TAF – an overviewWho? When? How?

co-infected/ monoinfected

Dr Kosh AgarwalInstitute of Liver StudiesKing’s College Hospital

ICVH Chicago 2017

Disclosures

I am a Hepatologist

Involved in the global TAF program

EASL panel

Abbvie, Astellas, Achillion, BMS, Gilead, Merck, Intercept, Vir

Acknowledge R Byrne

3 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.3 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.

TFV

HEPATOCYTE

TFV

OAT1 & 3OAT

1 & 3

OAT 1 & 3OAT 1 & 3

RENAL TUBULAR

CELL

TFV

RENAL TUBULAR

CELL

PLASMA

~90% LOWERPLASMA TFV

ESTER

AMIDATE

DIANION

TDF(tenofovir disoproxil

fumarate)

300 mg

TAF(tenofovir

alafenamide)25 mg

TFV(tenofovir)

longer plasma half-life † - greater plasma stability

short plasma half-life†

TFV HBV

GI TRACT

Tenofovir alafenamide (TAF) – A Novel Prodrug of Tenofovir

Prodrug Pharmacology

TFV-DP

† T1/2 based on in vitro plasma data - TDF = 0.4 minutes, TAF = 30-90 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 M et al. Lancet G&H 2016; doi: 10.1016/S2468-1253(16)30107-8; Chan HLY et al. Lancet G&H 2016; doi: /10.1016/S2468-1253(16)30024-3

‡

Older patients: risk of co-morbidities in European real-world cohorts

1. Marcellin P, et al. Dig Dis Sci 2016;61:3072–83; 2. Petersen J, et al. Dig Dis Sci 2016;61:3061–71 DDI: drug–drug interaction

0

2

4

6

8

10

12 10.9

9.1

3.6 3.4 3.22.3 2.1

6.07.0

5.0

2.0 2.0

Pa

tie

nts

(%

)VIREAL cohort (n=440)1

Mean age 45 years (11% ≥65 years)Treatment experienced: 59%

GEMINIS cohort (n=400)2

Mean age 45 years (9% ≥65 years)Treatment experienced: 54%

Consider DDIs if using polypharmacyto manage co-morbidities

Multiple factors affect CHB disease progression

Fattovich G. Semin Liver Dis 2003;23:47–58, Fattovich G, et al. J Hepatol 2008;48:335–52

Patient

Many factors affect CHB disease progression

Gill, Zissimopoulos et al., J. Infect Dis. 2014

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

Submitted to J Hep

Antiviral Efficacy of TAF and TDF at Week 48Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF

Seto, AASLD 2016, Oral 67

0.0 8.0 16.024.032.040.048.056.064.072.00

20

40

60

80

100

Week

0

20

40

60

80

100

Week0.0 8.0 16.024.032.040.048.056.064.072.00

20

40

60

80

100 TAFTDF

Week

Prop

orti

on o

f Pat

ient

s, %

(95%

CI)

0

20

40

60

80

100 TAFTDF

Week

Prop

ortio

n of

Pat

ient

s, %

(95%

CI)

HBeAg+

Rates of Viral SuppressionHBV DNA <29 IU/mL

HBV DNA suppression rates were lower in HBeAg+ vs HBeAg− patients No significant difference between TAF and TDF No resistance was detected through 48 weeks

HBV DNA suppression was comparable between TAF and TDF treatment up to Week 72

Treatment difference +1.8 (-3.6, +7.2); p=0.47 Treatment difference: −3.6 (−9.8, 2.6); p=0.25

TAF: 64% TDF: 67%

TAF: 94% TDF: 93%

HBeAg-

4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 40.0 44.0 48.0 56.0 64.0 72.00

20

40

60

80

100

TAF TDFPatie

nts W

ith A

LT N

orm

aliza

tion,

%

AASLD Criteria¤

*†

†

†‡

‡‡‡‡‡‡‡‡‡‡

*

ALT Normalisation of TAF and TDF at Week 72

Fung, AASLD 2016, Poster 1852; Data on File, Gilead Sciences Inc.

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

Significantly higher ALT normalisation rate with TAF vs TDF4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 40.0 44.0 48.0 56.0 64.0 72.0

0

20

40

60

80

100

Patie

nts W

ith A

LT N

orm

aliza

tion,

%

*p<0.05†p<0.005‡p 0.001

 

Central Lab Criteria§

‡‡

‡

**

* * * * *† †

¤ <19 and <30 U/L for females and males, respectively§ 34 and 43 U/L for females and males, respectively, aged <69 y, and 32 and 35 U/L, respectively, aged >69 y 

TAF: 49.1%TDF: 39.0%

TAF: 76.1%TDF: 68.4%

Renal Laboratory Parameters in CHB Patients Treated with TAF or TDF

• Smaller eGFR declines with TAF vs TDF in patients with older age and those with comorbid conditions (HTN/DM/CVD)

Agarwal, AASLD 2016, Poster 1844

In patients at greater risk for kidney disease, TAF treatment resulted in smaller declines in eGFRCG and fewer patients showed CKD stage worsening compared

with TDF treatment*p-values from Wilcoxon 2-sample test; †Hypertension (HTN), diabetes mellitus (DM), and cardiovascular disease (CVD) determined by medicalhistory or concomitant medication.

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

Age <50 y Age ≥50 y

-6

-4

-2

0

-0.4

-3.4

-4.8-5.4

Med

ian

eGFR

Cha

nge,

%

n=5 n=8

Age

n=642 n=294 n=185 n=123

P<0.001 P=0.01

No HTN/DM/CVD HTN/DM/CVD

-10

-5

0

-0.6

-3.4

-4.8

-7

Med

ian

eGFR

Cha

nge,

%

n=5 n=8

Comorbid Conditions

n=691 n=136 n=337 n=80

P<0.001 P=0.003

TAF Phase 3: Week 96 Results

TAF Group Performance Relative to TDF Group Week 48 Week 96

Viral Suppression Non-inferior Non-inferior

ALT Normalization Significantly Better Significantly Better

Bone Safety Significantly Better Significantly Better*

Renal Safety Significantly Better Significantly Better*

Viral Resistance None None

early biomarkers ≠clinical endpoints

Management of HIV co-infected patients

EASL 2017 CPG HBV, J Hepatol 2017

Recommendations:

1) All HIV-positive patients with HBV co-infection should start antiretroviral therapy (ART) irrespective of CD4 cell count. (Evidence level II-2, grade of recommendation 1)

2) HIV-HBV co-infected patients should be treated with a TDF- or TAF-based ART regimen. (Evidence level I for TDF, II-1 for TAF, grade of recommendation 1)

NA for naïve CHB patients

EASL 2017 CPG HBV, J Hepatol 2017

Recommendations:

1) The long-term administration of a potent NA with high barrier to resistance is the treatment of choice regardless of the severity of liver disease. (Evidence level I, grade of recommendation 1)

2) The preferred regimens are ETV, TDF and TAF as monotherapies. (Evidence level I, grade of recommendation 1)

3) LAM, ADV and TBV are not recommended in the treatment of CHB. (Evidence level I, grade of recommendation 1)

Indications for selecting ETV or TAF over TDF*

EASL 2017 CPG HBV, J Hepatol 2017

* TAF should be preferred to ETV in patients with previous exposure to nucleoside analogues.

** ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) 15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysis.

SurvivalSurvival EfficacyEfficacy TolerabilityTolerability

HIV

Background

• Tenofovir disoproxil fumarate (TDF) is included in most recommended antiretroviral regimens, and although potent and generally well tolerated, has been associated with clinically significant renal and bone toxicity1-3

• Relative to TDF 300 mg, tenofovir alafenamide (TAF) 25 mg has 90% lower circulating plasma TFV, while maintaining high antiviral activity4

16

1. DeJesus E, et al. Lancet 2012;379:2429-38; 2. Gallant JE, et al. J Infect Dis 2013;208:32-9; 3. Sax PE, et al. Lancet 2012;379:2439-48; 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-55.

FDA TAF Timeline

• Elvitegravir/cobicistat/emtricitabine/TAF - Genvoya; approved November 2015

• Emtricitabine/rilpivirine/TAF- Odefsey; approved March 2016

• Emtricitabine/TAF- Descovy; approved April 2016

• TAF (compensated HBV)- Vemlidy; approved November 2016

E/C/F/TAF QD

TAF as initial HIV Therapy: Studies 104 and 111

18

Tx-Naïve AdultsHIV-1 RNA ≥1000 c/mLeGFR ≥50 mL/min

1:1

E/C/F/TDF QD (Stribild, STB)

n=866

n=867

Two Phase 3 randomized, double-blind, double-dummy, active-controlled studies

– Study 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America)

– Stratified by HIV-1 RNA, CD4 cell count, geographic region

Primary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0)

– Non-inferiority (12% margin) based on Week 48 FDA snapshot analysis

– Combined efficacy analysis pre-specified

– Pre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD

Primary Endpoint

48 144960Week

Primary Endpoint: HIV-1 RNA <50 copies/mL at Week 48Studies 104 and 111: Week 48 Combined Analysis

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

Favors E/C/F/TAF

0

4.7%‒0.7%2.0%

HIV

-1 R

NA

<50

c/m

L, %

Success Failure No Data0

20

40

60

80

100 92

4 4

90

4 6

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

Treatment Difference (95% CI) Virologic Outcome

‒12% +12%

Favors E/C/F/TDF

19

TAF vs. TDF Summary

HIV

-1 R

NA

<50

%

Success Failure No Data0

20

40

60

80

100 92

4 4

90

4 6

• Virologic efficacy: E/C/F/TAF non-inferior to E/C/F/TDF1

• TAF associated with:− Smaller decrease in eGFR

(-6.4 vs. -11 mL/min)− Less proteinuria− Smaller decrease in bone

mineral density (BMD)− But greater increase in

cholesterol, LDL, HDL, TGs D TC: +29 mg/dL D LDL: + 14 mg/dL D TC:HDL: same

E/C/F/TAF

E/C/F/TDF

1Sax P et al, Lancet, 2015; 2Pozniak A et al, JAIDS, 2016

• EVG/c/FTC/TAF approved for patients with CrCL down to 302

Conclusions

Studies 104 and 111: Week 48 Combined Analysis

• 92% of patients treated with E/C/F/TAF achieved virologic suppression through Week 48 (combined analysis)– Virologic response for E/C/F/TAF, 93% (Study 104) and 92%

(Study 111)

– E/C/F/TAF was non-inferior to E/C/F/TDF

– High and similar response rates, irrespective of age, sex, race, HIV-1 RNA, and CD4 cell count

• Low rates of virologic failure, with resistance <1% in both arms

• Both drugs were well tolerated and safe

─ Discontinuations due to AEs were low in both arms

─ 0.9% (8) for E/C/F/TAF vs 1.5% (13) for E/C/F/TDF

─ No proximal tubulopathy cases

─ Common AEs similar between treatment arms 21

GS-US-292-0112 - single-arm, open-label Phase 3 study of HIV-1-infected participants with mild-moderate renal impairment (eGFRCG 30-69 mL/min) who switched to

E/C/F/TAF

• Phase 3, 96-week, multicenter, open-label study of virologically suppressed adults switching from TDF- or non-TDF–containing regimens to E/C/F/TAF

• Eligibility: stable eGFRCG (30–69 mL/min)

• Primary endpoint: change from baseline in eGFR at Week 24

– Actual GFR assessed with iohexol clearance in a participant subset

Primary Endpoint

E/C/F/TAF QD N=242

24 96480 12Week

A Pozinak J Acquir immun Def Syn 2016

Proteinuria: Change From Baseline to Week 48

23

85

100

20

40

60

80

100

120

140

160

180

200

78

10

110

14

Med

ian

(mg/

g)

105

160

188

166 2140

500

1000

1500

2000

2500

3000

3500

151 207197 221

Med

ian

(µg/

g)

228

801

1525 1563

3477

399

Tubular Proteins

b-2-m:CrUPCR UACR RBP:Cr

*All Total and TDF changes statistically significant; †all non-TDF changes not statistically significant.

2941

18

Total* TDF* Non-TDF†

Baseline

Week 48

BMD: Mean Change from Baseline to Week 48

24*p<0.05 by two-sided Wilcoxon signed-rank test.

Spine Hip

Me

an

(S

D)

% Δ

Sp

ine

BM

D

2.95*

2.29*

0.99

1.85*

1.47*

0.70

Me

an

(S

D)

% Δ

Hip

BM

D

Week 24n=226

Baselinen=236

Week 48n=214

Week 24n=225

Baselinen=236

Week 48n=216

TDF Non-TDFTotal

Conclusions

• Participants on TDF at time of switch had

– No change in actual GFR– Significant improvements in urinary markers of

renal function – Significant improvements in BMD – Significant increases in lipids

• Participants not on TDF at time of switch had

– No changes in actual GFR– Stable urinary markers of renal function and BMD– Significant decreases in cholesterol fractions

25

HIV/HBV co-infection data

• Limited• GS US 292–1249 - open-label, small sample,

noncomparative switch study evaluating the efficacy and safety of E/C/F/TAF in HIV suppressed, HBV co-infected participants– At 48 weeks, 91.7% of the 72 participants

maintained or achieved virologic suppression (HIV-1 RNA <50 copies/mL; HBV DNA <29 IU/mL)

Gallant J Acquir immun Def Syn 2016

GS US 292–1249

• Participants maintained high rates of HIV and HBV suppression, had improved renal function, and reduced biomarkers of bone turnover, consistent with other E/C/F/TAF studies

• E/C/F/TAF was well tolerated with no discontinuations because of renal events• Seroconversion occurred in 2.9% of HBsAg-positive participants and 3.3% of

HBeAg-positive participants• 40% of those with abnormal ALT normalized by week 48; which is lower than

the percentage seen in naive HBV-monoinfected populations and similar to treatment-experienced coinfected populations

• There were no ALT flares, and assessments of other liver-related parameters did not suggest increased hepatic risk.

E/C/F/TAF was effective against HIV and HBV, well tolerated, and demonstrated improvements in renal and bone safety consistent with the clinical profile of TAF.

Management of HIV co-infected patients

EASL 2017 CPG HBV, J Hepatol 2017

Recommendations:

1) All HIV-positive patients with HBV co-infection should start antiretroviral therapy (ART) irrespective of CD4 cell count. (Evidence level II-2, grade of recommendation 1)

2) HIV-HBV co-infected patients should be treated with a TDF- or TAF-based ART regimen. (Evidence level I for TDF, II-1 for TAF, grade of recommendation 1)

• When should you definitely use TAF over TDF?– Patient with osteoporosis or osteopenia– Patient with renal disease (eGFR >30) or evidence for proximal

tubular dysfunction (e.g. proteinuria)– Growing proportion of patients: ‘greying of the epidemic’

• When should you definitely not use TAF?– Patient on rifamycin (may decrease TAF levels)– Pregnant women– For pre-exposure prophylaxis (PrEP)??

TAF or TDF

Should TAF replace TDF?

• TAF is virologically as effective as TDF.

• Compared with TDF, TAF has more favorable effects on renal and bone markers.

− Particularly important in patients who already have renal or bone disease or who are at high risk of these complications.

• Cost of TAF- and TDF-regimens currently similar

Reasons to choose TAF

• Compared with TAF, more and longer-term data with TDF, particularly in studies in treatment naïve patients.

• More favorable lipid effects.• Renal and bone marker advantages

of TAF not yet known to translate into better clinical outcomes.

• TDF-regimens likely to be cheaper than TAF when TDF goes generic.

Reasons to choose TDF

Issues?

• Cost and access• NAFLD/Lipids• Cost/generic TDF• Long term data• Short term data - ?significant clinical

outcomes

KOSH FYI – current NHSE policy for TAF in HIV

•  NHSE have approved funding of TAF for the following categories of patients:1. Patients with definite contra-indication or intolerance to tenofovir disoproxil fumarate (TDF) and abacavir.

– Confirmed osteoporosis on DEXA or a high risk of major fracture as determined by FRAX– Renal disease based on NICE definition CKD stage G3 or stage G1/2 plus stage A3 proteinurea – Previous renal toxicity or intolerance of TDF

– 2.Patients with relative contra-indication or intolerance to TDF and abacavir– Approaching threshold of osteoporosis – Renal markers approaching thresholds where TAF is thought to be more appropriate

VC referral??• Category 1 – Virtual clinic referral NOT required• Patients with a definite contra-indication or intolerance to tenofovir disoproxil and abacavir

– Confirmed osteoporosis on DEXA or a high risk of major fracture as determined by FRAX (FRAX score >10%)– Renal disease based on NICE definition CKD stage G3 (eGFR < 60ml/min) or stage G1/2 plus stage A3 proteinurea (eGFR >60ml/min plus severe proteinurea). Switch to TAF

should generally be based on more than an isolated reading for renal disease. – Previous renal toxicity or intolerance of TDF

• Patients starting or switching to TAF who fall in category 1 do not require referral and approval by the virtual clinic. • The reason for the choice of TAF as opposed to tenofovir disoproxil or abacavir must be clearly documented in the notes by the prescriber, for future audit

purposes.•  • Category 2 – virtual clinic referral required• Patients with relative contra-indication or intolerance to TDF and where abacavir is not a suitable alternative

– Where there is an increased risk of bone disease and fracture probability: children and young people below age of peak bone mass (approx. 25 years), post-menopausal women, those on long-term glucocorticoid therapy or those who have already had a low-trauma fracture or who fall frequently.

– Renal disease based on NICE definition CKD G1 or 2 plus A2 proteinurea (eGFR> 60mls/min and moderate proteinurea) and one of the following additional risk factors: older age, diabetes, cardiovascular disease and hypertension. Other co-morbidities and concomitant nephrotoxic medication should be considered if associated with a higher risk of chronic renal disease progression.

• Patients who are starting or switching to TAF under category 2 must be referred to the virtual clinic for approval. Ideally this should be done prospectively. If TAF is required urgently then this must be discussed with agreed with a consultant physician and a retrospective referral made to the virtual clinic.

• The reason for the choice of TAF as opposed to tenofovir disoproxil or abacavir must be clearly documented in the notes by the prescriber, for future audit purposes.