Tenofovir Alafenamide: To Switch or Not To Switch

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AIDS CLINICAL ROUNDS

Tenofovir Alafenamide: To Switch or Not To

Switch Maile Young Karris, MD

[email protected]

Disclosures !  Site PI of GS-US-311-1717 (more details coming at

the end of the talk)

!  Worked with Gilead Sciences and the FDA to obtain F/TAF for use as compassionate care for an individual patient

Contents

! What is Tenofovir Alafenamide?

! Why do we need it?

! But what about Abacavir?

! How does it compare to Tenofovir Disoproxil?

! Details about GS-US-511-1717

What is Tenofovir Alafenamide?

Tenofovir alafenamide (TAF)

Tenofovir disoproxil fumarate (TDF)

Tenofovir (TFV)

LYMPHOID CELL PLASMA

TFV-MP

TFV-DP

GUT TFV

TFV TAF

TDF TFV

X

TFV

Paul Sax CROI 2015 Abstract 143LB via Chuck Hicks

TAF Distribution

Lee Antimicrob Agents Chemother 2005 49

Why do We Need it?

!  OFF TARGET EFFECTS OF TFV!

!  TFV is associated with kidney disease

!  A decrease in plasma TFV levels may result in less nephrotoxicity

!  TFV is associated with decreases in bone mineral density !  A decrease in plasma TFV levels may result in

less bone toxicity

TDF and the Kids !  TDF induced nephrotoxicity is reported in ~ 15% of patients

treated for > 2 years [Quinn Int J STD AIDS 2010 21]

!  Include Fanconi syndrome, progressive decline in renal function, nephrogenic DI, reduced bone mineral density and osteomalacia and acute tubular necrosis

!  For every year of exposure to TDF risk of proteinuria, decline in kidney function and development of CKD increases by 34, 11 and 33% [Scherzer AIDS 2012 26]

!  Studies demonstrate stopping TDF does not always reverse the kidney injury and recovery may be significantly delayed

!  TDF is eliminated mostly through free glomerular filtration but 20-30% is secreted by the proximal tubules via OAT1 and OAT3 !  Studies suggest TDF accumulates within proximal renal

tubules resulting in mitochondrial injury and depletion [Kohler Lab Invest 2011 91; Kohler Lab Invest 2009 89]

The impact on bones !  PLWH have lower bone mineral density (BMD) and

higher fracture risk than uninfected peers

!  TDF use is one of many factors associated with loss of bone [Brown AIDS 2006 20]

!  Switching from TDF to ABC !  Increases BMD by 2.1% at 48 weeks (95% CI: -0.6-4.7,

p=0.043) [Negredo J Antimicrob Chemother 2014 69]

!  Decreases bone turnover markers and increasing circulating sclerostin [Negredo J Antimicrob Chemother 2015]

!  Specific populations at risk: women, adolescents !  A5224 demonstrated greater loss of BMD in subjects

on TDF < 30 compared to older

Why should I care I have Abacavir?

!  Not everyone is HLA-B5701 negative

!  Concerns about Abacavir efficacy

!  Concern of use in the setting of M184V mutation

!  Cardiovascular Disease

!  Hepatitis B Co-infection

Efficacy of TDF over ABC !  ACTG A5202 [Sax NEJM 2009 351]

!  ABC/3TC or FTC/TDF with EFV or r/ATV in naives

!  Interim review revealed significant differences in efficacy for pts with HIV-1 RNA > 100,000

!  Time to virologic failure significantly shorter with ABC/3TC than FTC/TDF (57 vs 26 failures)

!  BICOMBO [Martinez JAIDS 2009 5]

!  333 Persons suppressed for 6 months to switch to either ABC/3TC or FTC/TDF

!  Treatment failure (switching) occurred in 19% of persons on ABC/3TC vs 13% on FTC/TDF (p=0.06)

!  Virologic failure occurred in 4 persons on ABC and 0 on TDF (p=0.04)

!  SWIFT [Campo CID 2013 56]

!  311 persons on r/PI + ABC/3TC to continue OR switch FTC/TDF

!  Fewer subjects who switched experienced VF (3 vs 11 p = 0.034)

!  Metaregression analysis [Hill British HIV assoc 2009 10]

!  12 clinical trials of 5168 patients on either FTC/TDF or ABC/3TC with r/PI

!  HIV RNA response rate were significantly lower when ABC/3TC was used p =0.0015

!  Indirect comparison E/C/F/TDF vs Triumeq [Rogatto J Int AIDS Soc 2014 2]

!  GS102 and SINGLE 88% patients were virologicallly suppressed at 48 weeks and 84% for E/C/F/TDF and 80% for Triumeq at 96 weeks

!  No statisically significant differences

ABC and m184V !  Resistance mutations develop ABC monotherapy:

K65R, L74V, Y115F, M184V

!  M184V does decrease ABC efficacy [Miller AIDS 1998 7]

Harrigan JID 2000 181

ABC and CVD the sordid story !  2008 D:A:D demonstrated that recent exposure to

ABC was associated with increased risk of CVD [Sabin Lancet 2008 371]

!  Meta-analyses of RCTs did not find this association [Brothers JAIDS 2009 51; Ribaudo CID 2011 52; Cruciani AIDS 2011 25; Ding JAIDS 2012 61]

!  Biomarker studies inconclusive, other observational cohorts resulted in inconsistent findings

!  D:A:D stopping smoking > stopping ABC and absolute risk of events low

!  Observational studies may be subject to a channeling bias and RCTs were relatively short and had fewer participants and no clear mechanism has been identified

!  Evaluated over 164,059 person-years of follow up

!  934 patients had a CV Event

The effect of cumulating exposure to ABC on the risk of

CVD

!  11,856 patients were followed for median of 6.6 years

!  365 had a CVD event

!  ABC increased the risk of a CVD event – risk increased as exposure cumulates

!  Exposure during the past 6-36 months causes the greatest increase in risk

! Gradual increase in risk is not c/w a rapidly acting mechanism

Young JAIDS 2015 (Epub ahead of print)

TDFs lipid lowering effect

!  BICOMBO !  Cholesterol, LDL, and TG were significantly lower in

persons switched to FTC/TDF

!  SWIFT !  Greater decline in fasting LDL, TC, TG in those who

switched beginning at 12 weeks !  Translated to improved 10yr Framingham TC

calculated scores

!  Switching from ABC/3TC + EFV to EFV/FTC/TDF maintains virologic control and improves total cholesterol and LDL [Moyle Plos One 2015]

TDF and Hep B !  Treatment guidelines recommend TDF+FTC or TDF

+ 3TC

!  If TDF cannot be safely used the alternative recommendation is Entecavir + Fully suppressive HAART !  More pills !  Potential access issues

!  Country specific patterns of the management of chronic hepatitis B is affected by access ! Germany, France, Turkey – entecavir or TDF ! Poland and Romania – lamivudine, Peg IFN

[Arama et al Antivir Ther 2014 19]

Is TAF the best thing since…

Does TAF Work? !  38 subject PK/PD 10 day monotherapy in HIV+ adults

!  HIV VL decrease 1.08-1.73 log10 copies/mL

Ruane et al. J Acquir Immune Def Syndr 2013 63

Lower plasma levels but higher intracellular levels

c/Darunavir with TAF !  Phase 2 safety and efficacy of TAF for initial

treatment of HIV compared c/DRV/F/TAF or c + DRV + F/TDF

!  Week 24 74.8% on TAF and 74% on TDF were suppressed (95% CI: -11.4-18.1)

!  Week 48 76.7% on TAF and 84% on TDF were suppressed (95% CI: -19.9-7.4% )

!  Met criteria for non-inferiority

!  No emergence of resistance in those that had virologic failure.

Mills JAIDS 2015

But …

!  Two phase 3 randomized double blind, double dummy, active controlled studies

!  Stratified by HIV-1RNA, CD4 cell count and geography

!  Primary endpoint HIV < 50 at 48 weeks

!  1733 patients Sax Lancet 2015

Primary Endpoint: HIV-1 RNA <50 copies/mL at

Week 48 Studies 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, %

92

4 4

90

4 6

0

20

40

60

80

100

Success Failure No Data

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

31 David Wohl CROI 2015 Abstract113 LB Via Chuck Hicks

Cell Count

Efficacy by Baseline HIV-1 RNA and CD4 Count Studies 104 and 111: Week 48 Combined Analysis

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

32

92 94 90 91

Efficacy in Select Subgroups Studies 104 and 111: Week 48 Combined Analysis

92 95 91 87

674 733

673 740

126 133

111 127

Male Female

Sex

94 88

93

83

603 643

607 654

197 223

177 213

Non-Black Black

Race

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

716 777

<50 years ≥50 years

Age

680 753

84 89

104 114

92 90

0

20

40

60

80

100

Viro

logi

c S

ucce

ss (%

)

784 867

Overall

800 866

33

Median Change from Baseline in CD4 Count

Studies 104 and 111: Week 48 Combined Analysis

Med

ian

Cha

nge

from

Bas

elin

e in

C

D4

Cou

nt (c

ells

/µL)

0

100

200

300

0 4 8 12 16 20 24 28 32 36 40 44 48 52 2

Weeks

211 p=0.024

181

34

E/C/F/TAF E/C/F/TDF

Resistance Through Week 48 Studies 104 and 111: Week 48 Combined Analysis

E/C/F/TAF n=866

E/C/F/TDF n=867

Patients analyzed for resistance*, n (%) 16 (1.8) 19 (2.2)

Primary Genotypic Resistance

Any, n (%) 7 (0.8) 5 (0.6)

Study 104, n 3 3

Study 111, n 4 2

NRTI Resistance, n

Any 7 5

M184V/I 6 3

M184V/I + K65R 1 2

INSTI Resistance, n

Any 5 3

T66A 1 0

E92Q 2 1

Q148R 0 1

Q148R + T66I/A 1 0

Q148R + E92Q 0 1

N155H 1 0

*With 2 consecutive HIV-1 RNA ≥50 c/mL after first achieving <50 c/mL and the second ≥400 c/mL; or had ≥400 c/mL at Week 48 or last study visit.

35

36

E/C/F/TAF n=866

%

E/C/F/TDF n=867

%

Any AE 90 90

Any drug-related AE 40 42

Any Grade 3 or 4 AE 8 9

Any drug-related Grade 3 or 4 AE 1 1

Any serious AE 8 7

Any drug-related serious AE 0.3 0.2

Any AE-related discontinuation 0.9 1.5

Deaths 0.2* 0.3†

*Stroke (1), alcohol intoxication (1). †Alcohol and drug intoxication (1), myocardial infarction (2).

Overall Safety Studies 104 and 111: Week 48 Combined Analysis

E/C/F/TAF n=866

E/C/F/TDF n=867

% (n) 0.9% (8) 1.5% (13)

Type •  Blood triglycerides increased •  Cerebral infarction, hemorrhagic

transformation stroke •  Dyspnea, hyperkeratosis, abdominal

distention & pain, back pain, lipodystrophy acquired

•  Dysphagia, pharyngitis •  Erectile dysfunction •  Eye irritation, eye pain, eye pruritus •  Proctalgia, penile pain •  Rash erythematous

•  Arthropod bite, dermatitis •  Abdominal pain, temporomandibular

joint syndrome, headache, depression •  Cardiac arrest •  Dysphagia, nausea, vomiting •  Decreased GFR •  Hyperamylasemia •  Immune reconstitution inflammatory

syndrome •  Iridocyclitis •  Nephropathy •  Rash generalized •  Renal failure (2) •  Vomiting, bladder spasm, pyrexia,

headache, myalgia, rash maculopapular

Adverse Events Leading to Discontinuation

Studies 104 and 111: Week 48 Combined Analysis

37

37

Common Adverse Events (All Grades) Studies 104 and 111: Week 48 Combined Analysis

AEs in ≥5% of patients, % E/C/F/TAF

n=866 E/C/F/TDF

n=867

Diarrhea 17 19 Nausea 15 17 Headache 14 13 Upper respiratory tract infection 11 13 Nasopharyngitis 9 9 Fatigue 8 8 Cough 8 7 Vomiting 7 6 Arthralgia 7 5 Back pain 7 7 Insomnia 7 6 Rash 6 5 Pyrexia 5 5 Dizziness 5 4

38

Grade 3 or 4 Laboratory Abnormalities

Studies 104 and 111: Week 48 Combined Analysis E/C/F/TAF

n=866 %

E/C/F/TDF n=867

%

Any grade 3 or 4 lab abnormalities* 20 20

Creatine kinase elevation 7 6

LDL elevation (fasting) 5 2

Hypercholesterolemia (fasting) 2 1

Hematuria (quantitative) 2 2

AST elevation 2 2

Serum amylase elevation 2 3

Neutropenia (<1000 cells/µL) 2 2

ALT elevation 1 1

*≥1% on E/C/F/TAF arm.

39

Change in eGFR (Cockcroft-Gault)

Studies 104 and 111: Week 48 Combined Analysis

0 12 24 36 48

0

10

20 E/C/F/TAF

E/C/F/TDF

Time (Weeks)

Mea

n (S

D)

chan

ge fr

om b

asel

ine

eGF

R C

ockr

oft-G

ault

(mL/

min

)

-10

-20

40 *Cockroft-Gault (mL/min).

-6.6

-11.2 p <0.001

n (%)

E/C/F/TAF

n=866 E/C/F/TDF

n=867

Events

Renal adverse events leading to discontinuation 0 4 (0.5)*

Tubulopathy/Fanconi syndrome 0 0

Laboratory Abnormalities

Subclinical tubulopathy† 0 1 (0.1)

Serum creatinine (≥0.4 mg/dL increase) 0 0

Hypophosphatemia (≥1 grade decrease) 3 (0.3) 4 (0.5)

Normoglycemic glycosuria (≥1 grade increase urine glucose; serum glucose ≤100 mg/dL)

0 2 (0.2)

Proteinuria (≥2 grade increase) 2 (0.2) 2 (0.2)

Renal Adverse Events and Tubulopathy

Studies 104 and 111: Week 48 Combined Analysis

41

*Renal failure (2), decreased GFR (1), nephropathy (1). †Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits.

Changes in Spine and Hip BMD Through Week 48

Studies 104 and 111: Week 48 Combined Analysis

42

E/C/F/TAF, n 845

E/C/F/TDF, n 850

797

816

784

773

836

848

789

815

780

767

0

2

-2

-4

-6

2

-2

-4

-6

0‒0.66

p <0.001

‒2.95

‒1.30

p <0.001

‒2.86

Hip Spine

Mea

n (

SD

) %

Chan

ge

from

Bas

elin

e

24 48

Week

0 24 48

Week

0

163

104

44

100

160

101

44

95

0

50

100

150

200

3.6 3.6

0

1

2

3

4

5

Fasting Lipids at Week 48 Studies 104 and 111: Week 48 Combined Analysis

43

Total Cholesterol LDL HDL Triglycerides TC:HDL Ratio

Med

ian V

alues

(m

g/dL)

Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42).

p <0.001 p <0.001 p <0.001 p=0.027 p=0.84

189 177

115 109

51 48

108

3.7

114

3.7

E/C/F/TAF Baseline Week 48

E/C/F/TDF Baseline Week 48

Safety of TAF in Renal Impairment

!  Phase 3 open label study in virologicaly suppressed asults with eGFR 30-69 switched from TDF or non TDF regimens to E/C/F/TAF

!  92% maintained suppression at week 48

Pozniak CROI 2015 Abstract 795

In Conclusion

!  TAF is noninferior to TDF in combination with E/C/F and c/DRV

!  TAF has an improved safety profile !  Smaller decreases in creatinine clearance and bone

mineral density

!  Increases in lipids !  Appears safe to use in persons with eGRF 30-69

!  So for HIV infection it will be replacing TDF but will it also replace ABC?

GS-US-311-1717 !  Primary objective: To evaluate the efficacy of

switching ABC/3TC to F/TAF versus continuing ABC/3TC in HIV-1 positive persons who are virologically suppressed on a stable regimen containing ABC/3TC for > 6 months

!  Secondary Objective: To evaluate the efficacy, safety and tolerability of two regimens through Week 48 and Week 96

!  Randomized double-blind multicenter active-controlled study of switching ABC/3TC to F/TAF

Target Population !  HIV-1 positive adults who are virologically

suppressed on a stable regimen containing ABC/3TC for > 6 consecutive months (NOT Triumeq)

!  eGFR > 50 mL/min

!  Subjects will be getting studies evaluating renal function, DEXAs and will have blood and urine stored for future studies of inflammation and immune activation

!  CURRENTLY COMPLETING CONTRACTS AND HOPEFULLY WILL GO THROUGH UCSD IRB SOON!

CONTACT INFO

!  Maile Young Karris

!  [email protected]

!  Owen Clinic 619-543-3995

What will the future bring?

!  Will we be able to use it for PrEP? !  Oral TDF vs “topical” TAF infant macaques with oral

SIV [Koen JAIDS 2006 43]

!  No efficacy of topical TAF

!  Long acting TAF Subdermal Implant [Gunawardana Antimicrob Agents Chemother 2015 59]

!  In dogs maintained a low systemic exposure to TAF with high concentrations of TFV-DP in PBMCs

Acknowledgements !  Thanks Paul Sax and David Wohl via Chuck Hicks