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The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
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!
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