASLD

P=0.076

P<0.001

TAF TDF

ALT Normalization (48 Weeks) S

tudy

108

Central lab upper limit of normal (ULN): males ≤43 U/L, females ≤34 U/L (≥69 y, males ≤35 U/L, females ≤32 U/L); AASLD ULN: males ≤30 U/L, females ≤19 U/L. Buti EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12

P=0.18

P=0.014

Stu

dy 1

10

83% 75%

50%

32%

72% 67%

45% 36%

Increased ALT normalization rates with TAF utilizing AASLD ALT criteria


Serologic Results

n/N (%)

HBeAg+ (N=873)

TAF n=581

TDF n=292 P-value

HBeAg loss 78/565 (14) 34/285 (12) 0.47

HBeAg seroconversion 58/565 (10) 23/285 (8) 0.32

HBsAg loss 4/576 (<1) 1/288 (<1) 0.52

HBsAg seroconversion 3/576 (<1) 0 0.22

31

aULN 30 U/L males, 19 U/L females Buti EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12

TAF & TDF arms had similar serologic response in HBeAg-positive subjects

Study 110: Phase 3 CHB Study: TAF vs TDF

Results: Renal Safety

0 1 2 2 4 3 6 4 8-2 0

-1 0

0

1 0

2 0 T A F

T D F

S tu d y W e e k

Me

an

(S

D)

ch

an

ge

in

eG

FR

CG

(m

L/m

in)

-0.6

-4.7 p <0.001

TAF n=866

TDF n=432 P-value

Change in sCr, mg/dL 0.010 (0.11) 0.024 (0.10) 0.012

Continuous data are expressed as mean (SD) sCr, serum creatinine; eGFRCG, creatinine clearance by Cockcroft-Gault Buti EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12 Gilead Sciences, Data on File

Less change in eGFRCG and sCr at Week 48 with TAF compared to TDF


32

M

ean

(±SD

) cha

nge

in e

GFR

CG (m

L/m

in)

-5 0

-2 5

0

2 5

5 0

7 5

Results: Quantitative Proteinuria wk 48

33

Protein (UPCR) Albumin (UACR) Retinol-Binding Protein

β2-Microglobulin

TAF

TDF

Med

ian

(Q1,

Q3)

Cha

nge

Fr

om B

asel

ine,

%

6 17

7 12 25

-0.3 -3

38

Proximal tubular biomarkers Glomerular biomarkers

Changes in tubular proteinuria lower with TAF compared to TDF

Buti EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12 Gilead Sciences, Data on File

UPCR: Urine Protein Creatinine Ratio UACR: Urine Albumin Creatinine Ratio


Total protein

p=0.010 p=0.073 p <0.001 p <0.001

2

-2

-4

-6

0

Me

an

(S

D)

% C

ha

ng

efr

om

Ba

se

lin

e

2

-6

-4

-2

0

P<0.001 -0.88

-2.51

P<0.001

-0.29

-2.16

24 48 Week 0 24 48 Week 0

Wk 48: Changes in Spine and Hip BMD

Buti, EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12

Stu

dy 1

08

Stu

dy 1

10

P<0.001 ‒0.42

‒2.29

P<0.001

‒0.10

‒1.72

TAF

TDF


Decreases in hip/spine BMD smaller with TAF compared to TDF

Mea

n (S

D)%

Cha

nge

from

B

asel

ine

Mea

n (S

D)%

Cha

nge

from

B

asel

ine

Spine Hip

Summary • HIV Mono-infection

– Non-inferior efficacy to TDF for HIV suppression

– Smaller decline in BMD, smaller decreases in eGFRCG, improved

markers of renal tubular function compared to TDF

• HIV/HBV Co-infection** – High HIV and HBV suppression when used in switch setting

• HBV Mono-infection** – Similar Efficacy to TDF 300 mg; similar rates of eAg loss and Hep B

sAgAb seroconversion to TDF

– Smaller decline in BMD, smaller decreases in eGFRCG improved

markers of renal tubular function compared to TDF

• **Not FDA approved for this indiation • Buti, EASL 2016, Oral GS06 Chan, EASL 2016, Oral GS12

.

36

Questions?

(www.cdc.gov/hepatitis), Lavanchy D. J Viral Hepat. 2004;11:97-107

Percutaneous, sexual

Risk of Chronicity

1-5%

30%

90%!!

Hep B – geographic variability

(young adult)

Low Endemicity Country

High Endemicity Country

http://www.cdc.gov/hepatitis

Hepatitis B – Diagnostic Testing

HBV Markers Antibodies to HBV

Surface Antigen Surface Antibody

e Antigen e Antibody

core Antigen Core Antibody (IgG, IgM)

HBV DNA

(www.hepwebstudy.com) ‘Hep B eAb’ = ‘Anti-HBe’

Baseline Demographics and Disease Characteristics

N=72

Demographics

Median age, y (Q1, Q3) 51 (45, 55) Male, n (%) 66 (92) Asian, n (%) 7 (10) Black, n (%) 13 (18)

HIV

Median Cockcroft-Gault eGFR, mL/min (Q1, Q3) 95 (77, 117) Median CD4 count, cells/mm3 (Q1, Q3) 605 (438, 789) Median duration of HIV infection, y (Q1, Q3) 18 (9, 24) ART regimen characteristics TDF-based ART (TDF and FTC or 3TC), n (%) 69 (96)* FTC or 3TC only as part of ART, n 1 No TDF, FTC, or 3TC in ART, n 2

HBV

HBsAg+, n (%) 71 (99)†

HBeAg+, n (%) 30 (42) HBV DNA <29 IU/mL, n (%) 62 (86) Median duration of HBV, y (Q1, Q3) 12 (5, 20) ALT ≤ULN, n (%) 62 (86)

FibroTest category moderate/severe‡, n (%) 43 (60)

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*3 patients received non-TDF-based antiretroviral therapy (ART): ABC/3TC+LPV/r; RAL+ATV+RTV; ATV+RTV only. †1 patient was positive at screening, negative at baseline, positive at Week 12, and negative afterwards. ‡ (F1‒F2→F4)


Overall Safety Summary

41


Patients, n (%) N=74 Any AE 61 (82) Any nonserious AE in ≥5% of patients 28 (38) URI 12 (16) Nasopharyngitis 6 (8) Back pain 5 (7) Diarrhea 5 (7) GERD 5 (7) Allergic rhinitis 4 (5) Pyrexia 4 (5) Grade 3 or 4 4 (5) Study drug-related AE 12 (16) Serious AE* 6 (8) Study drug-related serious AE 0 AE leading to drug discontinuation† 1 (1)


*Community-acquired pneumonia, pneumococcal meningitis/pneumonia/bacteremia, thigh abscess, appendicitis, prostatitis/benign prostatic hyperplasia and non-ST elevation myocardial infarction. †Weight gain and increased appetite. URI= upper respiratory infection; GERD= gastroesophageal reflux disease.

Changes in Renal Biomarkers and eGFR

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-10

-4

-13 -15

-20

-15

-10

-5

0

UPCR 63.4 mg/g

p=0.87 p=0.88 p=0.80 p=0.96

UACR 6.9 mg/g Baseline

Med

ian

% C

hang

e Fr

om B

asel

ine

Week 24 Week 48

-22

-36

-6

-22

-40-35-30-25-20-15-10-50

RBP:Cr 98.8 μg/g

p=0.024 p=0.73 p=0.003 p=0.058

β2-µG:Cr 138.8 μg/g

Tubular Proteinuria

• By 48 weeks, eGFR improved post-switch to E/C/F/TAF – Median (Q1, Q3) eGFR by Cockcroft-Gault mL/min, 99.4 (85.7, 121.1), p=0.01


UPCR= Urine Protein:Creatinine Ratio; UACR= Urine Albumin: Creatinine Ratio; RBP:Cr= Retinol Binding Protein: Creatinine Ratio; β-2-µG= Cr: β-2-microglobulin:Creatinine Ratio

Didactic Series - PAETCpaetc.org/wp-content/uploads/2016/12/HIVLN-TAF... · Myers Squibb, Clinical...

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