Maile Ann Young Karris MD of UC San Diego presents "Tenofovir Alafenamide: To Switch or Not To Switch" at AIDS Clinical Rounds

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AIDS CLINICAL ROUNDS

2. Tenofovir
Alafenamide: To
Switch or Not To
Switch
Maile Young Karris, MD
m1young@ucsd.edu

3. 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

4. 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

6. What is Tenofovir Alafenamide?
Tenofovir
alafenamide
(TAF)
Tenofovir
disoproxil
fumarate
(TDF)
Tenofovir
(TFV)
LYMPHOID CELLPLASMA
TFV-MP
TFV-DP
GU
T
TFV
TFV
TAF
TDF TFV
X
TFV
Paul Sax CROI 2015 Abstract 143LB via Chuck

7. TAF Distribution
Lee Antimicrob Agents Chemother 2005 49

8. 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

10. 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]

11. 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

12. 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

13. 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)

14. ! 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

15. 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

16. 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

17. ! Evaluated over
164,059 person-years
of follow up
! 934 patients had a
CV Event

18. 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)

20. 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]

21. 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]

23. Is TAF the best thing since…

24. 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

25. Lower plasma levels but
higher intracellular levels

26. 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

30. But …

31. ! 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

32. 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-1RNA<50c/mL,%
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
31David Wohl CROI 2015 Abstract113 LB Via Chuck Hicks

33. 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
VirologicSuccess(%)
92 90
0
20
40
60
80
100
800
866
784
867
Overall
32

34. 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
VirologicSuccess(%)
784
867
Overall
800
866
33

35. Median Change from
Baseline in CD4 Count
Studies 104 and 111: Week 48 Combined Analysis
MedianChangefromBaselinein
CD4Count(cells/µL)
0
100
200
300
0 4 8 12 16 20 24 28 32 36 40 44 48 522
Weeks
211
p=0.024
181
34
E/C/F/TAF E/C/F/TDF

36. 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; 35

37. 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

38. 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
337

39. 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

40. 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

41. 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)
Mean(SD)changefrombaseline
eGFRCockroft-Gault(mL/min)
-10
-20
40
*Cockroft-Gault (mL/min).
-6.6
-11.2
p <0.001

42. 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
Abnormalitie
s
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.

43. 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
HipSpine
Mean(SD)%Change
fromBaseline
24 48
Week
0 24 48
Week
0

44. 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
MedianValues(mg/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

45. 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

49. 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?

50. 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

51. 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!

52. CONTACT INFO
! Maile Young Karris
! m1young@ucsd.edu
! Owen Clinic 619-543-3995

53. 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

54. Acknowledgements
! Thanks Paul Sax and David Wohl via Chuck Hicks