Conditions: Chronic Hepatitis B
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability and virologic response of tenofovir alafenamide (TAF) in virologically suppressed chronic hepatitis B participants with renal and/or hepatic impairment.

Detailed description:

Arms:
arm 1: Participants with chronic hepatitis B (CHB) and moderate or severe renal impairment who were virologically suppressed and taking tenofovir disoproxil fumarate (TDF), a TDF-containing anti-hepatitis B virus (HBV) regimen, or other oral antivirals (OAVs), will switch to tenofovir alafenamide (TAF) and receive TAF 25 milligram (mg) tablet once daily orally for 96 weeks. arm 2: Participants with CHB and end stage renal disease who were virologically suppressed and taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF and receive TAF 25 mg tablet once daily orally for 96 weeks. arm 3: Participants with CHB and moderate or severe hepatic impairment who were virologically suppressed and taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF and receive TAF 25 mg tablet once daily orally for 96 weeks.

Interventions: intervention 1: TAF
Intervention descriptions: intervention 1: Tablet administered orally once daily

Protocol document:
SAP_002.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N A D D E N D U M F O R FI N A L A N A L Y SI S
St u d y Title:
A P hase 2, O pe n -la bel St u d y t o E val uate t he Efficac y a n d 
Safet y  of S witc hi n g t o Te n of o vir Alafe na mi de ( T A F) fr o m 
Te n of o vir Dis o pr o xil F u marate ( T D F) a n d/ or Ot her Oral 
A nti viral Treat me nt ( O A V) i n Vir ol o gicall y S u p presse d 
C hr o nic He patitis B S u bjects wit h R e nal a n d/ or He patic 
I m pair me nt
N a me of Test Dr u g:
Te n of o vir Alafe na mi de ( T A F) 
St u d y N u m ber:
G S -U S - 3 2 0- 4 0 3 5
Pr ot oc ol Versi o n ( D ate):
A me n d me nt 1 ( 2 3 Ma y  2 0 1 7)
A n al ysis T y pe:
Fi nal A nal ys is
A n al ysis Pl a n Versi o n:
1. 0
A n al ysis Pl a n D ate:
0 5 Oct o ber 2 0 2 0
A n al ysis Pl a n A ut h or(s):
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
P P D
P P D
GI L E A U 


Te n of o vir Alafe na mi de ( T A F)
G S -U S -3 2 0 -4 0 3 5
Statistical A nal ysis Pla n A d de n d u m f or Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2
0 5 Oct o ber 2 0 2 0
T A B L E O F C O N T E N T S
T A B L E O F C O N T E N T S ..............................................................................................................................................2
LI S T O F I N -T E X T T A B L E S ........................................................................................................................................2
1. 
A S S E S S M E N T O F C O VI D -1 9 I M P A C T ............................................................................................................3
1. 1. 
St u d y Dr u g or St u d y Disc o nti n uati o n D ue t o t he C O VI D -1 9 Pa n de mic .................................................3
1. 2. 
Pr ot oc ol De viati o ns D ue t o t he C O VI D -1 9 Pa n de mic .............................................................................3
1. 3. 
Misse d or Virt ual Visits D ue t o t he C O VI D-1 9 Pa n de mic ......................................................................3
2. 
A N A L Y SI S WI N D O W S F O R W E E K 9 6 ............................................................................................................3
3. 
I M P U T A TI O N F O R L A S T D O S E D A T E ...........................................................................................................4
4. 
S E R U M C R E A TI NI N E C O R R E C TI O N ..............................................................................................................4
5. 
A P P E N DI C E S ......................................................................................................................................................5
A p pe n di x 1. 
Deter mi ni n g Misse d a n d Virt ual visits d ue t o t he C O VI D -1 9 Pa n de mic ................................. 5
LI S T O F I N -T E X T T A B L E S
Ta ble 4- 1. 
Met h o d of Ser u m Creati ni ne C orrecti o n
..................................................................................4


Te n of o vir Alafe na mi de ( T A F)
G S -U S -3 2 0 -4 0 3 5
Statistical A nal ysis Pla n A d de n d u m f or Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3
0 5 Oct o ber 2 0 2 0
T his statistical a nal y sis pla n ( S A P) a d de n d u m descri bes t he statistical a nal yses a n d data
prese ntati o ns t o be a d de d or m o difie d f or t he Fi nal Cli nical St u d y Re p ort ( C S R) f or t he P hase 2 
St u d y  G S-U S - 3 2 0- 4 0 3 5. T his S A P a d de n d u m is base d o n t he a p pr o ve d S A P date d 0 9 Ma y  2 0 1 9. 
T he S A P a d de n d u m will be fi nalize d bef ore data fi nalizati o n. A n y  c ha n ges ma de after t he 
fi nalizati o n of t he S A P a d de n d u m will be d oc u me nte d i n t he fi nal C S R.
1. 
A S S E S S M E N T O F  C O VI D-1 9 I M PA C T
T his st u d y  was o n g oi n g d uri n g t he n o vel c or o na vir us ( 2 0 1 9 n C O V [ C O VI D- 1 9]) pa n de mic, 
w hic h has ca use d a disr u pti o n i n t he re g ular visit sc he d ules f or t his st u d y. S o me st u d y s u bjects 
were u na ble t o atte n d o nsite visits d ue t o s helter i n place g ui deli nes, site cl os ures, or ot her 
reas o ns. T his secti o n pr o vi des g ui da nce o n ha n dli n g s pecial sit uati o ns d ue t o t he C O VI D - 1 9
pa n de mic i n t he fi nal a nal ysis. 
A d verse e ve nts ( A Es) attri b ute d as bei n g d ue t o t he C O VI D-1 9 pa n de mic will be i ncl u de d i n all 
A E a nal ys es s pecifie d i n t he S A P, if a p plica ble. A b y -s u bject listi n g of all AEs d ue t o t he 
C O VI D -1 9 pa n de mic will be pr o vi de d. 
1. 1. 
St u d y Dr u g or St u d y Disc o nti n u ati o n D ue t o t he C O VI D - 1 9 P a n de mic
A b y -s u bject listi n g of reas o ns f or pre mat ure st u d y  dr u g or st u d y disc o nti n uati o n d ue t o t he 
C O VI D -1 9 pa n de mic will be pr o vi de d.
1. 2.  
Pr ot oc ol De vi ati o ns D ue t o t he C O VI D -1 9 P a n de mic
B y- s u bject listi n gs will be pr o vi de d f or s u bjects wit h i m p orta nt a n d n o n-i m p orta nt pr ot oc ol 
de viati o ns d ue t o t he C O VI D-1 9 pa n de mic , res pecti vel y. 
1. 3.   
Misse d or Virt u al Visits D ue t o t he C O VI D -1 9 P a n de mic
I nf or mati o n re gar di n g misse d or virt ual visits d ue t o t he C O VI D-1 9 pa n de mic will be c ollecte d 
as free te xt i n t he C R F c o m me nt fiel ds. T he deter mi nati o n of miss e d or virt ual visits d ue t o t he 
C O VI D -1 9 pa n de mic will be d o ne usi n g a Nat ural L a n g ua ge Pr ocessi n g ( N L P) al g orit h m b y 
a nal yz i n g t he C R F c o m me nt fiel ds. A detaile d e x pla nati on of t he al g orit h m is pr o vi de d i n 
A p pe n di x 1 .
A b y -s u bject listi n g of s u bjects wit h misse d or virt ual visits d ue t o t he C O VI D-1 9 pa n de mic will 
be pr o vi de d b y s u bject I D n u m ber i n asce n di n g or der .
2. 
A N A L Y SI S WI N D O W S F O R W E E K 9 6
F or t he fi nal a nalys is, n o u p per li mit will be a p plie d t o t he Wee k 9 6 a nal ys is wi n d o w i n 
Ta ble 3- 2 t o Ta ble 3 -8 i n t he S A P. 


Te n of o vir Alafe na mi de ( T A F)
G S -U S -3 2 0 -4 0 3 5
Statistical A nal ysis Pla n A d de n d u m f or Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4
0 5 Oct o ber 2 0 2 0
3. 
I M P U TA T I O N F O R L A S T D O S E D AT E
If t he last d ose date is c o m pletel y missi n g, please refer t o t he S A P Secti o n 3. 8. 1 f or i m p utati o n 
r ules. 
If t he last d ose date is partiall y missi n g, t he latest of n o n-missi n g st u d y  dr u g start dates a n d e n d 
dates, t he cli nical visit dates, a n d t he la b orat or y  visit dates will be use d t o i m p ute t he last d ose 
date if t he i m p ute d m o nt h/ y ear is n o earlier t ha n t he partial last d ose m o nt h/ y ear (if m o nt h/ year is 
n ot missi n g). 
4. 
S E R U M C R E A TI NI N E C O R R E C TI O N
A p ositi ve s hift i n ser u m creati ni ne val ues was o bser ve d d ue t o a l ot cali b rati o n c ha n ge o n 0 1 
J ul y, 2 0 1 8, occ urri n g acr oss C o va nce la b orat or y  sites w orl d wi de . A c orrecti o n was t heref ore 
a p plie d t o rec or ds o n or after 0 1 J ul y, 2 0 1 8 t o ser u m creati ni ne, f oll o wi n g t he re gressi o n 
e q uati o n s pecifie d i n Ta ble 4- 1 . T he c orrecte d ser u m creati ni ne val ues will be use d f or t he 
a nal ys es of ser u m creati ni ne, ser u m creati ni ne t o xicit y , e G F R esti mate d b y t he C oc kcr oft Ga ult
f or m ula, e G F R b y t he C K D-E PI met h o d a n d ot her rele va nt para meters .
T h e c orrecte d val ues m ust be i n t he sa me u nit as t he ori gi nal val ues after g oi n g t hr o u g h t he 
re gressi o n f or m ula i n Ta ble 4- 1 .

If t he u nit of ser u m creati ni ne is “μ m ol/ L”, t he n use t he f or m ula directl y. 

If t he u nit of ser u m creati ni ne is “ m g/ d L”, t he val ues s h o ul d be c o n verte d t o “μ m ol/ L” bef ore 
usi n g t he f or m ula. 
After t he c orrecti o n, u nit of ser u m crea ti ni ne s h o ul d be c o n verte d bac k t o “ m g/ d L” f or s u m mar y 
a n d c o m paris o n p ur p ose. 
T a ble 4- 1. 
Met h o d of Ser u m Cre ati ni ne C orrecti o n
Re gi o n al L a b Ce nter
Accessi o n N u m ber a
Re g ul ar Re gressi o n f or Ser u m 
Cre ati ni ne ( μ m ol/ L)
b , c
I n di a n a p olis 
starts wit h 6 5
Y = 1. 0 0 2 × X + 1. 7 7
Ge ne v a 
starts wit h 6 2 or 6 3
Y = 1. 0 2 5 × X + 2. 6 2
S h a n g h ai 
starts wit h 6 7
Y = 0. 9 7 1 × X + 5. 4 2
S i n g a p ore 
starts wit h 6 4 or 6 6
Y = 1. 0 0 9 × X −1. 4 2
J a p a n 
start wit h 6 8
Y = 1. 0 3 3 × X + 7. 2 5
a 
Accessi o n n u m bers s pecifie d w hic h re gi o nal la b ce nter teste d t he sa m ple. F or e xa m ple, sa m ples wit h accessi o n n u m ber
starti n g wit h 6 5 were teste d i n I n dia na p olis A ut o C he mistr y Ce nter.
b   
X a n d Y are t he ser u m creati ni ne val ues fr o m pre vi o us l ot bef ore 0 1 J ul y, 2 0 1 8 a n d ser u m creati ni ne val ues fr o m ne w l ot o n 
or after 0 1 J ul y, 2 0 1 8, res pecti vel y. 
c  
T he ser u m creati ni ne c orrecti o n is base d o n t he u nit of u m ol/ L. T he u nit s h o ul d be c o n verte d t o m g/ d L f or s u m mar y
p ur p ose s. 


Te n of o vir Alafe na mi de ( T A F)
G S -U S -3 2 0 -4 0 3 5
Statistical A nal ysis Pla n A d de n d u m f or Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 5
0 5 Oct o ber 2 0 2 0
5. 
A P P E N DI C E S
A p pe n di x 1. 
Deter mi ni n g Miss e d a n d Virt u al visits d ue t o t he C O VI D -1 9
P a n de mic
T his a p pe n di x descri bes t he site c ollecti o n of C O VI D -1 9 data as pertai ns t o misse d/ virt ual visits 
a n d t he data pr ocessi n g al g orit h m use d t o deter mi ne w hic h visits were missi n g a n d w hic h visits 
were virt ual.
Data c ollecti o n
A C O VI D -1 9 s u p ple me nt t o t he e C R F C o m pleti o n G ui deli nes ( C C G) was pr o vi de d b y  data 
ma na ge me nt t o i nstr uct cli nical trial sites wit h res pect t o data e ntr y  e x pectati o ns pertai ni n g t o 
sce nari os relate d t o t he C O VI D-1 9 pa n de mic. If a visit was misse d, sites s h o ul d ha ve e nter e d
“ Visit misse d d ue t o C O VI D -1 9.” If a visit w hic h was t o be c o n d ucte d i n-pers o n was c o n d ucte d 
virt uall y , sites s h o ul d ha ve e nter e d “ Virt ual visit d ue t o C O VI D -1 9.”  
Deter mi nati o n of Misse d a n d Virt ual visits
Nat ural La n g ua ge Pr ocessi n g ( N L P) was use d t o searc h t he C R F c o m me nt fiel ds t o i de ntif y  
i nsta nces of “ C O VI D- 1 9” ( or sy n o n y m s, see Ta b l e 1 ) a n d “ Virt ual” ( or sy n o n y ms, see Ta b le 1 ). 
T he searc h ter ms a re mai ntai ne d i n a gl o bal l o o k u p a n d ca n be m o difie d a n d/ or c orrecte d t o t u ne 
t he N LP m o del. F or eac h c o m me nt fiel d t he f oll o wi n g al g orit h m was a p plie d:
S T E P 1: Eli mi nate e x tra ne o us te xt fr o m eac h c o m me nt fiel d, e. g. “a n d”, “ or”, “f or”, etc.  T his is 
d o ne usi n g t he list of e xtra ne o us ter ms gi ve n i n Ta ble 2 .
S T E P 2: C hec k eac h of t he re mai ni n g c o m me nt te xt stri n gs a gai nst t he “ C O VI D -1 9” ter ms a n d 
“ Virt ual” ter ms wit h t he Le ve ns htei n dista nce, usi n g S A S f u ncti o n C O M P G E D ( co m p utes a 
ge neralize d e dit dista nce usi n g t he Le ve ns htei n o perati o ns t o c o m p ute/s u m marize t he de g ree of 
differe nce bet wee n t w o te xt stri n gs): 
i. 
f Le ve ns htei n dista nce < 1 4 9 f or a ny of t he “ C O VI D -1 9” ter ms t he n 
C O VI D F L 
1, else C O VI D F L
 0
ii. 
If Le ve ns htei n dista nce < 14 9 f or a ny of t he “ Virt ual” ter ms t he n VI R T F L
 1, 
else VI R T F L
 0
S T E P 3: F or a n y c o m me nts wit h C O VI D F L 
 1, assi g n “ Misse d visit” or “ Virt ual visit” as 
f oll o ws
i. 
I F C O VI D F L 1 a n d t he visit date is missi n g t he n res ult is ‘ Misse d Visit’
ii. 
I F C O VI D F L 1 a n d VI R T F L  1 t he n res ult is  ‘ Virt ual Visit’
iii. 
Ot her wise res ult is missi n g


Te n of o vir Alafe na mi de ( T A F)
G S -U S -3 2 0 -4 0 3 5
Statistical A nal ysis Pla n A d de n d u m f or Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 6
0 5 Oct o ber 2 0 2 0
T a b le 1.
E x a m ples of se arc h ter ms f or “ C O VI D -1 9 ” a n d “ Virt u al ” use d t o 
i de ntif y misse d a n d virt u al visits
Se arc h ter ms f or “ C O VI D -1 9 ”
Se arc h ter ms f or “ Virt u al ”
C O VI D 1 9
C O R O N A
C O R O N A VI R U S
P A N D E MI C
O U T B R E A K
C RI SI S
L O C K D O W N
Q U A R A N TI N E
S H E L T E R
VI R T U A L
T E L E M E D
T E L E H E A L T H
T E L E P H O N E
R E M O T E
T E L E M E DI CI N E 
T E L E C O N S U L T A TI O N
T E L E P H O NI C A L L Y
P H O N E
H O M E VI SI T
Z O O M
S K Y P E
T a ble 2 .
E x a m ples of e xtr a ne o us te xt ter ms t o eli mi n ate fr o m t he c o m me nt 
fiel ds
a
d o w n
i n
s he' d
U ntil
a b o ut
d uri n g
i nt o
s he'll
U p
a b o ve
eac h
is
s he's
Ver y
after
fe w
it
s h o ul d
Was
a gai n
f or
its
s o
We
a gai nst
fr o m
it's
s o me
we' d
all
f urt her
itself
s uc h
we'll
a m
ha d
i' ve
t ha n
Were
a n
has
let's
t hat
we're
a n d
ha ve
me
t hat's
we' ve
a n y
ha vi n g
m ore
t he
W hat
are
he
m ost
t heir
w hat's
as
he' d
m y
t heirs
W he n
at
he'll
m yself
t he m
w he n's
be
her
n or
t he msel ves
W here
beca use
here
of
t he n
w here's
bee n
here's
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t here
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bef ore
hers
o nce
t here's
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bei n g
herself
o nl y
t hese
W h o
bel o w
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or
t he y
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bet wee n
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t he y' d
w h o's
b ot h
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t he y' ve
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t h ose
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t hr o u g h
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t o o
Y o ur
d o w n
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y o u're
y o u' ve
y o urself
y o ursel ves
Y o urs


G S- U S- 3 2 0- 4 0 3 5- Fi n al- A n al y si s- S A P- A d d e n d u m
E L E C T R O NI C SI G N A T U R E S
Si g n e d b y
M e a ni n g of Si g n at ur e 
S er v er D at e
( d d- M M M-
y y y y h h: m m: s s)
Bi o st ati sti c s e Si g n e d 
0 5- O ct- 2 0 2 0
2 1: 0 9: 1 4
Cli ni c al R e s e ar c h e Si g n e d 
0 6- O ct- 2 0 2 0
1 7: 3 0: 1 1
P P D
P P D-

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-label Study to Evaluate the Safety and Efficacy 
of Switching to Tenofovir Alafenamide (TAF) from Tenofovir 
Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment 
(OAV) in Virologically Suppressed Chronic Hepatitis B Subjects 
with Renal and/or Hepatic Impairment
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
115561
2016-004625-16
Indication:
Chronic Hepatitis B
Protocol ID:
GS-US-320-4035
Gilead Sciences
Study Director:
Name:
Telephone:
Fax:
Mobile:
Email:
Gilead Sciences 
Medical Monitor:
Name:
Telephone:
Fax:
Mobile:
Email: 
Protocol Version/Date:
Original:
07 March 2017
Amendment 1:
23 May 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
(r) GILEAU 


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 2
23 May 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................20
1.
INTRODUCTION ..............................................................................................................................................24
1.1.
Background ............................................................................................................................................24
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................26
1.2.1.
General Information .............................................................................................................26
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................27
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF).................................................................29
1.2.4.
Clinical Trials of Tenofovir Alafenamide in Subjects with Renal 
Impairment...........................................................................................................................44
1.3.
Rationale for this Study..........................................................................................................................48
1.4.
Risk/Benefit Assessment for the Study..................................................................................................50
1.5.
Compliance ............................................................................................................................................50
2.
OBJECTIVES.....................................................................................................................................................51
3.
STUDY DESIGN................................................................................................................................................52
3.1.
Study Treatment Plan and Regimen.......................................................................................................52
3.2.
Biomarker Testing..................................................................................................................................54
3.2.1.
Biomarker Samples to Address the Study Objectives ..........................................................54
3.2.2.
Biomarker Samples for Optional Future Research...............................................................54
3.2.3.
Biomarker Samples for Optional Pharmacogenomic Research............................................55
3.3.
End of Study...........................................................................................................................................55
3.4.
Post Study Care......................................................................................................................................55
4.
SUBJECT POPULATION..................................................................................................................................56
4.1.
Number of Subjects and Subject Selection ............................................................................................56
4.2.
Inclusion Criteria....................................................................................................................................56
4.3.
Exclusion Criteria...................................................................................................................................57
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................60
5.1.
Description and Handling of TAF..........................................................................................................60
5.1.1.
Formulation..........................................................................................................................60
5.1.2.
Packaging and Labeling .......................................................................................................60
5.1.3.
Storage and Handling...........................................................................................................60
5.2.
Dosage and Administration of Tenofovir Alafenamide (TAF) ..............................................................60
5.3.
Prior and Concomitant Medications.......................................................................................................61
5.4.
Accountability for Tenofovir Alafenamide (TAF).................................................................................62
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................62
6.
STUDY PROCEDURES ....................................................................................................................................63
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................63
6.2.
Pretreatment Assessments......................................................................................................................63
6.2.1.
Screening Visit .....................................................................................................................63
6.2.2.
Baseline Assessments...........................................................................................................64
6.3.
Treatment Assessments..........................................................................................................................66


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6.3.1.
Week 4 (Visit Window ± 3 days).........................................................................................66
6.3.2.
Week 8 (Visit Window ± 3 days).........................................................................................67
6.3.3.
Week 12 (Visit Window ± 3 days).......................................................................................69
6.3.4.
Week 24 (visit window is −7 days) ......................................................................................71
6.3.5.
Week 36 (Visit Window ± 14 days).....................................................................................73
6.3.6.
Week 48 (Visit Window is −7 days) ....................................................................................73
6.3.7.
Week 60 (Visit Window ± 14 days).....................................................................................74
6.3.8.
Week 72 (Visit Window ± 14 days).....................................................................................75
6.3.9.
Week 96 (Visit Window is −7 days) ....................................................................................76
6.4.
Post-Treatment Assessments..................................................................................................................77
6.4.1.
HBsAg Loss and Seroconversion Subjects ..........................................................................77
6.4.2.
All Other Subjects Who Discontinue Study Drug................................................................77
6.4.3.
Treatment-Free Follow Up Visit Assessments (Part A Subjects).........................................77
6.5.
Early Discontinuation (ED)/Unscheduled Visit .....................................................................................78
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................79
6.7.
Other Evaluations...................................................................................................................................80
6.7.1.
Bone and Renal Markers ......................................................................................................80
6.7.2.
Intensive Pharmacokinetic Substudy (Optional) ..................................................................80
6.8.
Resistance Surveillance and Virologic Rebound Management..............................................................81
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................82
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................82
7.1.1.
Adverse Events.....................................................................................................................82
7.1.2.
Serious Adverse Events........................................................................................................82
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................83
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................83
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................83
7.2.2.
Assessment of Severity ........................................................................................................84
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................84
7.4.
Gilead Reporting Requirements.............................................................................................................86
7.5.
Toxicity Management ............................................................................................................................86
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................87
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................87
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................87
7.5.4.
Management of Bone Evaluation.........................................................................................87
7.5.5.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................88
7.5.6.
Management of Potential Nephrotoxicity.............................................................................90
7.6.
Special Situations Reports......................................................................................................................91
7.6.1.
Definitions of Special Situations..........................................................................................91
7.6.2.
Instructions for Reporting Special Situations.......................................................................91
8.
STATISTICAL CONSIDERATIONS................................................................................................................93
8.1.
Analysis Objectives and Endpoints........................................................................................................93
8.1.1.
Analysis Objectives..............................................................................................................93
8.1.2.
Primary Endpoint .................................................................................................................94
8.1.3.
Secondary Endpoint .............................................................................................................94
8.1.4.
Other Endpoints of Interest ..................................................................................................94
8.2.
Analysis Conventions.............................................................................................................................95
8.2.1.
Analysis Sets ........................................................................................................................95
8.3.
Data Handling Conventions ...................................................................................................................96
8.4.
Demographic Data and Baseline Characteristics ...................................................................................96


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8.5.
Efficacy Analysis ...................................................................................................................................96
8.5.1.
Primary Analysis..................................................................................................................96
8.5.2.
Secondary Analyses .............................................................................................................97
8.6.
Safety Analysis.......................................................................................................................................97
8.6.1.
Primary Safety Analysis.......................................................................................................97
8.6.2.
Secondary Safety Analysis...................................................................................................97
8.6.3.
Extent of Exposure...............................................................................................................97
8.6.4.
Adverse Events.....................................................................................................................97
8.6.5.
Laboratory Evaluations ........................................................................................................98
8.7.
Pharmacokinetic Analysis......................................................................................................................98
8.8.
Biomarker Analysis................................................................................................................................98
8.9.
Sample Size............................................................................................................................................99
8.10.
Data Monitoring Committee ..................................................................................................................99
9.
RESPONSIBILITIES........................................................................................................................................100
9.1.
Investigator Responsibilities ................................................................................................................100
9.1.1.
Good Clinical Practice........................................................................................................100
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ........................................................100
9.1.3.
Informed Consent...............................................................................................................100
9.1.4.
Confidentiality....................................................................................................................101
9.1.5.
Study Files and Retention of Records ................................................................................101
9.1.6.
Case Report Forms.............................................................................................................102
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................103
9.1.8.
Inspections..........................................................................................................................103
9.1.9.
Protocol Compliance..........................................................................................................103
9.2.
Sponsor Responsibilities ......................................................................................................................104
9.2.1.
Protocol Modifications.......................................................................................................104
9.2.2.
Study Report and Publications ...........................................................................................104
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................104
9.3.1.
Payment Reporting.............................................................................................................104
9.3.2.
Access to Information for Monitoring................................................................................105
9.3.3.
Access to Information for Auditing or Inspections ............................................................105
9.3.4.
Study Discontinuation........................................................................................................105
10.
REFERENCES .................................................................................................................................................106
11.
APPENDICES ..................................................................................................................................................111
Appendix 1.
Investigator Signature Page..................................................................................................112
Appendix 2.
Study Procedures Table........................................................................................................113
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................117
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............118
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................140
Appendix 6.
Optional Intensive Pharmacokinetic Sub-study Recommended Meal Examples.................143
Appendix 7.
Child-Pugh-Turcotte Score {Pugh 1973}.............................................................................144


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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................31
Table 1-2.
GS-US-320-0108 and GS-US-320-0110: HBV DNA Outcome at Week 48 Using 
HBV DNA of < 29 IU/mL, Missing = Failure (Full Analysis Set) ........................................32
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with ALT 
Normalization at Week 48, Missing = Failure (Full Analysis Set with Baseline ALT 
> ULN) ...................................................................................................................................33
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or Seroconversion at 
Week 48, Missing = Failure (Serologically Evaluable Full Analysis Set) .............................34
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................36
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for ≥5% of 
Subjects in Either Treatment Group in the TAF Phase 3 Safety Population (Safety 
Analysis Set)...........................................................................................................................37
Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by Treatment 
Regimen in > 1 Subject in the TAF Phase 3 Safety Population (Safety Analysis Set)...........38
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral Density at 
Week 48 (Hip DXA Analysis Set and Spine DXA Analysis Set) ..........................................39
Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine Creatinine 
Ratios at Week 48 in the TAF Phase 3 Safety Population (Safety Analysis Set)...................41
Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent Grade 3 or 4 
Laboratory Abnormalities Reported for at Least 1% of Subjects in Either Treatment 
Group in the Overall TAF Phase 3 Safety Population (Safety Analysis Set) .........................42
Table 1-11.
GS-US-120-0108: Statistical Comparisons of TAF PK Parameter Estimates in 
Subjects With Severe Renal Impairment and Subjects With Normal Renal Function ...........44
Table 1-12.
GS-US-120-0108: Statistical Comparisons of TFV PK Parameter Estimates 
Between Subjects With Severe Renal Impairment and Subjects With Normal Renal 
Function..................................................................................................................................45
Table 5-1.
Disallowed Concomitant Medications....................................................................................61
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted Steady-State TFV PK Profile After Administration of TAF in Subjects 
With CHB with ESRD on Chronic HD..................................................................................46
Figure 3-1.
Study Design Schematic.........................................................................................................53


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of
Switching to Tenofovir Alafenamide (TAF) from Tenofovir 
Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment 
(OAV) in Virologically Suppressed Chronic Hepatitis B Subjects 
with Renal and/or Hepatic Impairment
IND Number:
EudraCT Number:
115561
2016-004625-16
Study Centers Planned:
Approximately 60 centers in North America, Europe, and 
Asia Pacific regions
Objectives:
The primary objectives of this switch study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD at 
Week 24

To measure the proportion of subjects achieving virologic 
response (HBV DNA < 20 IU/mL) at Week 24
The secondary objectives of this switch study are as follows: 

To evaluate the safety and tolerability of TAF 25 mg QD at 
Weeks 48 and 96

To measure the proportion of subjects achieving virologic 
response (HBV DNA < 20 IU/mL) at Weeks 48 and 96

To evaluate biochemical (ALT normal and ALT normalization) 
and serological (loss of HBeAg with seroconversion to 
anti-HBe in HBeAg-positive subjects and loss of HBsAg with 
seroconversion to anti-HBs) responses at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on renal parameters at 
Weeks 24, 48, and 96 in subjects with moderate or severe renal 
impairment and hepatically impaired subjects

To evaluate the safety of TAF 25 mg QD as determined by 
percentage change from Baseline in hip and spine bone mineral 
density (BMD) at Weeks 24, 48, and 96


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
To evaluate the effect of TAF 25 mg QD on fibrosis as assessed 
by Fibrotest® at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on changes in 
Child-Pugh-Turcotte (CPT) and Model for End-stage Liver 
Disease (MELD) scores at Weeks 24, 48, and 96 in hepatically 
impaired subjects
The exploratory objectives of this switch study are as follows:
Study Design:
This is an open label, multi-center study to evaluate the safety and 
efficacy of switching to TAF 25 mg QD from TDF and/or other 
OAV in virologically suppressed subjects who have chronic 
hepatitis B (CHB) with renal and/or hepatic impairment.
Approximately 120 subjects will be enrolled into the 2 Parts of the 
study.
Part A (Renally Impaired Subjects):
Approximately 90 subjects will be enrolled into 2 cohorts and 
stratified by the level of renal impairment. Approximately 50% 
(target n = 42 to 46) of subjects enrolled into Part A should be 
virologically suppressed (HBV DNA < LLOQ) for at least 
6 months on TDF or a TDF-containing anti-HBV regimen for CHB
at time of Screening.
Cohort 1: Moderate or Severe renal impairment

Moderate renal impairment: (estimated glomerular filtration 
rate by the Cockcroft-Gault formula {Cockcroft 1976}
30 mL/min ≤[eGFRCG] ≤59 mL/min)

Severe renal impairment: (15 mL/min ≤eGFRCG < 30 mL/min)
eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
CCI


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Cohort 2: End-stage renal disease (ESRD)

Estimated glomerular filtration rate (eGFR) < 15 mL/min and 
maintained on hemodialysis (HD) at time of Screening
Approximately 20% (target n = 16 to 18) of subjects enrolled into 
Part A will be enrolled into Cohort 2. 
Part B (Hepatically Impaired Subjects):
Approximately 30 subjects, all of whom are virologically 
suppressed (HBV DNA < LLOQ) for at least 6 months on TDF, or 
a TDF-containing anti-HBV regimen, or other OAV(s) for CHB at 
time of Screening, will be enrolled with:

Moderate hepatic impairment (CPT Class B [Appendix 7]; 
Score of 7-9 inclusive) OR

Severe hepatic impairment (CPT Class C; Score of 10-12 
inclusive) 
The duration of study drug treatment for all subjects is 96 weeks.
Subjects in Part A (renally impaired) with HBsAg loss with 
confirmed seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion 
to anti-HBs. Subjects with HBsAg loss with confirmed 
seroconversion prior to Week 24 are not permitted to discontinue 
study drug prior to the Week 24 visit. Subjects with HBsAg loss 
with confirmed seroconversion will be followed off treatment every 
4 weeks for 12 weeks and then per the study visit schedule 
(Appendix 2) through Week 96/Early Discontinuation (ED). 
Discontinuation of study drug for subjects experiencing HBsAg 
loss with confirmed seroconversion, who have known bridging 
fibrosis or compensated cirrhosis, should be considered on a case 
by case basis.
Subjects with moderate or severe hepatic impairment (Part B) who 
experience HBsAg loss and seroconversion to anti-HBs should not
discontinue study drug.
Subjects in Part A (renally impaired) who permanently discontinue 
study drug (either prematurely or after completing 96 weeks of 
treatment) for reasons other than HBsAg loss with confirmed 
seroconversion to anti-HBs will be followed every 4 weeks for 
24 weeks off treatment or until initiation of appropriate, alternative 
HBV therapy, whichever occurs first. Use of appropriate, 
alternative HBV therapy is strongly encouraged. 
For subjects in Part B (hepatically impaired) who permanently 
discontinue study drug, immediate initiation of appropriate, 
alternative HBV therapy is strongly recommended.


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A data monitoring committee (DMC) will review the progress of 
the study and perform review of safety data after 30 subjects have 
completed 12 weeks of treatment. However, Gilead will defer to the 
DMC for any decision to convene earlier or more frequently. The 
DMC will examine the safety results of the trial and also focus on 
logistical issues such as accrual, retention, quality of clinical and 
laboratory data, and implications of results of external studies. No 
formal stopping rules will be used by the DMC for safety outcomes. 
Rather, a clinical assessment will be made to determine if the 
nature, frequency, and severity of adverse effects associated with 
study treatment warrant the early termination of the study to be in 
the best interests of the participants.
Number of Subjects 
Planned:
Approximately 120 subjects will be enrolled into the 2 Parts of the 
study:
Part A (renally impaired; approximately 90 subjects):
Approximately 50% (target n = 42 to 46) of subjects enrolled into
Part A should be virologically suppressed (HBV DNA < LLOQ) for 
at least 6 months on TDF or a TDF-containing anti-HBV regimen
for CHB at time of Screening.
Approximately 20% (target n = 16 to 18) of subjects enrolled into
Part A should have ESRD and be maintained on HD at time of 
Screening (Cohort 2). 
Part B (hepatically impaired; approximately 30 subjects):
Subjects should have moderate or severe hepatic impairment and 
should be virologically suppressed (HBV DNA < LLOQ) for at 
least 6 months on TDF, or a TDF-containing anti-HBV regimen, or 
other OAV(s) for CHB at time of Screening.
Target Population:
Adult subjects with CHB who are virologically suppressed 
(HBV DNA < LLOQ) for ≥6 months on TDF and/or other OAV
treatment(s) and have renal impairment (Part A), and those who are 
virologically suppressed (HBV DNA < LLOQ) for ≥ 6 months on 
TDF, or a TDF-containing anti-HBV regimen, or other OAV(s) for 
CHB with hepatic impairment (Part B).
Duration of Study 
Drug Treatment:
96 weeks


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Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be 
eligible to participate in the study:
All Subjects (Parts A and B):
1) Must have the ability to understand and sign a written informed 
consent form; consent must be obtained prior to initiation of 
study procedures
2) Adult male or non-pregnant female subjects, ≥18 years of age 
based on the date of the Screening visit. A negative serum 
pregnancy test at Screening is required for female subjects of 
childbearing potential (as defined in Appendix 5).
3) Documented evidence of chronic HBV infection 
(e.g. HBsAg positive for ≥ 6 months) 
4) Normal ECG (or if abnormal, determined by the Investigator
not to be clinically significant)
5) ALT ≤10 × upper limit of normal (ULN) at Screening by 
central laboratory
6) Must be willing and able to comply with all study requirements
Part A Only (renal impairment):
1) Maintained on TDF and/or other OAV treatment(s) for CHB for 
at least 48 weeks and with viral suppression (HBV DNA 
< LLOQ) for ≥ 6 months prior to Screening 

All subjects must have HBV DNA < 20 IU/mL at Screening
by central laboratory

Both HBeAg positive and negative subjects are eligible to 
participate
2) Moderate renal impairment (30 mL/min ≤eGFRCG ≤59 mL/min), 
severe renal impairment (15 mL/min ≤eGFRCG < 30 mL/min) 
using the Cockcroft-Gault equation {Cockcroft 1976}, or ESRD 
(eGFR < 15 mL/min) maintained on HD

eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)

Stable renal function (for subjects with moderate or severe 
impairment): serum creatinine measured at least once within 
three months prior to Screening. The measurement 
difference between the value measured within three months 
prior to Screening versus the Screening value must be 
≤25% of the Screening value


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Part B Only (hepatic impairment): 
1) Maintained on TDF and/or other OAV(s) for CHB for at least 
48 weeks and with viral suppression (HBV DNA < LLOQ) for 
≥ 6 months prior to Screening

All subjects must have HBV DNA < 20 IU/mL at Screening
by central laboratory

Both HBeAg positive and negative subjects are eligible to 
participate
2) CPT score (Appendix 7) of 7-12 (inclusive) OR a past history of 
CPT score ≥ 7 and any CPT score ≤ 12 at Screening
3) eGFRCG ≥30 mL/min using the Cockcroft-Gault equation 
{Cockcroft 1976}:

eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible to participate in the study:
All Subjects (Parts A & B):
1) Pregnant women, women who are breastfeeding or who believe
they may wish to become pregnant during the course of the
study
2) Males and females of reproductive potential who are unwilling
to use an “effective”, protocol-specified method(s) of
contraception during the study (Appendix 5).
3) Co-infection with HCV, HIV, or HDV

Subjects who are HCV positive, but have a documented 
negative HCV RNA, are eligible
4) Prior Interferon (IFN) use within 6 months of Screening
5) Evidence of hepatocellular carcinoma (i.e. evidenced by 
imaging within 6 months of Screening)
6) Received solid organ or bone marrow transplant
7) Significant cardiovascular, pulmonary, or neurological disease 
in the opinion of the investigator


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8) Malignancy within 5 years prior to screening, with the
exception of specific cancers that are cured by surgical resection 
(basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible
9) Currently receiving therapy with immunomodulators
(e.g. corticosteroids), nephrotoxic agents, or agents capable of 
modifying renal excretion
10) Known hypersensitivity to study drugs, metabolites, or
formulation excipients
11) Current alcohol or substance abuse judged by the investigator to
potentially interfere with subject compliance
12) Any other clinical condition or prior therapy that, in the opinion
of the Investigator, would make the subject unsuitable for the
study or unable to comply with dosing requirements.
13) Use of investigational agents within 3 months of Screening, 
unless allowed by the Sponsor
14) Use of any prohibited medication as described in Section 5.3.
Part A Only (renal impairment):
1) Current or historical evidence of clinical hepatic decompensation 
(e.g., ascites, encephalopathy or variceal hemorrhage)
2) Abnormal hematological and biochemical parameters, including:

Hemoglobin < 9 g/dL

Absolute neutrophil count < 750/mm3

Platelets ≤ 50,000/mm3

AST > 10 × ULN

Albumin < 3.0 g/dL

Total bilirubin > 2.5 × ULN

INR > 1.5 × ULN (unless stable on anticoagulant regimen)
3) Subjects with ESRD (i.e. eGFRCG < 15 mL/min) not on HD, or 
those on other forms of renal replacement therapy 
(i.e. peritoneal dialysis)
Part B Only (hepatic impairment): 
1) Active variceal bleeding within 6 months or prior placement of 
a portosystemic shunt (such as transjugular intrahepatic 
portosystemic shunt [TIPS])
2) History of hepatorenal syndrome, hepatopulmonary syndrome, 
Grade 3 or Grade 4 hepatic encephalopathy, or spontaneous 
bacterial peritonitis within 6 months of Screening


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3) Grade 2 hepatic encephalopathy at Screening
4) MELD score ≥30
5) Abnormal hematological and biochemical parameters, including

Absolute neutrophil count < 750/mm3

Platelets < 30,000/mm3

Hemoglobin < 8.0 g/dL
Study Procedures/
Frequency:

Screening Visit

Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 24, 
36, 48, 60, 72, and 96/Early Discontinuation (ED)

Subjects in Part A (renally impaired) who permanently 
discontinue study drug (either prematurely or after completing 
96 weeks of treatment) for reasons other than HBsAg loss with 
confirmed seroconversion to anti-HBs will be followed every 
4 weeks for 24 weeks off treatment or until initiation of 
appropriate, alternative HBV therapy, whichever occurs first.
Use of appropriate, alternative HBV therapy is strongly 
encouraged. 

For subjects in Part B (hepatic impairment) who permanently 
discontinue study drug, immediate initiation of appropriate, 
alternative HBV therapy is strongly recommended.

Review of concomitant medications, assessment for adverse 
events, and vital signs and weight measurement will be 
conducted at all study visits.

Laboratory analyses (serum chemistry and liver function tests, 
hematology, eGFRCG, urinalysis [for all subjects except only 
where available for subjects in Part A, Cohort 2 (ESRD subjects 
on HD)], and plasma HBV DNA level) will be conducted at all 
study visits.
Screening visit assessments include:

Complete physical examination with height, body weight, vital 
signs, and medical history (including HBV disease and 
treatment history)

Pregnancy testing (for females of childbearing potential)

Plasma HBV DNA level (must be < 20 IU/mL by central 
laboratory at time of Screening to be eligible)

HBV serology (qualitative HBsAg and HBeAg; HBeAb and 
HBsAb reflex testing will be performed as needed) and 
quantitative HBsAg


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
HCV, HDV and HIV testing

Baseline DXA scans of the hip and spine can be performed at 
any time during the Screening period, but should be conducted 
at least 14 days prior to the first dose of study drug to ensure an 
acceptable pre-dose DXA scan.

INR and alpha fetoprotein (AFP); an AFP > 50 ng/mL at 
Screening must have an appropriate evaluation (e.g., CT scan if 
not performed within the previous 6 months) in order to rule out 
HCC prior to being permitted to enter the study.

CPT (Appendix 7) and MELD Scores for Part B subjects 
(hepatic impairment) only

Urine drug screen (for all subjects except only where available 
for subjects in Part A, Cohort 2 [ESRD subjects on HD])

ECG
Baseline and On Treatment assessments include:

Complete physical examinations with body weight and vital 
signs will be performed at Baseline, Weeks 24, 48, 72, and 
96/ED. A symptom driven physical exam will be performed at 
all other visits.

Pregnancy testing (for females of childbearing potential)

HBV serology (qualitative HBsAg and HBeAg) and 
quantitative HBsAg will be performed at Baseline and 
Weeks 12, 24, 36, 48, 60, 72, and 96/ED. HBeAb and HBsAb 
reflex testing will be performed as needed.

Fasting blood sample for metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and 
triglycerides]) at Baseline and Weeks 24, 48, 72, and 96/ ED

Fibrotest® at Baseline and at Weeks 24, 48, and 96/ED

CPT (Appendix 7) and MELD Scores at Baseline and at 
Weeks 24, 48, and 96/ED for Part B subjects 
(hepatic impairment) only

Fracture Risk Assessment (Baseline only)

Vitamin D assessment at Baseline and at Weeks 24 and 48

Fasting blood for serum bone biomarkers at Baseline, and at 
Weeks 4, 12, 24, 48, 72, 96/ED

Fasting urine for renal biomarkers at Baseline, and at 
Weeks 4, 12, 24, 48, 72, and 96/ED for all subjects except
Part A, cohort 2 (ESRD subjects on HD) 


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
Hip and Spine DXA Scans will be conducted at Weeks 24, 48, 
72, and 96/ED. The ED visit DXA should be done if not done 
within the last 12 weeks of this visit.

ECG will be performed at Weeks 48 and 96/ED

 
 
 
 
 
 
 
 
 

Sequence analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance may be performed at
Baseline for subjects with HBV DNA ≥69 IU/mL and may be 
attempted for viremic subjects (HBV DNA ≥69 IU/mL) at 
Weeks 24, 48, and 96/ED. Phenotypic analysis will be 
performed for subjects that are subjected to sequence analysis.
As it may not be known at the time of the visit whether a 
subject is viremic or if it will be their last study visit, a separate 
virology sample for potential resistance surveillance will be 
collected at each study visit.

In the event of unconfirmed virologic rebound (HBV DNA 
≥20 IU/mL), subjects will be asked to return to the clinic for a 
scheduled or unscheduled blood draw.
For virologic rebound occurring within the first 12 weeks of 
the study, the next scheduled visit will used for follow up. 
For virologic rebound occurring after Week 12, the subject 
will return for an unscheduled visit 2-3 weeks after the date 
of the original test that resulted with HBV DNA virologic 
rebound for confirmation of virologic rebound. At this follow 
up visit, a serum blood sample for resistance testing will be 
obtained. For unscheduled visits, the subject will be required 
to bring their supply of study drug with them and be assessed 
for adherence by pill count, and if necessary, the subject will 
be re-counseled on adherence to study medication.

Plasma, serum, and urine will be collected at Baseline and at 
every on-treatment visit thereafter for storage for all subjects. 
Urine for storage will be collected where available for subjects 
in Part A, Cohort 2 (ESRD subjects on HD).
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
Health Related Quality of Life (HRQoL) Surveys (SF-36, 
CLDQ, WPAI, and EQ-5D-3L) at Baseline, Weeks 24, 48, and 
96/ED. The ED visit HRQoLs should be done if not done within 
the last 24 weeks of this visit.

Health Utilization Questionnaire will be administered by site 
staff at Baseline and at every on-treatment visit thereafter.

Serum Cystatin C will be assessed at Baseline for all subjects. 
Ongoing assessments of renal function using eGFRCG will be 
done in all subjects except Part A, Cohort 2 (ESRD subjects on 
HD). In addition to eGFRCG, renal function by the eGFRCKD-EPI
formula for Cystatin C for management of potential 
nephrotoxicity will be assessed per Section 7.5.6.

Sparse PK samples
All subjects except Part A, Cohort 2 (ESRD subjects on HD):
A single PK blood sample will be collected at Baseline and 
at each subsequent on treatment visit. At the Week 4, 
Week 8, and Week 12 visit, study drug will be administered 
in clinic, and the single PK blood sample will be collected 
between 15 minutes and 4 hours post dose.
Part A, Cohort 2 Subjects (ESRD subjects on HD at selected 
sites):
4 samples will be collected at each of 4 hemodialysis 
sessions between Weeks 4 and Week 24, inclusive. 
At each session:
■
1 sample will be collected within 10 minutes before a 
hemodialysis session begins
■
During the hemodialysis session, 1 sample will be 
collected approximately 1 hour prior to conclusion of 
the hemodialysis session from both the arterial and 
venous sides of the dialyzer
■
Finally, 1 sample will be collected within 10 minutes 
after a hemodialysis session concludes.
On the day of hemodialysis, study drug should not be 
administered to subjects until after the completion of 
hemodialysis and collection of any required 
post-hemodialysis samples for Part A, Cohort 2.


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
Optional Intensive PK Substudy (separate consent required)

Plasma concentrations of TAF and TFV may be determined and 
PK parameters (including the hemodialysis extraction ratio for 
Part A, Cohort 2 subjects [ESRD subjects on HD]) may be 
estimated as appropriate.
See Section 6 (Study Procedures) for further information.
Test Product, Dose, and 
Mode of Administration:
Tenofovir alafenamide (TAF) 25 mg QD, oral administration with 
food
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Reference Therapy, 
Dose, and Mode of 
Administration:
NA
Criteria for Evaluation:
Safety:
The primary safety endpoint is

Incidence of graded adverse events and graded laboratory 
abnormalities at Week 24
The secondary safety endpoints are:

Incidence of graded adverse events and graded laboratory 
abnormalities at Week 48 and 96

Change from baseline in eGFRCG at Weeks 24, 48, and 96 in 
subjects with moderate or severe renal impairment and 
hepatically impaired subjects

Percent change from baseline in hip and spine bone mineral 
density (BMD) at Weeks 24, 48, and 96
The exploratory safety endpoints are: 
Efficacy:
The primary efficacy endpoint is:

Proportion of subjects achieving virologic response 
(plasma HBV DNA < 20 IU/mL ) at Week 24
The secondary efficacy endpoints are:

Proportion of subjects achieving virologic response 
(plasma HBV DNA < 20 IU/mL ) at Weeks 48 and 96

Proportion of subjects with plasma HBV DNA < 20 IU/mL 
and target detected/not detected (i.e. < LLOD) at 
Weeks 24, 48, and 96

Proportion of subjects with serological response (loss of HBsAg 
and seroconversion to anti-HBs, loss of HBeAg and 
seroconversion to anti-HBe in HBeAg-positive subjects) at 
Weeks 24, 48, and 96

Proportion of subjects with biochemical response (normal ALT 
and normalized ALT) at Weeks 24, 48, and 96
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
Change in fibrosis as assessed by FibroTest® at 
Weeks 24, 48, and 96

Change from baseline in CPT score (Appendix 7) and MELD 
score at Weeks 24, 48, and 96 in hepatically impaired subjects
Other exploratory endpoints are:
Pharmacokinetics:
Pharmacokinetic parameters will be listed and summarized for TAF 
and TFV using descriptive statistics (e.g., sample size, arithmetic 
mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum) by study Part and 
cohort. Plasma concentrations over time will be plotted in semi 
logarithmic and linear formats as mean ± standard deviation.
Statistical Methods:
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. 
The change from baseline in eGFRCG and eGFRCKD-EPI will be 
summarized. The change from baseline in serum creatinine will 
also be summarized using standard descriptive methods.
The percent change from baseline in hip and spine BMD will be 
summarized using standard descriptive methods (ie sample size, 
mean, standard deviation, median, Q1, Q3, minimum, maximum). 
The proportion of subjects with plasma HBV DNA < 20 IU/mL 
will be summarized descriptively (missing = failure) (M = F).
All secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum). All categorical secondary endpoints will 
be summarized by number and percentage of subjects who meet the 
endpoint.
Sample Size:
No formal sample size calculation was performed. A sample size of 
120 subjects is based on practical considerations and is considered 
sufficient to evaluate the primary objectives of the study.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
Degrees Celsius
°F
Degrees Fahrenheit
AASLD
American Association for the Study of Liver Diseases
ADV
Adefovir dipivoxil
AE
Adverse event
AFP
Alpha-fetoprotein
AhR
Aryl hydrocarbon receptor
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil counts
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
Anti-HBe
Anti-Hepatitis B e-antigen
Anti-HBs
Anti-Hepatitis s-antigen
AR
Adverse reaction
ARV
Antiretroviral
AST
Aspartate aminotransferase (SGOT)
AUCinf
Area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUC0last + (Clast/z)
AUCtau
Area under the plasma concentration versus time curve over the dosing interval (tau)
BCRP
Breast Cancer Resistance Protein
BMD
Bone mineral density
BMI
Body Mass Index
B2M
Beta-2-Microglobulin
bSAP
Bone specific alkaline phosphatase
CatA
Cathepsin A
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CLDQ
Chronic Liver Disease Questionnaire
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CPT
Child-Pugh-Turcotte
CRF/eCRF
case report form(s)/electronic case report form(s)
CRO
Contract (or clinical) research organization
CTX
C-type collagen sequence
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee


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DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry
EC
Ethics committee
EC50
50% Effective Concentration
EudraCT
European clinical trials database
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
eGFRCG
Estimated glomerular filtration rate by the Cockcroft-Gault formula
EKG / ECG
Electrocardiogram
EQ-5D-3L
EuroQol-5 Dimensions-3 Levels
ESRD
End Stage Renal Disease
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HD
Hemodialysis
HDL
High-density lipoprotein
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
IC20
20% inhibitory concentration
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation


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IEC
Independent ethics committee
IFN
Interferon
IMP
Investigational Medicinal Product
INR
International Normalized Ratio of Prothrombin time (INR)
IRB
Institutional review board
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LDL
Low-density lipoprotein
LdT
Telbivudine
LAM
Lamivudine
LLOD
Lower Limit of Detection
LLOQ
Lower Limit of Quantitation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
MT-2
Human T-lymphotrophic virus-1 transformed cells
M = E
Missing = Excluded
M = F
Missing = Failure
NDA
New Drug Application
NOAEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OAV
Oral antivirals
OL
Open-label
P1NP
Procollagen type 1 amino-terminal propeptide
PD
Pharmacodynamic
P-gp
P-glycoprotein
PK
Pharmacokinetic
pol
Polymerase
PXR
Pregnane X receptor
PT/INR
Prothrombin time/International normalized ratio
QD
Once daily (use only in tables)
RBP
Retinol binding protein
RPV
Rilpivirine
RT
Reverse transcriptase
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SF-36
Short Form (36)


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SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
Scys
Serum cystatin C
TAF
Tenofovir Alafenamide, GS-7340
TAF Fumarate
Tenofovir Alafenamide Fumarate, GS-7340-03
TBV
Telbivudine
TDF
Tenofovir Disoproxil Fumarate
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TIPS
Transjugular Intrahepatic Portosystemic Shunt
Tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
T3
Triiodothyronine
UACR
Urine albumin-to-creatinine ratio
UGT1A1
Uridine glucuronosyltransferase 1 family, polypeptide A1 
ULN
Upper limit of the normal range
UPCR
Urine protein-to-creatinine ratio
US
United States
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a major public health care issue worldwide and one of the principal 
causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The hepatitis B 
virus (HBV) is easily transmissible through perinatal, percutaneous, and sexual exposure 
{Lok 2009}. Following acute HBV infection, 5% to 10% of adults and up to 90% of children fail 
to produce an immune response adequate to clear the infection; these individuals become chronic 
carriers of the virus {Zuckerman 1996}. Individuals who develop CHB are at substantial risk of 
cirrhosis, hepatic decompensation, and HCC, which will afflict 15% to 40% of subjects with 
CHB in the absence of effective treatment {World Health Organization (WHO) 2015a, 
Wright 2006}. Liver cancer is the third leading cause of cancer deaths globally, with the highest 
burden of disease found in regions where HBV is endemic {Global Burden of Disease Cancer 
Collaboration 2015}. Recent reports estimated that 250 to 350 million individuals were living 
with HBV (i.e., are hepatitis B surface antigen [HBsAg] positive) in 2010, representing a 
worldwide prevalence of 3.6%, with considerable geographic variability {Schweitzer 2015, 
World Health Organization (WHO) 2015b}. For example, HBV prevalence rates of 0.01%, 
0.76%, 4.0%, 5.5%, and 22.4% have been reported for the United Kingdom, Canada, Turkey, 
China, and South Sudan, respectively. In 2013, an estimated 686,000 deaths were due to HBV 
infection, placing it among the top 20 causes of mortality worldwide {G. B. D. Mortality Causes 
of Death Collaborators 2015, Ott 2012}.
Worldwide universal vaccination remains the goal for eliminating HBV infection and its 
complications, yet despite the availability of HBV vaccine programs in many countries, new 
HBV infections are still common even in areas of low prevalence. The World Health 
Organization estimates that each year there are over 4 million acute clinical cases of HBV 
infection globally {World Health Organization (WHO) 2015b}. In the United States (US), 
approximately 20,000 people become acutely infected each year according to an estimate from 
the Centers for Disease Control and Prevention {Centers for Disease Control (CDC) 2013}.
The natural history of chronic hepatitis B virus infection and disease is complex and highly 
variable. Following acute hepatitis B infection, up to 90% of newborns who are vertically 
infected, and 25-50% of children who acquire HBV within the first 6 years of life, will become 
chronic carriers of the virus when the immune system is thought to be immature, compared to 
immunocompetent individuals who become infected during adulthood (< 1%) {Fattovich 2008, 
Sarin 2015}. CHB has traditionally been characterized by four distinct phases of variable duration 
that reflect the dynamics of viral replication and the evolving host immune response 
{Fattovich 2008, Sokal 2013}. In the first, or the immune tolerant phase, individuals have high 
plasma levels of HBV DNA, detectable hepatitis B surface antigen (HBsAg) and hepatitis B e 
antigen (HBeAg), with normal or slightly elevated serum alanine transaminase (ALT) levels 
reflective of minimal inflammation and fibrosis. This phase typically extends into late childhood 
or adolescence, and is followed by an HBeAg-positive, immune-active phase wherein ALT levels 
are persistently elevated along with fluctuating levels of HBV DNA, reflective of moderate to 
severe inflammation or fibrosis. This phase may be followed by loss of HBeAg with 
seroconversion to anti-HBe. In the inactive CHB phase, subjects have undetectable or low levels 


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of HBV DNA (< 2000 IU/mL), the presence of anti-HBe antibody, and normal or minimal 
elevation in serum ALT, which reflects minimal inflammation but with variable fibrosis. This 
third phase can evolve in a subgroup of individuals to an HBeAg-negative, immune reactivation 
phase, in which ALT levels and HBV DNA levels are increased. Subjects develop 
HBeAg-negative CHB as a result of variants that arise in the precore or core promoter region of 
the virus {Sarin 2015}. The goal of anti-HBV therapy is to improve long-term survival and 
quality of life by reducing disease progression to cirrhosis, decompensated liver disease, and HCC 
{Sarin 2015, Terrault 2015}. As seroclearance of HBsAg is a rare spontaneous occurrence in 
patients with CHB, durable anti-HBe seroconversion in HBeAg-positive subjects is sometimes 
considered a reasonable endpoint, associated with improved prognosis, including a reduced risk of 
HCC. However, in many subjects who discontinue treatment following anti-HBe seroconversion, 
disease relapse with increased levels of viremia can occur {Sarin 2015}. Successful reduction of 
viremia to levels below assay detection leads to reduced inflammation and slowing or reversal of 
fibrosis, and in some patients with decompensated liver disease progression to liver failure and the 
need for liver transplantation is reduced {Chang 2010, Marcellin 2013}.
Currently, there are 2 approved options for treatment of CHB: injectable interferons and oral 
antiviral (OAV) agents. Of these, treatment with OAV agents has been more successful in 
achieving and maintaining a high degree of viral suppression in subjects with CHB. The 
development of nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) was a major breakthrough 
for the treatment of CHB, providing effective suppression of viral replication and reducing the risk 
of long-term complications {Marcellin 2013, World Health Organization (WHO) 2015a}. 
However, several N[t]RTIs possess a low barrier for viral resistance development, including 
lamivudine (LAM), telbivudine (TBV), and adefovir dipivoxil (ADV) {European Association for 
the Study of the Liver (EASL) 2017, Liaw 2012}. Additionally, while development of resistance to 
entecavir (ETV) is low in treatment-naïve subjects, the cumulative probability of ETV resistance 
increases substantially with long-term use in subjects, particularly in subjects who are refractory to 
lamivudine, and those with lamivudine resistance (up to 57% through 6 years of treatment) 
{Tenney 2009}. In contrast, resistance to tenofovir disoproxil fumarate (TDF; Viread®) has not 
been documented through 8 years of use {Kitrinos 2014, Liu 2016}.
Tenofovir (TFV) is a nucleotide analog with limited oral bioavailability that inhibits reverse 
transcription in HIV-1 and HBV. TDF, an oral prodrug of TFV, was first approved for the 
treatment of HIV infection in 2001 to be given in combination with other antiretroviral (ARV) 
agents and was approved for treatment of CHB as monotherapy in 2008. TDF is currently 
approved in over 165 countries, including the US, Canada, Europe, Japan, Taiwan, South Korea, 
and China, with more than 3,393,649 patient-years of use worldwide for both HIV and HBV 
infections since first marketing approval. TDF is a first-line treatment for CHB in all major 
treatment guidelines {European Association for the Study of the Liver (EASL) 2017, Sarin 2015, 
Terrault 2015}. Although highly effective, use of TDF is associated with nephrotoxicity and 
bone-related toxicity in some subjects. 
Tenofovir alafenamide (TAF) is a phosphonamide prodrug of TFV that is more stable in plasma 
than TDF, and provides higher intracellular levels of the active phosphorylated metabolite 
TFV-DP to target cells (eg, HBV-infected hepatocytes and HIV-infected lymphoid cells) with 
approximately 90% lower circulating levels of TFV relative to TDF at therapeutically active doses 


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{Agarwal 2015, Babusis 2013, Murakami 2015, Ruane 2013}. The distinct metabolism of TAF 
offers the potential for an improved safety profile when compared with TDF. In support of this 
concept are recent results from a large dataset of 1733 HIV-infected, treatment naive subjects 
randomized to receive treatment with the fixed-dose combination [FDC] of elvitegravir (E), 
cobicistat (C), emtricitabine (F), TAF [E/C/F/TAF; Genvoya®] or E/C/F/TDF [STB; Stribild®]). 
Renal and bone parameters were significantly less affected in subjects who received E/C/F/TAF 
compared with E/C/F/TDF {Sax 2015, Wohl 2016}. Furthermore, in a large open-label Phase 3 
study, virally suppressed HIV-1-infected patients were switched from TDF-based regimens to a 
TAF-based regimen (E/C/F/TAF) with data supporting the efficacy and safety of switching 
regimens {Gallant 2016, Mills 2016, Pozniak 2016}. In studies of suppressed HIV-infected 
patients taking TDF-containing antiretroviral regimens, including those with mild or moderate 
renal impairment, switching to at TAF-based regimen was associated with improved bone and 
renal parameters while viral suppression was well maintained. In adult subjects with CHB, a 
global Phase 3 program for TAF consisting of 2 prospective, randomized, active-controlled 
studies with 1 each in HBeAg-negative (Study GS-US-320-0108) and HBeAg-positive 
(Study GS-US-320-0110) subjects is currently ongoing as described below. Efficacy and safety 
results at Week 48 from Studies GS-US-320-0108 and GS-US-320-0110 are summarized below 
in Section 1.2.3. Based on Week 48 results, TAF (Vemlidy®) was approved by the US FDA on 
10 November 2016 for the treatment of CHB infection in adults with compensated liver disease 
{VEMLIDY® 2016}, in Japan on 19 December 2016 for the suppression of viral replication in 
CHB patients with evidence of HBV replication and abnormal liver function, in the European 
Union (EU) on 09 January 2017 for the treatment of CHB in adults and adolescents 
(aged 12 years and older with body weight at least 35 kg) {Vemlidy 2017}, in Australia on 
21 February 2017 for the treatment of CHB in adults, and in Canada on 17 May 2017 for the 
treatment of CHB in adults with compensated liver disease. Marketing Applications for TAF 
25 mg tablets for the treatment of CHB have been filed in a number of global territories.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy] methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1) is 
a novel oral prodrug of TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. 
Tenofovir is metabolized intracellularly to the active metabolite, TFV-DP, a competitive 
inhibitor of HIV-1 reverse transcriptase (RT) and HBV reverse transcriptase (HBV RT) that 
terminates the elongation of the viral DNA chain. In the development of TAF, three forms of the 
drug substance have been used in various studies: GS-7340, synonym for GS-7340 as the free 
base; GS-7340-02, synonym for TAF monofumarate (1:1); and GS-7340-03 as the hemifumarate 
(2:1). GS-7340-03, also known as TAF fumarate, which is being used in the Phase 3 studies 
GS-US-320-0108 and GS-US-320-0110, is considered comparable based on physical/chemical 
properties to GS-7340-02 that has been used in previous studies and a number of ongoing 
studies. GS-7340-03 was also used in the Phase 1b study GS-US-320-0101. GS-7340-03 and 
GS-7340-02 exist as the free base, TAF, in blood and biological fluids. 
For further information on TAF, please refer to the current Investigator’s Brochure.


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1.2.2.
Preclinical Pharmacology and Toxicology
Virology
Following its release from the prodrug TAF, TFV is metabolized intracellularly to the active 
metabolite, TFV-DP, a competitive inhibitor of HBV polymerase/reverse transcriptase (pol/RT) 
and HIV-1 RT that terminates the elongation of the viral DNA chain during the process of HBV 
and retroviral replication.
Compared to TDF, TAF is relatively stable in plasma, but rapidly converts to TFV inside cells. 
The cellular enzymes responsible for conversion of TAF to TFV are cathepsin A (CatA), which 
is broadly expressed in cells, and carboxylesterase 1 (CES1), which is highly expressed in liver. 
In HBV target cells, primary human hepatocytes, TAF is primarily hydrolyzed by CES1 with 
CatA making a minor contribution {Murakami 2015}. In HIV-1 target cells, primary human 
lymphoid cells, CatA is the major enzyme hydrolyzing TAF to TFV. In vitro studies have shown 
no significant variation for conversion to TFV and antiviral activity of TAF within PBMCs and 
macrophages from multiple donors. The covalent anti-hepatitis C virus (HCV) protease 
inhibitors (PIs) telaprevir and boceprevir were identified as the only potent inhibitors of CatA 
mediated hydrolysis of TAF in a biochemical assay (PC-120-2001).
TAF is a potent inhibitor of HBV replication, exhibiting in vitro activity comparable to that of 
TDF with an effective concentration (EC50) value of 18 nM. Additionally, TAF is similarly 
active in vitro against wild-type genotype A-H HBV clinical isolates (PC-320-2003). TAF also 
exhibits potent anti-HIV activity in lymphoid T-cells, primary human PBMCs, and macrophages 
with EC50 values ranging from 3 to 14 nM. The in vitro activity of TAF against HIV-1 is 
100- to 600-fold greater than TFV and 4- to 6-fold greater than TDF {Robbins 1998}. In MT-2 
cells, TAF shows low cytotoxicity with a selectivity index of > 10,000. Based on data generated 
with the parent nucleotide TFV, TAF is active against a wide range of HIV-1 subtypes and also 
against HIV-2. 
For further information on the virology of TAF, refer to the current Investigator’s Brochure for 
TAF.
Safety Pharmacology
The IC20 and the IC50 for the inhibitory effect of TAF fumarate on human ether-a-go-go-related 
gene (hERG) potassium current was estimated to be greater than 30 μM (PC-120-2005). TAF in 
the monofumarate form has been evaluated to determine potential functional effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006), and 
gastrointestinal systems (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). TAF at 1000 mg/kg reduced distal transit and 
increased stomach weights starting 2 hours postdosing, with reversibility beginning by 6 hours 
after dosing. The no observed effect level (NOEL) for gastrointestinal motility was 100 mg/kg.


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Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments were performed using TAF monofumarate 
(GS-7340-02), and all study data described reflect the dosage of the monofumarate. For 
reference, 100 mg of TAF monofumarate is equivalent to 80 mg of the GS-7340 free base (TAF). 
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted) and
8.1 to 2.5 hours in rhesus monkeys.
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system. The primary 
route of elimination of TFV is renal excretion of unchanged drug based on intravenous studies of 
TFV. Following oral administration of GS-7340-02, approximately 15% of a radiolabeled dose is 
recovered in dog urine in 24 hours. TFV was the major species present in the urine (90%), with 
about 3.4% of TAF also present. Biliary excretion of TFV in dogs and fecal elimination of TFV
in rats and dogs are negligible.
TFV was the only species found in the intestinal contents and feces. In human systems, TAF is 
metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed oxidation 
(AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4 inhibition or 
induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by
clinically relevant drug-drug interactions is very low.
Nonclinical Toxicology
Because of lack of exposure to the prodrug TAF in mice and rats and achievable TFV exposures 
being less than previously tested in studies with TDF, Gilead and regulatory agencies have 
agreed that neither carcinogenicity studies nor a peri/postnatal study with TAF were warranted as 
they would not add to the overall risk evaluation or risk management of TAF.


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The oral toxicity of TAF was evaluated in mice, rats, dogs, and monkeys for treatment periods 
up to 9 months. Based on recommendations that renal karyomegaly is not a dose-limiting effect 
{Foran 1997} and observations in the rat that renal karyomegaly is not sufficient to induce renal 
toxicity or predict oncogenicity (M990205) (M990204), its toxicological significance is 
questionable and, therefore, it was not considered an adverse effect in determining the NOAEL.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day; the 9-month dog 
study defined a No observed adverse effect level (NOAEL) of 2 mg/kg/day, and the 28-day 
nonhuman primate study defined a NOAEL of ≥ 30 mg/kg/day. While no NOAEL was 
determined in the 13-week mouse study, the relevance of the nasal findings to humans is unclear.
TAF had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day. There was 
some evidence at 6 and 18/12 mg/kg/day for an effect to slightly prolong PR intervals. 
Additionally, at Week 39, TAF appeared to reversibly reduce heart rate with an associated mild 
QT prolongation. At Week 39, significant decreases in serum tri-iodothyronine (T3) were noted 
for animals receiving 18/12 mg/kg/day when compared to controls, which may have been 
associated with the slight prolongation of PR intervals. After the 3-month recovery period, serum 
T3 values returned to levels similar to the control group animals at the end of the study.
TAF was not genotoxic in either in vitro or in vivo assays. TAF fumarate had no adverse effects on 
male or female fertility parameters in rats. There was no effect on fetal viability or fetal 
development in pregnant rats administered doses of TAF monofumarate up to 200 mg/kg/day or in 
pregnant rabbits administered TAF monofumarate up to 100 mg/kg/day the highest doses tested. In 
the rat, a minor (7.7%) decrease in mean fetal body weight compared to the control group was 
observed at 200 mg/kg/day, which was a maternally toxic dose. At the NOAEL for embryo-fetal 
development of 200 mg/kg/day in rats, AUCtau values for TAF and TFV on Day 17 were 
0.65 and 35.7 μg•h/kg, respectively. At the NOEL for embryo-fetal development of 100 mg/kg/day 
in rabbits, AUCtau values for TAF and TFV on Day 20 were 10.7 and 23.5 μg•h/kg, respectively. 
The TFV exposures in both species were > 30-fold higher than the TFV AUCinf after a 25-mg dose 
of TAF monofumarate in humans.
For further information on TAF, refer to the current investigator’s brochure.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF)
Overall, approximately 2403 subjects have been enrolled in the TAF clinical program, of which 
approximately 1856 subjects have received Vemlidy single agent (439 healthy volunteers, 
1331 CHB infected subjects, and 86 HIV-1 infected subjects). The TAF clinical development 
program for CHB includes 2 ongoing Phase 3 studies in HBeAg-negative and HBeAg-positive 
subjects with CHB, a completed Phase 1b antiviral activity and safety/tolerability study in 
subjects with CHB, and a comprehensive Phase 1 program that also included evaluations of TAF
and TFV PK in subjects with impaired renal or hepatic function (additional information is 
provided in the IB).


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TAF clinical studies which are ongoing are listed below:

GS-US-320-1092, a Phase 2/3 study to evaluate the pharmacokinetics, safety, and antiviral 
Efficacy of TAF in Adolescents with Chronic Hepatitis B Virus Infection (ongoing)

GS-US-320-3912, a Phase 2 study to evaluate the efficacy and safety of TAF versus TDF 
300 mg in subjects with CHB and Stage 2 or greater chronic kidney disease who have 
received a liver transplant (ongoing)

GS-US-320-4018, a Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and 
Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) 300 mg QD to Tenofovir 
Alafenamide (TAF) 25mg QD in Subjects with Chronic Hepatitis B who are Virologically 
Suppressed (ongoing)
Please refer to the latest version of the investigator’s brochure for information on the clinical 
program.
An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF for Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described as follows:

GS-US-320-0108: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-negative subjects.

GS-US-320-0110: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-positive subjects.
In both of these similarly designed noninferiority studies, treatment naïve as well as treatment 
experienced subjects, including those with compensated cirrhosis, were randomized in a 2:1 ratio 
to receive either TAF 25 mg or TDF 300 mg once daily for 96 weeks. Randomization was 
stratified by plasma HBV DNA level (< 7, ≥ 7 to < 8, and ≥ 8 log10 IU/mL for 
Study GS-US-320-0108; < 8 and ≥ 8 log10 IU/mL for Study GS-US-320-0110) and OAV 
treatment status (treatment naive vs treatment experienced) at screening. In both studies, all 
subjects completing 96 weeks of double-blind therapy were eligible to continue open-label 
treatment with TAF 25 mg for an additional 48 weeks. Both protocols were amended in 
February 2016 (Amendment 3 of GS-US-320-0108 and GS-US-320-0110) in order to extend the 
duration of double-blind treatment to 144 weeks (3 years) and the duration open-label TAF 
treatment from Week 144 to Week 384 (8 year total study period).


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Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen 
(Number of Subjects)
Primary Endpoint 
Analysis
GS-US-320-0108
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-negative subjects with CHB
TAF 25 mg once daily (N = 285)
TDF 300 mg once daily (N = 140)
Week 48 efficacy, 
PK, and safety
GS-US-320-0110
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-positive subjects with CHB
TAF 25 mg once daily (N = 581)
TDF 300 mg once daily (N = 292)
Week 48 efficacy, 
PK, and safety
Demographic and disease characteristics were generally similar between the TAF and TDF 
groups in both studies and are representative of patient population of HBeAg-negative subjects 
in Study GS-US-320-0108 and HBeAg-positive subjects in Study GS-US-320-0110. In both 
studies the majority of subjects were male (> 60%) and Asian (> 70%). As would be expected 
based on the 2 distinct study populations, subjects in Study GS-US-320-0108 were older 
(median age: 47 years; range: 19-80 years) than subjects in Study GS-US-320-0110 (median age: 
36 years; range: 18-69 years). Differences in baseline characteristics between the 2 studies 
included HBV DNA levels (median levels were 5.7 and 7.9 log10 IU/mL for GS-US-320-0108
and GS-US-320-0110, respectively), serum ALT levels (median values were 67 and 85 U/L for 
GS-US-320-0108 and GS-US-320-0110, respectively), and number of years positive for HBV 
(6.0 and 4.0 years [median values] for GS-US-320-0108 and GS-US-320-0110, respectively). 
The distribution of HBV genotypes was similar between treatment groups in both studies with 
the most common genotypes being C (46.1%), D (24.3%), and B (20.4%).
Efficacy of TAF in Subjects with CHB
Primary Endpoint Analysis
For both studies, the primary efficacy endpoint was the proportion of subjects with plasma
HBV DNA < 29 IU/mL at Week 48. Table 1-2 presents HBV DNA outcomes for
Studies GS-US-320-0108 {Buti 2016} and GS-US-320-0110 {Chan 2016} for subjects at 
Week 48. In both studies, similar rates of HBV DNA suppression were achieved in the 
2 treatment groups when assessed using the M = F method at Week 48 for the Full Analysis Set 
(FAS). The percentages of subjects with HBV DNA levels < 29 IU/mL at Week 48 were as 
follows:

Study GS-US-320-0108: TAF 94.0%, TDF 92.9%; difference in proportions
(baseline stratum-adjusted): 1.8%, 95% CI: −3.6% to 7.2%

Study GS-US-320-0110: TAF 63.9%, TDF 66.8%; difference in proportions
(baseline stratum-adjusted): −3.6%, 95% CI: −9.8% to 2.6%


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In both studies, because the lower bound of the 2-sided 95% CI of the difference (TAF − TDF)
in the response rate was greater than the prespecified −10% margin, the TAF group met the
primary endpoint of noninferiority to the TDF group.
Table 1-2.
GS-US-320-0108 and GS-US-320-0110: HBV DNA Outcome at 
Week 48 Using HBV DNA of < 29 IU/mL, Missing = Failure 
(Full Analysis Set)
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
(N = 285)
TDF 300 mg
(N = 140)
TAF 25 mg
(N = 581)
TDF 300 mg
(N = 292)
HBV DNA < 29 IU/mL
268 (94.0%)
130 (92.9%)
371 (63.9%)
195 (66.8%)
P-valuea
0.47
0.25
Difference in Proportions (95% CI)b
1.8% (−3.6% to 7.2%)
−3.6% (−9.8% to 2.6%)
HBV DNA ≥ 29 IU/mL
7 (2.5%)
4 (2.9%)
183 (31.5%)
88 (30.1%)
No Virologic Data at Week 48
10 (3.5%)
6 (4.3%)
27 (4.6%)
9 (3.1%)
Discontinued Study Drug Due to Lack of Efficacy
0
0
1 (0.2%)
0
Discontinued Study Drug Due to AE/Death
3 (1.1%)
1 (0.7%)
6 (1.0%)
3 (1.0%)
Discontinued Study Drug Due to Other Reasonsc
6 (2.1%)
4 (2.9%)
19 (3.3%)
6 (2.1%)
Missing Data During Window but on Study Drug
1 (0.4%)
1 (0.7%)
1 (0.2%)
0
a
P-value for the superiority test comparing the percentages of HBV DNA < 29 IU/mL was from the CMH test stratified by 
baseline HBV DNA categories and oral antiviral treatment status strata.
b
Difference in the proportion between treatment groups and its 95% CI were calculated based on the MH proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
c
Discontinuation due to other reasons included subjects who prematurely discontinued study drug due to investigator's 
discretion, withdrew consent, lost to follow-up, noncompliance with study drug, protocol violation, pregnancy, and study 
termination by sponsor.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Table 12; GS-US-320-0110 Week 48 CSR, Section 15.1, Table 12
Biochemical Analyses
Table 1-3 presents the proportion of subjects with ALT normalization at Week 48 for both 
studies (GS-US-320-0108) and (GS-US-320-0110) when determined by central laboratory 
criteria and by AASLD criteria (ULN range: ≤ 30 U/L for males and ≤ 19 U/L for females 
{Lok 2009, Terrault 2015}), respectively.
For Study GS-US-320-0108, the percentage of subjects with normalized ALT (i.e., ALT > ULN 
at baseline but within the normal range at Week 48) using the central laboratory criteria was 
numerically higher for the TAF group compared with the TDF group for all time points from 
Weeks 4 through 48. When assessed at Week 48, rates of ALT normalization were not
significantly different between the 2 treatment groups by the M = F method for the Full Analysis 
Set (FAS). Using the AASLD criteria, the percentage of subjects with normalized ALT was 
significantly higher in the TAF group than in the TDF group at for all time points from Week 8 
onward using the M = F method.


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For Study GS-US-320-0110, the percentage of subjects with normalized ALT using the central 
laboratory criteria was numerically higher for the TAF group compared with the TDF group for 
all time points from Weeks 8 through 48. When assessed at Week 48, rates of normalization 
were not significantly different between the 2 treatment groups by the M = F method for the 
FAS. Using the AASLD criteria, the percentage of subjects with normalized ALT was 
significantly higher in the TAF group than in the TDF group for all time points from 
Weeks 8 through 48 using the M = F method.
Overall, the percentage of subjects with normalized ALT at Week 48 was higher in 
Study GS-US-320-0108 compared with Study GS-US-320-0110 using the central laboratory 
criteria and similar across the 2 studies using the AASLD criteria.
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with 
ALT Normalization at Week 48, Missing = Failure (Full Analysis Set 
with Baseline ALT > ULN)
Normalized ALT
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
TDF 300 mg
TAF 25 mg
TDF 300 mg
Central Laboratorya
(N = 236)
(N = 121)
(N = 537)
(N = 268)
Week 48
196/236 (83.1%)
91/121 (75.2%)
384/537 (71.5%)
179/268 (66.8%)
Proportion Difference (95% CI)
8.0% (−1.3% to 17.2%)
4.6% (−2.3% to 11.4%)
p-value
0.076
0.18
AASLDb
(N = 276)
(N = 138)
(N = 572)
(N = 290)
Week 48
137/276 (49.6%)
44/138 (31.9%)
257/572 (44.9%)
105/290 (36.2%)
Proportion Difference (95% CI)
17.9% (8.0% to 27.7%)
8.7% (1.8% to 15.6%)
p-value
< 0.001
0.014
a
Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males
≥69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.
b
AASLD ULN for ALT criteria are as follows: ≤ 30 U/L for males and ≤ 19 U/L for females.
P-value was from the Cochran-Mantel-Haenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment 
status strata
Difference in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Tables 23.1.1 and 23.2.1; GS-US-320-0110 Week 48 CSR, Section 15.1, 
Tables 23.1.1 and 23.2.1
Serological Analyses
In Study GS-US-320-0108, no subject in either treatment group experienced HBsAg loss by
Week 48. In Study GS-US-320-0110, 4 subjects (0.7%) in the TAF group and 1 subject (0.3%)
in the TDF group experienced HBsAg loss at Week 48. Three of the 4 subjects in the TAF group
and none in the TDF group also experienced HBsAg seroconversion at Week 48.


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In Study GS-US-320-0110, the proportion of subjects with HBeAg loss or seroconversion to
anti-HBe at Week 48 was also evaluated; these data are presented on Table 1-4. A total of
78 (13.8%) and 34 (11.9%) subjects in the TAF and TDF groups, respectively, had HBeAg loss
at Week 48. A total of 58 (10.3%) and 23 (8.1%) subjects in the TAF and TDF groups,
respectively, experienced HBeAg seroconversion at Week 48.
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or 
Seroconversion at Week 48, Missing = Failure 
(Serologically Evaluable Full Analysis Set)
GS-US-320-0110
TAF 25 mg
(N = 565)
TDF 300 mg
(N = 285)
TAF 25 mg vs TDF 300 mg
p-value
Prop Diff
(95% CI)
HBeAg Loss, n (%)
78/565 (13.8%)
34/285 (11.9%)
0.47
1.8%
(−3.0% to 6.5%)
HBeAg Seroconversion, n (%)
58/565 (10.3%)
23/285 (8.1%)
0.32
2.1%
(−2.0% to 6.3%)
P-values were from the Cochran-Mantel-Haenszel test stratified by baseline HBV DNA categories and oral antiviral treatment 
status. Differences in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel 
proportions adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion included subjects who were HBeAg positive and 
HBeAb negative/missing at baseline. HBeAg loss was defined as changes from HBeAg-positive at baseline to HBeAg-negative 
at a post-baseline visit with baseline anti-HBe negative/missing. HBeAg seroconversion was defined as HBeAg loss and 
anti-HBe change from negative/missing at baseline to positive at a post-baseline visit.
Source: GS-US-320-0110 Week 48 CSR, Section 15.1, Table 19.1
Virologic Resistance Analysis
In an integrated analysis of Studies GS-US-320-0108 and GS-US-320-0110, 24 subjects (2.8%)
in the TAF group and 14 subjects (3.2%) in the TDF group qualified for population-based
sequence analysis after up to 48 weeks of treatment. Among the 24 subjects in the TAF group
who qualified for population-based sequence analysis, 15 had no changes detected in the pol/RT
sequence from baseline, 4 were unable to be sequenced, and 5 had unique polymorphic site
substitutions. Among the 14 subjects in the TDF treatment group who qualified for
population-based sequence analysis, 6 had no changes detected in the pol/RT sequence from
baseline, 4 were unable to be sequenced, 2 had unique polymorphic site substitutions, and
2 had a unique conserved site substitution. Overall, no HBV pol/RT amino acid substitutions 
associated with resistance to TFV were detected by sequencing and phenotypic analysis through 
48 weeks of the study in either treatment group.
Safety of TAF in CHB Subjects
The principal sources of safety data for TAF are presented above in Table 1-1 and consist of 
2 Phase 3 studies in subjects with CHB, Study GS-US-320-0108 and GS-US-320-0110. Subjects
included in the Safety Analysis Set received at least 1 dose of study drug.


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Overall Extent of Exposure
Of the 2387 subjects screened in Studies GS-US-320-0108 and GS-US-320-0110 combined,
1301 were randomized (TAF 867 subjects; TDF 434 subjects), and 1298 received at least 1 dose
of study drugs (TAF 866 subjects; TDF 432 subjects); 3 subjects (TAF 1 subject; TDF 
2 subjects) did not receive study drug due to withdrawal of consent. As of the Week 48 data
cutoff date for each Phase 3 study, a total of 1208 subjects (TAF 93.1%, 806 subjects; 
TDF 93.1%, 402 subjects) were continuing double-blind study drugs, and 27 subjects
(TAF 2.1%, 18 subjects; TDF 2.1%, 9 subjects) had entered the open-label phase as of the
Week 48 data cutoff date. Of the 1298 subjects randomized and treated, 63 subjects (4.9%)
discontinued blinded study drugs (TAF 4.8%, 42 subjects; TDF 4.9%, 21 subjects), and
61 subjects (TAF 40 subjects; TDF 21 subjects) discontinued from the study prior to the
Week 48 data cutoff date. Similar rates of discontinuation and reasons for treatment
discontinuation were observed for TAF compared with TDF. The most common reasons for
premature discontinuation of blinded study treatment were withdrew consent (TAF 1.6%,
14 subjects; TDF 1.6%, 7 subjects); adverse event (AE; TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects); and lost to follow-up (TAF 0.7%, 6 subjects; TDF 0.7%, 3 subjects). The most
common reasons for discontinuation from the study were: subjects withdrew consent (TAF 2.0%,
17 subjects; TDF 2.1%, 9 subjects), lost to follow-up (TAF 0.8%, 7 subjects; TDF 0.7%, 
3 subjects), and AEs (TAF 0.3%, 3 subjects; TDF 0.9%, 4 subjects).
The median (first quartile [Q1], third quartile [Q3]) duration of exposures to blinded study drug 
in the TAF Phase 3 Safety Population were nearly identical between the 2 treatment groups 
(TAF 56.1 [48.1, 64.4] weeks; TDF 56.1 [48.1, 64.7] weeks. More than half of the subjects in 
each treatment group had received blinded study drug for ≥56 weeks at the time of the Week 48 
data cutoff date for each Phase 3 study (TAF 60.5 %, 524 subjects; TDF 62.0 %, 268 subjects). 
There was no statistically significant difference between groups in the overall Kaplan-Meier 
estimate of time to premature discontinuation of blinded study drug.
Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-5 presents an overall summary of AEs by treatment group for the TAF Phase 3 Safety 
Population. Similar percentages of subjects in each treatment group had experienced at least 
1 AE (TAF 70.2 %, 608 subjects; TDF 67.4%, 291 subjects) and had experienced at least
1 Grade 3 or 4 AE (TAF 4.5 %, 39 subjects; TDF 3.9 %, 17 subjects). In addition, 57 subjects
(TAF 4.2%, 36 subjects; TDF 4.9 %, 21 subjects) had at least 1 SAE, with no subjects
experiencing a treatment-related SAE. A similar percentage of subjects in each treatment group
experienced an AE leading to discontinuation of study drugs (TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects). No deaths occurred in any subject on treatment. There were 2 deaths which occurred
after treatment was discontinued and were considered non-treatment emergent (1 subject in each
treatment group).


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Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of 
Adverse Events in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Adverse Events
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Subjects Experiencing Any AE
608 (70.2%)
291 (67.4%)
Subjects Experiencing Any Grade 2, 3, or 4 AE
221 (25.5%)
120 (27.8%)
Subjects Experiencing Any Grade 3 or 4 AE
39 (4.5%)
17 (3.9%)
Subjects Experiencing Any Study Drug-Related AE
123 (14.2%)
68 (15.7%)
Subjects Experiencing Any Grade 2, 3, or 4 Study Drug-Related AE
33 (3.8%)
21 (4.9%)
Subjects Experiencing Any Grade 3 or 4 Study Drug-Related AE
6 (0.7%)
2 (0.5%)
Subjects Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Subjects Experiencing Any Study Drug-Related SAE
0
0
Subjects Experiencing Any AE Leading to Premature Study Drug 
Discontinuation
9 (1.0%)
5 (1.2%)
Subjects Experiencing Any AE Leading to Dose Modification or 
Study Drug Interruption
17 (2.0%)
7 (1.6%)
Deatha
0
0
a
Treatment-emergent death refers to the death occurred between the first dose date and the last dose date (inclusive). 
Adverse events were mapped according to MedDRA Version 18.
Treatment-emergent AEs was defined as follows:
1)
Any AEs with onset date of on or after the study drug start date and no later than the study drug stop date for those who 
discontinued study drug permanently, or
2)
Any AE with an onset date on or after the study drugs start date for those who had not discontinued study drug permanently, 
or
3)
Any AEs leading to study drug discontinuation
Source: TAF Week 48 ISS, Table 6
Common Adverse Events
Table 1-6 presents AEs reported for ≥ 5% of subjects for any treatment group by system organ
class (SOC) and preferred term (PT) in the TAF Phase 3 Safety Population. The rate and types of
AEs were similar in the 2 treatment groups. Overall, the 3 most frequently reported AEs by
treatment group were as follows:

TAF group — upper respiratory tract infection (9.9%, 86 subjects), nasopharyngitis 
(9.9%, 86 subjects), and headache (9.5%, 82 subjects)

TDF group — headache (8.3%, 36 subjects), upper respiratory tract infection
(7.4%, 32 subjects), and nasopharyngitis (7.2%, 31 subjects)


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Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for 
≥5% of Subjects in Either Treatment Group in the TAF Phase 3 
Safety Population (Safety Analysis Set)
Adverse Events by System Organ Class and Preferred Terma,b,c
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects Experiencing Any Adverse Event
608 (70.2%)
291 (67.4%)
Gastrointestinal disorders
227 (26.2%)
108 (25.0%)
Nausea
43 (5.0%)
22 (5.1%)
General disorders and administration site conditions
125 (14.4%)
62 (14.4%)
Fatigue
49 (5.7%)
23 (5.3%)
Infections and infestations
259 (29.9%)
121 (28.0%)
Upper respiratory tract infection
86 (9.9%)
32 (7.4%)
Nasopharyngitis
86 (9.9%)
31 (7.2%)
Nervous system disorders
149 (17.2%)
60 (13.9%)
Headache
82 (9.5%)
36 (8.3%)
Respiratory, thoracic and mediastinal disorders
106 (12.2%)
44 (10.2%)
Cough
55 (6.4%)
27 (6.3%)
a
Adverse events were mapped according to MedDRA Version 18.
b
SOC were presented alphabetically, and PT was presented by decreasing order of the total frequencies.
c
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 7
Adverse Events by Severity
The majority of AEs reported in the TAF Phase 3 Safety Population were Grade 1 or 2. A similar
percentage of subjects in each treatment group experienced at least 1 Grade 3 AE (TAF 4.5%,
39 subjects; TDF 3.9%, 17 subjects). No subjects in either group had a Grade 4 AE. The only
Grade 3 AE that occurred in more than 2 subjects in either treatment group were increased ALT
(TAF 0.6%, 5 subjects; TDF 0.7%, 3 subjects) and hepatocellular carcinoma (HCC)
(TAF 0 subjects; TDF 0.7%, 3 subjects). Four Grade 3 ALT increases (TAF 3 subjects;
TDF 1 subject) were assessed as related to study drug.
Serious Adverse Events
Table 1-7 presents SAEs reported for > 1 subjects for any treatment group in the TAF Phase 3
Safety Population. A similar percentage of subjects experienced SAEs in each treatment group
(TAF 4.2%, 36 subjects; TDF 4.9%, 21 subjects). None of the SAEs were considered related to
study drugs by the investigators. Hepatocellular carcinoma was reported for 6 subjects
(TAF 0.1%, 1 of 866 subjects; TDF 1.2%, 5 of 432 subjects). Other SAEs reported in > 1 subject
in either treatment group were cellulitis, hand fracture, dizziness, and calculus ureteric.


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Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by 
Treatment Regimen in > 1 Subject in the TAF Phase 3 Safety 
Population (Safety Analysis Set)
Preferred Terma,b
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects (%) Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Hepatocellular carcinoma
1 (0.1%)
5 (1.2%)
Cellulitis
0
3 (0.7%)
Hand fracture
2 (0.2%)
0
Dizziness
2 (0.2%)
0
Calculus ureteric
2 (0.2%)
0
a
Adverse events were mapped according to MedDRA Version 18.
b
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 14
Summary of Bone Safety
Bone safety was assessed in the TAF Phase 3 Safety Population due to decreases in bone mineral 
density (BMD) and mineralization defects that have been seen in subjects treated with TDF.
Summary of Fractures
In the TAF Phase 3 Safety Population, the incidence of fracture events was uncommon 
(TAF 0.7%, 6 of 866 subjects; TDF 0.2%, 1 of 432 subjects; p = 0.44). Six of the 7 reported 
fractures were associated with trauma and 1 subject, in the TAF group, had a spinal compression 
fracture identified incidentally on a computed tomography (CT) scan. In the TAF group, 
4 fractures were reported as SAEs (hand fracture [3 subjects] and 1 spinal compression fracture). 
In the TDF group, 1 fracture (lower limb fracture) was reported as an SAE. Of the 7 subjects 
who had fractures, 4 subjects in the TAF group (tibia fracture, spinal compression identified 
incidentally, hand fracture [2 subjects]) had normal hip and spine BMD T-scores at all 
timepoints, 2 subjects in the TAF group (hand fracture and traumatic spinal compression 
fracture) had hip and/or spine baseline BMD T-scores consistent with osteoporosis at baseline, 
1 subject in the TDF group (lower limb fracture) had normal hip and spine BMD at baseline 
which worsened while on treatment. All fractures were considered unrelated to the study drugs 
by the investigators and, none resulted in discontinuation of study drugs.
Summary of Bone Mineral Density
Percentage change from baseline in hip BMD and spine BMD were the first and second key 
alpha-controlled safety endpoints, respectively, for both studies. Subjects receiving TAF 
experienced significantly less BMD reduction than those receiving TDF. At Week 48, the mean 
(SD) percentage decreases from baseline were as follows:

Hip: TAF −0.163% (2.2437 %); TDF −1.860 % (2.4525 %)

Spine: TAF −0.570 % (2.9147 %); TDF −2.366 % (3.2051 %)


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Table 1-8 presents measure of BMD at Week 48. Percentage changes from baseline in hip and 
spine BMD were the first and second key alpha-controlled safety endpoints in 
Studies GS-US-320-0108 and GS-US-320-0110. Mean percentage decreases from baseline in 
BMD at the hip or spine were smaller in the TAF group compared with the TDF group 
(p < 0.001). A lower percentage of subjects in the TAF group had a > 3% decrease in hip BMD 
compared with subjects in the TDF group (8.4% TAF; 26.7% TDF). Similarly, a lower 
percentage of subjects in the TAF group had a > 3% decrease in spine BMD compared with 
subjects in the TDF group (TAF 19.5%; TDF 38.1%). At Week 48, fewer subjects had ≥7% 
decrease in hip BMD (TAF 0.4%; TDF 2.0%) and ≥ 5% decrease in spine BMD (TAF 6.3%; 
TDF 20.4%) in the TAF group compared with the TDF group.
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral 
Density at Week 48 (Hip DXA Analysis Set and Spine DXA 
Analysis Set)
N
TAF 25 mg
N
TDF 300 mg
Hip DXA Analysis Set
Mean (SD) Percent Change in Hip BMD
807
−0.163 (2.2437)
404
−1.860 (2.4525)
P-Valuea
< 0.001
Difference in LSM
1.697 (1.420, 1.974)
Subjects with > 3% Decrease in Hip BMD, n (%)
807
68 (8.4%)
404
108 (26.7%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Hip BMD, n (%)
807
55 (6.8%)
404
8 (2.0%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Hip BMD, n (%)
807
383 (47.5%)
404
83 (20.5%)
Spine DXA Analysis Set
Mean (SD) Percent Change in Spine BMD
814
−0.570 (2.9147)
407
−2.366 (3.2051)
P-Valuea
< 0.001
Difference in LSM
1.796 (1.437, 2.155)
Subjects with > 3% Decrease in Spine BMD, n (%)
814
159 (19.5%)
407
155 (38.1%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Spine BMD, n (%)
814
89 (10.9%)
407
11 (2.7%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Spine BMD, n (%)
814
331 (40.7%)
407
89 (21.9%)
DXA = dual-energy x-ray absorptiometry; LSM = least-squares mean
a
P-values, difference in least squares means, and its 95% CI were from the ANOVA model including treatment as a 
fixed effect.
b
P-values were calculated from the Cochran-Mantel-Haenszel test for ordinal data (row mean scores differ statistic was used).
Source: TAF Week 48 ISS, Tables 23.1.2, 23.2.2, 25.1, and 25.2 and Request 7633 Tables 2.1 and 2.2
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
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Renal Safety
In the TAF Phase 3 Safety Population in Studies GS-US-320-0108 and GS-US-320-0110
(TAF 25 mg N = 866, TDF 300 mg N = 432; Total N = 1301), no cases of proximal renal
tubulopathy (including Fanconi syndrome) or renal failure were reported in either treatment
group. No subject in the TAF Phase 3 Safety population experienced a renal SAE or AE
resulting in discontinuation of study drugs while on study.
Summary of Renal Laboratory Parameters
Change from baseline in serum creatinine was the third key alpha-controlled safety endpoint.
Overall, increases from baseline in mean values for serum creatinine were smaller in the TAF
group compared with the TDF group. Mean (SD) changes from baseline at Week 48 were
0.010 (0.1140) mg/dL for the TAF group and 0.024 (0.0974) mg/dL for the TDF group
(p = 0.012). Graded serum creatinine abnormalities were reported for 6 subjects (0.7%) in the
TAF group; all of which were Grade 1 or 2. Of the 6 subjects, 5 subjects had isolated serum 
creatinine elevations that were not associated with decreased eGFR. One subject, who had a 
relevant medical history of hypertension and diabetes, had multiple instances of graded
creatinine elevations and eGFR ≤ 50 mL/min. No subjects in the TDF group had graded serum
creatinine elevations.
In the TAF group, decreases from baseline in median eGFRCG values were significantly smaller
compared with the TDF group. Median (Q1, Q3) changes from baseline at Week 48 were
−1.2 (−8.4, 7.5) mL/min in the TAF group and −5.4 (−12.0, 3.0) mL/min in the TDF group
(p < 0.001). The overall number of subjects who had any confirmed renal laboratory abnormality
(ie, confirmed increases from baseline in creatinine of at least 0.5 mg/dL, or eGFRCG below
50 mL/min, or confirmed phosphorus < 2 mg/dL, was small (TAF 0.6%, 5 subjects; TDF 1.6%,
7 subjects). Most instances were isolated, transient, and resolved without treatment.
Summary of Proteinuria by Urinalysis (Dipstick) and by Quantitative Assessment
A similar percentage of subjects in each treatment group had at least 1 recorded, graded
proteinuria by dipstick while on study; most of which were Grade 1. Table 1-9 presents a
summary of the quantitative markers of proteinuria, urine protein to creatinine ratio (UPCR) and
urine albumin to creatinine ratio (UACR). There was a significant difference between the
2 treatment groups in median percentage changes from baseline in 1 of the quantitative markers
of proteinuria UPCR at Week 48. The median (Q1, Q3) percentage change in UPCR was
6.0 (−31.0, 57.6) mg/g in the TAF group and 16.5 (−21.6, 72.4) mg/g in the TDF group
(p = 0.010). Although not statistically significant, the median percentage change from baseline in
UACR was lower in the TAF group compared with the TDF group. Median percentage changes
from baseline in the markers of proximal tubular dysfunction, urine retinol binding protein
(RBP) to creatinine ratio and urine beta-2-microglobulin to creatinine ratio were smaller in the
TAF group compared with the TDF group (p < 0.001 for the differences between the 2 groups at
Weeks 24 and 48).


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Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine 
Creatinine Ratios at Week 48 in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Parameter
Median Percentage Change (%) (Q1, Q3)
P-Valuea
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
UPCR (mg/g)
6.0 (−31.0, 57.6)
16.5 (−21.6, 72.4)
0.010
UACR (mg/g)
6.9 (−25.8, 46.7)
12.2 (−21.0, 63.5)
0.073
Urine RBP to Urine Creatinine Ratio (μg/g)
−0.3 (−23.2, 33.3)
25.1 (−7.9, 73.2)
< 0.001
Urine Beta-2-Microglobulin to Creatinine Ratio (μg/g)
−3.5 (−34.3, 32.0)
37.9 (−4.6, 152.4)
< 0.001
UACR = urine albumin to creatinine ratio; UPCR = urine protein to creatinine ratio
% Change = Change from baseline at a postbaseline visit/baseline × 100%.
a
P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.
Source: TAF Week 48 ISS, Tables 34.1, 34.2, 34.3, and 34.4
Graded Laboratory Abnormalities
Most subjects participating in Studies GS-US-320-0108 and GS-US-320-0110 experienced at
least 1 laboratory abnormality of Grade 1 or higher (TAF 94.8%, 814 of 859 subjects; TDF
91.1%, 390 of 428 subjects). The majority of subjects had abnormalities that were Grade 1 or 2
at worst severity (TAF 63.4%, 545 subjects; TDF 61.7%, 264 subjects). Grade 3 laboratory
abnormalities occurred in 26.2% (225 subjects) in the TAF group and 22.4% (96 subjects) in the
TDF group; Grade 4 laboratory abnormalities were less common, occurring in 5.1% 
(44 subjects) in the TAF group and 7.0% (30 subjects) in the TDF group. In total, a similar 
percentage of subjects in each group had at least 1 Grade 3 or 4 laboratory abnormality 
(TAF 31.3%, 269 subjects; TDF 29.4%, 126 subjects).
Table 1-10 presents a summary of the subject incidence of Grade 3 or 4 serum chemistry or
urinalysis abnormalities reported for ≥ 1% in either treatment group for the overall TAF Phase 3
Safety Population. The only Grade 3 or 4 serum chemistry laboratory abnormality that occurred
in > 5% of subjects overall in each of the treatment groups individually was ALT elevation
(TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects). In the TDF group, Grade 3 or 4 elevations of
AST also occurred in > 5% of subjects overall (TAF 3.3%, 28 subjects; TDF 5.4%, 23 subjects).
Grade 3 urinalysis abnormalities included occult blood (TAF 7.7%, 66 subjects; TDF 7.0%,
30 subjects), urine erythrocytes (TAF 7.7%, 59 subjects; TDF 9.1%, 35 subjects), and urine
glucose (TAF 4.8%, 41 subjects; TDF 1.2%, 5 subjects). The majority of subjects (88.6%;
124 of 140 subjects) who had Grade 3 urine occult blood or urine erythrocytes were women of
child bearing potential (defined as age ≤ 54 years). The abnormalities were generally
asymptomatic and not associated with AEs; none of the events were considered related to study
drugs. Among the 41 subjects in the TAF group with Grade 3 urine glucose on treatment,
18 subjects (43.9%) had Grade 3 urine glucose at either screening or baseline, while the majority
of the remaining 23 subjects had a medical history relevant for diabetes mellitus and/or had a 
graded elevation in blood glucose, or experienced an isolated and transient occurrence of 
Grade 3 urine glucose.


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Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent 
Grade 3 or 4 Laboratory Abnormalities Reported for at Least 
1% of Subjects in Either Treatment Group in the Overall TAF 
Phase 3 Safety Population (Safety Analysis Set)
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Maximum Postbaseline Toxicity Grade (N)
859
428
Grade 3
225 (26.2%)
96 (22.4%)
Grade 4
44 (5.1%)
30 (7.0%)
Chemistry
Alanine Aminotransferase (N)
859
428
Grade 3
52 (6.1%)
27 (6.3%)
Grade 4
18 (2.1%)
13 (3.0%)
Amylase (N)
859
427
Grade 3
22 (2.6%)
9 (2.1%)
Aspartate Aminotransferase (N)
859
428
Grade 3
25 (2.9%)
18 (4.2%)
Grade 4
3 (0.3%)
5 (1.2%)
Creatine Kinase (N)
859
428
Grade 3
16 (1.9%)
7 (1.6%)
Grade 4
9 (1.0%)
6 (1.4%)
Fasting Glucose (Hyperglycemia) (N)
857
425
Grade 3
9 (1.1%)
0
Fasting LDL Cholesterol (N)
837
417
Grade 3
37 (4.4%)
1 (0.2%)
Nonfasting Glucose (Hyperglycemia) (N)
856
426
Grade 3
25 (2.9%)
7 (1.6%)
Urinalysis
Occult Blood (N)
859
426
Grade 3
66 (7.7%)
30 (7.0%)
Urine Erythrocytes (N)
768
386
Grade 3
59 (7.7%)
35 (9.1%)
Urine Glucose (N)
859
426
Grade 3
41 (4.8%)
5 (1.2%)
Denominator for percentage (N) is the number of subjects in the safety analysis set with at least 1 postbaseline laboratory value 
for the test.
Subjects were counted once for the maximum postbaseline severity for each laboratory test. For urinalysis (ie, urine glucose, 
urine protein, and urine RBC), the highest grade is Grade 3.
For nonfasting glucose, the maximum postbaseline toxicity grades, instead of treatment-emergent abnormalities, were 
summarized, because nonfasting glucose test was not done at baseline.
‘Hyper’ means high and ‘Hypo’ means low.
Source: TAF Week 48 ISS, Table 20
Hepatic Laboratory Abnormalities
In Studies GS-US-320-0108 and GS-US-320-0110 the incidence of graded hepatic laboratory 
abnormalities through the Week 48 data cutoff date was generally lower for subjects in the TAF
group compared with subjects in the TDF group, and included ALT increased 


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(TAF 22.8%,196 subjects; TDF 30.4%, 130 subjects), AST increased (TAF 22.2%, 191 subjects; 
TDF 25.2%, 108 subjects), total bilirubin increased (TAF 12.7%, 109 subjects; TDF 10.0%, 
43 subjects), gamma-glutamyltransferase (GGT) increased (TAF 7.5%, 64 subjects; TDF 10.0%, 
43 subjects), alkaline phosphatase increased (TAF 2.2%, 19 subjects; TDF 5.4%, 23 subjects), 
and albumin decreased (TAF 0.9%, 8 subjects; TDF 1.9%, 8 subjects).
Hepatic laboratory abnormalities in both treatment groups were generally Grade 1 or 2 at
maximum severity; Grade 3 or 4 ALT abnormalities and Grade 3 or 4 AST abnormalities were
observed in lower percentages of subjects in the TAF group compared with the TDF group
(ALT: TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects; AST: TAF 3.3%, 28 subjects; TDF 5.4%,
23 subjects), while Grade 3 or 4 bilirubin elevations were observed in comparable percentages of
subjects in the TAF group (0.3%, 3 subjects) compared with the TDF group (0.2%, 1 subject).
Hepatic laboratory abnormalities were generally not associated with hepatic AEs.
Hepatic Flares
An ALT elevation was defined as treatment-emergent serum ALT > 2 × baseline value and
> 10 × ULN, with or without associated symptoms. Through Week 48, ALT elevations were
observed for 16 subjects (1.8%) in the TAF group and 9 subjects (2.1%) of subjects in the TDF
group. Most of the events were at isolated time points within the first 8 weeks of dosing and
resolved without recurrence while the subject remained on study drug. An ALT elevation that
was confirmed at 2 consecutive postbaseline visits was considered an ALT flare. The incidence
of these events was balanced between the treatment groups. Five subjects (0.6%) in the TAF
group and 4 subjects (0.9%) in the TDF group had a treatment-emergent ALT flare. With the
exception of 2 events, ALT flares occurred early in the dosing period; for 7 of the 9 subjects, the
ALT flares resolved without recurrence while the subject remained on study drug.
Metabolic Laboratory Parameters
Administration of TDF has been associated with lower fasting low-density lipoprotein (LDL) 
and high-density lipoprotein (HDL) as compared with other antiviral agents. As plasma TFV
exposures are approximately 90% lower with TAF administration than with TDF, fasting lipid
concentrations remained relatively stable through Week 48 in the TAF treatment group, while
TDF administration resulted in the expected lipid-lowering TFV effect, with decreases from
baseline in fasting lipid parameters observed in the TDF group. Median decreases from baseline
in total cholesterol, LDL, HDL, and triglycerides were greater in the TDF group than the TAF
group, with TDF subjects demonstrating reductions in all parameters at Week 48. The difference
between groups in median change from baseline was statistically significant a Week 48 for total
cholesterol, direct LDL, HDL, and triglycerides (p < 0.001). Median (Q1, Q3) changes from
baseline at Week 48 for fasting lipid parameters were as follows:

Total cholesterol: TAF −2 (−17, 17) mg/dL; TDF −24 (−42, −6) mg/dL

LDL: TAF 4 (−9, 20) mg/dL; TDF −9 (−25, 5) mg/dL


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
HDL: TAF −3 (−10, 2) mg/dL; TDF −9 (−17, −3) mg/dL

Triglycerides: TAF 6 (−13, 26) mg/dL; TDF −7 (−27, 10) mg/dL
The median (Q1, Q3) change from baseline at Week 48 in total cholesterol to HDL ratio was
0.2 (−0.1, 0.5) in the TAF group and 0.2 (−0.2, 0.5) in the TDF group (p = 0.16 for the difference 
between treatment groups).
Eight subjects (0.9%) in the TAF group had Grade 3 elevated fasting cholesterol; 
7 of the 8 subjects had a history of hyperlipidemia and/or elevated fasting cholesterol at baseline.
There were no subjects with Grade 4 elevated fasting cholesterol in the TAF group, and none
with Grade 3 or 4 elevated fasting cholesterol in the TDF group. Thirty-seven subjects (4.4%) in
the TAF group and 1 subject (0.2%) in the TDF group had Grade 3 elevated fasting LDL.
Overall, changes in median values of total cholesterol, LDL, HDL, and triglycerides in the TAF
group were not clinically relevant, and none of the subjects with Grade 3 elevations in fasting
lipids had clinical AEs associated with lipid abnormalities.
1.2.4.
Clinical Trials of Tenofovir Alafenamide in Subjects with Renal Impairment
1.2.4.1.
Phase 1 Study of Tenofovir Alafenamide in Subjects with Renal Impairment
(GS-US-120-0108)
A Phase 1 open-label study was performed to evaluate the PK of TAF and its metabolite TFV in 
subjects without HIV or HBV infection and with severe renal impairment (defined as subjects 
with eGFRCG between 15 and 29 mL/min [inclusive] who were not on dialysis) and in age- and 
sex-matched subjects with normal renal function (eGFRCG ≥90 mL/min) following a single dose 
of TAF 25 mg {Custodio 2016}. Subjects with severe renal impairment had a 1.9-fold higher 
TAF systemic exposure (as assessed by AUCinf) relative to age- and sex-matched subjects with 
normal renal function (Table 1-11). 
Table 1-11.
GS-US-120-0108: Statistical Comparisons of TAF PK Parameter 
Estimates in Subjects With Severe Renal Impairment and Subjects 
With Normal Renal Function
TAF PK Parameter
Mean (%CV)
GLSM Ratio
(90% CI), %
Test
Severe Renal Impairment
(N = 14)
Reference
Normal Renal Function
(N = 13)
AUCinf (ng•h/mL)
513.2 (47.3)
267.3 (49.2)
191.89 (137.81, 267.18)
AUClast (ng•h/mL)
510.6 (47.4)
265.9 (49.5)
192.26 (137.81, 268.21)
Cmax (ng/mL)
363.7 (65.7)
198.8 (62.1)
179.43 (123.73, 260.20)
Source: GS-US-120-0108, Section 15.1, Tables 4.1 and 6.1


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Additionally, based on population PK analyses of pooled data from Phase 3 studies in subjects 
with CHB receiving TAF, baseline eGFRCG was not a statistically significant or clinically 
relevant covariate influencing TAF PK which is consistent with the established PK profile of 
TAF from the E/C/F/TAF development program that included a dedicated study in HIV-infected 
subjects with mild to moderate renal impairment {Pozniak 2016}. Accordingly, as eGFRCG is not 
covariate for TAF, no clinically relevant exposure differences are anticipated in subjects with 
various degrees of renal impairment following administration of TAF, including in ESRD with 
HD.
In line with its renal route of elimination, following a single dose of TAF, subjects with severe 
renal impairment (Study GS-US-120-0108) had a 5.7-fold increase in systemic TFV exposure 
(as assessed by AUCinf) relative to age- and sex-matched subjects with normal renal function 
(Table 1-12). The plasma TFV exposure observed in this study in subjects with severe renal 
impairment was below the exposure observed in historical studies after administration of TDF 
300 mg in subjects with normal renal function (3300 ng•h/mL) {Gilead Sciences Inc. 2015, 
Gilead Sciences Ltd 2016}.
Table 1-12.
GS-US-120-0108: Statistical Comparisons of TFV PK Parameter 
Estimates Between Subjects With Severe Renal Impairment and 
Subjects With Normal Renal Function
TFV PK Parameter
Mean (%CV)
GLSM Ratio
(90% CI), %
Test
Severe Renal Impairment
(N = 14)
Reference
Normal Renal Function
(N = 13)
AUCinf (ng•h/mL)
2073.8 (47.1)
342.6 (27.2)
573.76 (457.21, 720.01)
AUClast (ng•h/mL)
1694.9 (43.1)
298.0 (26.1)
545.91 (442.82, 672.99)
Cmax (ng/mL)
26.4 (32.4)
9.5 (36.5)
279.31 (231.48, 337.02)
Source: GS-US-120-0108, Section 15.1, Tables 4.2 and 6.1
TAF Population Pharmacokinetics and PK Modelling of TAF and TFV in Subjects with 
End-Stage Renal Disease on Hemodialysis
Based on popultion PK analyses of the pooled data from Phase 3 studies in subjects with CHB 
receiving TAF, a statistically significant effect of baseline eGFRCG on TFV exposure was 
observed based on covariate analyses. These findings were expected with TFV being primarily 
renally eliminated. Although TFV exposure was higher in subjects with CHB with lower 
baseline eGFRCG relative to those with normal renal function, the TFV exposure observed in 
subjects with CHB with renal function 30 ≤eGFRCG < 60 mL/min receiving TAF 
(515.8 ng•h/mL) was below the exposure observed in historical studies after administration of 
TDF 300 mg in subjects with normal renal function (3300 ng•h/mL) {Gilead Sciences Inc. 2015, 
Gilead Sciences Ltd 2016}.


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As eGFRcG is not covariate for TAF, no clinically relevant differences in TAF exposure are 
expected in subjects with ESRD on HD. However, for the renally eliminated metabolite TFV, 
simulation was conducted to predict TFV exposures using the population PK model for TFV 
following once-daily administration ofTAF 25 mg in subjects with ESRD on HD, incorporating 
info1mation on the HD clearance of plasma TFV from a previously conducted Gilead Study 
(GS-01-919) {Kearney 2006} where TDF 300 mg was administered in subjects with ESRD 
(Figure 1-1). 
Figure 1-1. 
-
...J 
-€ 
0) 
-S 
0 
LU 
0:::: 
a.. 
0 
0 
N 
0 0) 
0 co 
0 ...... 
0 co 
0 
LO 
Predicted Steady-State TFV PK Profile After Administration of TAF 
in Subjects With CHB with ESRD on Chronic HD 
5% C.I. 
Median 
95% C.I. 
0 
24 
48 
72 
96 
120 144 168 192 216 240 264 288 312 336 360 
Time (hours) 
Simulated TFV PK profile following TAF once daily for 2 weeks in subjects with ESRD on chronic HD 3 times per week. 
IPRED represents the model-predicted plasma concentration ofTFV. The shaded regions in dark gray represent HD duration 
(4 how-s) and interval. HD session(s) on the first week (0-156 hours) are represented during the time intervals of 44-48 hours and 
92-96 hours; in the sec.and week (156-324 hours) are represented during the time intervals 164-168 hours, 212-216 hours, and 
260-264 how·s; and in the third week (324-336 hours) is represented during the time interval 332-336 hours. The shaded region in 
light gray represents steady-state, maximum TFV exposure that was used in calculation of PK parameters. 
Som·ce: TAF HBV ESRD Modeling Report 
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In subjects with CHB with ESRD on chronic HD 3 times per week, systemic TFV exposures are 
expected to be higher following administration of TAF relative to administration of TAF in 
subjects with eGFRCG ≥30 mL/min, due to reduced renal function and the resulting decreased 
elimination of TFV. TAF administered once daily in subjects on chronic HD 3 times per week is 
predicted to result in a mean (%CV) TFV exposure of 2360 (26.7) ng•h/mL. Given the extensive 
safety data available for TDF in HIV-infected subjects and those with CHB, TFV exposures 
following administration of TAF in subjects with CHB with ESRD on chronic HD are expected 
to be in the range of those following TDF-containing regimens in patients with normal renal 
function and, as such, a dose modification of TAF would not be required in this population.
In line with these results, no dose adjustment of TAF is required in patients with mild, moderate 
or severe renal impairment {Vemlidy 2017, VEMLIDY® 2016}. In accordance with the EU 
Summary of Product Characteristics (SmPC), TAF may be used in patients with ESRD who are
receiving hemodialysis {Vemlidy 2017}. 
1.2.4.2.
Phase 3 Open-label Safety Study of Elvitegravir/Cobicistat/Emtricitabine/ 
Tenofovir Alafenamide in HIV-1 Positive Patients with Mild to Moderate Renal 
Impairment (GS-US-292-0112)
GS-US-292-0112, is a single-arm, Phase 3 open-label safety study of E/C/F/TAF in virally 
suppressed HIV-1 positive patients with mild to moderate renal impairment
(eGFR 30 - 69 mL/min), including 65% who were suppressed on antiretroviral regimens 
containing TDF. In this study, a total of 242 patients were treated (80 patients with eGFR
< 50 mL/min and 162 patients with eGFR ≥50 mL/min) {Pozniak 2016}. At Week 48, patients 
who switched to E/C/F/TAF had no change in eGFR, and had significant improvements in
measures of renal function including proteinuria, albuminuria, retinol binding protein and
beta-2-microglobulin (p <0.001 for all). These subjects also had improvements in measures of 
bone mineral density (mean % change of +1.47% and 2.29% for hip and spine BMD, 
respectively, p <0.05). In addition, 92% of study participants maintained virologic suppression 
(HIV-1 RNA < 50 copies/ml) at Week 48 after switching to E/C/F/TAF.
1.2.4.3.
Safety and Efficacy of TDF in CHB Patients with Decompensated Liver Disease
(Study GS-US-174-0108)
The safety and efficacy of TAF have not been evaluated in CHB patients with decompensated 
cirrhosis (CPT Class B and C). Given that TAF demonstrated non-inferior efficacy to TDF in 
HBeAg-negative (GS-US-320-0108) and HBeAg-positive (GS-US-320-0110) patients with 
CHB, including patients with compensated cirrhosis, it is important to consider results from TDF 
clinical studies as background to assessing the potential efficacy and safety of TAF in patients 
with decompensated liver disease.
The safety and efficacy of TDF in patients with decompensated liver disease were assessed in a 
double-blind, randomized, active controlled Phase 2 study (GS-US-174-0108) {Liaw 2011}. 
One hundred twelve CHB patients with decompensated liver disease (CPT score ≥7 and ≤12) 
with screening HBV DNA ≥103 copies/mL and creatinine clearance ≥50 mL/min (by 
Cockcroft-Gault method) were randomized 2:2:1 to receive TDF 300 mg once daily (n = 45), 


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emtricitabine (FTC)/TDF 200 mg/300 mg once daily (n = 45), or entecavir (ETV) (n = 22). 
Patients randomized to ETV were dosed at 0.5 mg once daily or 1.0 mg once daily in those with 
prior LAM exposure (≥6 months of LAM treatment and/or history of LAM resistance 
mutations). Patients with inadequate early viral suppression (i.e. < 2 log10 decrease in HBV DNA 
at Week 8), those with virologic breakthrough (i.e. ≥1 log10 increase from nadir), or patients 
with confirmed HBV DNA ≥69 IU/mL (≥400 copies/mL) could be switched to open-label 
FTC/TDF treatment at the investigator’s discretion; however, these patients were declared 
treatment failures at time of switch. Patients undergoing orthotopic liver transplantation (OLT) 
were allowed to continue on study but were censored in regard to secondary efficacy analyses at 
the time of liver transplant. 
The co-primary endpoints of GS-US-174-0108 were proportion with tolerability failure 
(adverse event [AE] resulting in permanent study drug discontinuation), and confirmed renal 
event (an increase from baseline in serum creatinine [sCr] of ≥0.5 mg/dL or decrease in serum 
phosphate [PO4] below 2.0 mg/dL). At Week 48, rates of tolerability failure were comparable 
across treatment groups (TDF 6.7%, FTC/TDF 4.4%, ETV 9.1%). Confirmed increases in sCr or 
decreases in PO4 occurred in a similar percentage of patients in the TDF and FTC/TDF groups 
(8.9% and 6.7%, respectively); however, confirmed renal events occurred in a lower percentage 
of ETV-treated patients (4.5%). The percentages of patients with AEs and SAEs considered 
related to study drug, and AEs resulting in permanent study drug discontinuation, or treatment 
emergent deaths (2 subjects in each group), were low and similar between treatment groups.
Although the study was not sufficiently powered to assess antiviral efficacy, the proportions of 
patients (95% confidence interval) in GS-US-174-0108 achieving HBV DNA < 69 IU/mL 
(< 400 copies/mL) at Week 48 were comparable between treatment groups (TDF 70% 
[57%, 84%], FTC/TDF 88% [78%, 98%], ETV 73% [54%, 91%] when evaluated by 
non-completers or switch equals failure [NC/S=F]), as were the rates of ALT normalization 
(TDF 46% [27%, 65%], FTC/TDF 64% [45%. 83%], ETV 41% 18%, 65%] [NC/S=F]). No 
patient in any treatment group developed resistance to study drug, and similar percentages of 
patients in each group showed improvements in CPT and model for end-stage liver disease 
(MELD) scores at Week 48 {Liaw 2011}.
When patients in GS-US-174-0108 were followed longer-term, a total of 69/112 (62%) patients 
completed 168 weeks of double-blind therapy with 12 (6-TDF, 3-FTC/TDF, and 3-ETV) patients 
switching to open-label FTC/TDF (10 patients prior to Week 48), and 11 (3-TDF, 7-FTC/TDF, 
1-ETV) patients receiving OLT (8 of 11patients completed the study through 168 weeks). In 
general, the safety and efficacy of TDF, FTC/TDF, and ETV were comparable and maintained 
through Week 168. No TDF resistance was documented over the entire (168 weeks) duration of 
treatment.
1.3.
Rationale for this Study
As the population of patients with CHB ages, the prevalence of chronic kidney disease (CKD) 
will likely increase along with the increasing development of co-morbid conditions that require 
medical management {Kazancioglu 2013, Pipili 2013}. This population is also more vulnerable 
to bone loss as well as renal complications {Chen 2015a, Chen 2015b}. Recent evidence from 


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prospective cohort studies in Taiwan suggest that the risk of CKD is significantly higher in 
individuals with CHB compared to those without CHB {Chen 2015b}, and that CHB infection 
increases the risk of developing ESRD (12-year cumulative incidence 1.9% compared with 
0.49% for CHB and non\-CHB cohorts, respectively) {Chen 2015c}. In another analysis from 
the Taiwan nationwide cohort, patients with CHB demonstrated an increased risk of osteoporosis 
compared with a comparison cohort without CHB; the incidence of this complication increased 
with advancing age (adjusted hazard ratio [aHR], 95% confidence interval, 13.3 [11.8-14.9] for 
age ≥65 years), and coexisting cirrhosis (aHR 1.62 [1.24-2.12]) {Chen 2015a}.
Further, the patient population with CHB and CKD is complex requiring special treatment 
strategies. Interferons are poorly tolerated in this population, and in addition, all of the oral 
nucleos(t)ide reverse transcriptase inhibitors (e.g. LAM, ADV, TBV, ETV, and TDF) approved 
for the treatment of CHB must undergo dose modification in patients with renal impairment to 
avoid accumulation due to predominant renal elimination pathways {Pipili 2013}. Increased 
monitoring is also required for certain OAVs such as ADV and TDF due to the increased risk of 
renal complications in patients with underlying renal compromise {Amet 2015}. While ETV has 
demonstrated high potency and a good safety/tolerability profile in treatment naïve patients with 
CHB, increased rates of resistance development have been seen in patients previously treated 
with LAM {Tenney 2009}, making ETV a less useful treatment option for many patients, 
including those with CKD. Thus, there remains a need for new options for the treatment of CHB 
in patients with CKD.
Given the current lack of clinical data for TAF in patients with CHB and CKD, the present study 
(Part A) is being undertaken to evaluate the safety and efficacy of TAF 25 mg given once daily 
in CHB patients with moderate or severe renal impairment, and includes a cohort of subjects 
with ESRD patients who are maintained on chronic HD.
Subjects with decompensated liver disease and active HBV replication are at increased risk of 
developing progressive liver disease and death {Fattovich 1991}. Furthermore, renal 
complications occur more commonly in this population, and CHB patients with cirrhosis are also 
more prone to bone loss and osteoporosis {Chen 2015a}. Peg-IFN is contraindicated in the 
setting of decompensated liver disease; OAV therapy with either TDF or ETV is recommended 
{European Association for the Study of the Liver (EASL) 2017, Sarin 2015, Terrault 2015}. 
With the advent of these potent OAVs for CHB, clinical disease progression can be slowed or 
reversed {Chang 2010, Marcellin 2013}, and fewer patients with established decompensated 
liver disease will require liver transplantation while under potent anti-HBV treatment
{Zanetto 2016}. While results from Study GS-US-174-0108 suggest that TDF improves the 
clinical course of patients with decompensated liver disease and is generally safe and well 
tolerated, confirmed renal abnormalities were observed in a higher percentage of TDF-treated 
patients compared to those treated with ETV {Liaw 2012}. Results from a recent retrospective 
analysis in India of 400 CHB patients with cirrhosis, including 210 patients with decompensated 
liver disease without access to liver transplantation, who were treated with TDF (55%) or ETV 
(45%) showed higher rates of nephrotoxicity (sCr increase ≥0.5 mg/dL from baseline) with TDF 
compared with ETV (5% vs. 1%) when followed for a median of 45 and 36 months, respectively 
{Goyal 2015}.


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Given 90% lower TFV exposures from TAF 25 mg relative to TDF 300 mg once daily, and lack 
of clinically relevant alteration in the PK of TAF or TFV in moderate or severe hepatic 
impairment, TAF 25 mg offers the potential for an improved safety profile in CHB patients with 
hepatic impairment. This study (Part B) will include a cohort of subjects with CPT Class B or C 
(CPT score 7 to 12 [inclusive]) cirrhosis to assess the safety and efficacy of TAF in this 
important patient population.
1.4.
Risk/Benefit Assessment for the Study
In the setting of renal impairment, TAF represents an important new option given its potent 
efficacy and absence of resistance (through 48 weeks of treatment), and the lack of need for dose 
adjustment. This is supported by pharmacokinetic data, safety data in HIV-1 patients and 
underlying renal impairment treated with E/C/F/TAF once daily over 48 weeks, and by PK 
simulation of subjects with ESRD on HD. Further, in Studies GS-US-320-0108 and 
GS-US-320-0110 conducted in treatment naïve and experienced patients with CHB and eGFRCG
≥50 mL/min, TAF has demonstrated improved renal and bone safety compared with TDF. Thus, 
patients with CHB, particularly those with CKD who are suppressed on oral antiviral therapy 
including TDF, may benefit from switching therapy to TAF in regard to maintenance of viral 
suppression with the potential for improved bone parameters and maintenance or improvement in 
renal parameters.
In CHB patients with decompensated liver disease (CPT Class B and C), TAF offers the 
advantages of potent antiviral therapy without resistance development with the potential for 
improved bone and renal safety. This is important given that fewer patients with decompensated 
cirrhosis experience disease progression requiring liver transplantation, and life-long therapy is 
required in this special population. 
Potential risks of a patient’s involvement in this study include switching to a new treatment 
regimen with the potential loss of virologic control and/or emergence of new adverse events. 
Other risks common to clinical trials such as this include the inconvenience of frequent clinic 
visits and laboratory blood draws, and the associated pain and discomfort of phlebotomy. 
Strategies to mitigate these risks include frequent monitoring of viral load and other laboratory
parameters as well as ongoing monitoring of adverse events. Parameters for discontinuation of 
study drug due to adverse events or lack of efficacy are well-defined and will be closely 
followed. In addition, an independent data monitoring committee will be convened early in the 
course of the study to evaluate safety data and determine whether the risks/benefits warrant 
continuation of the study.
Considering the above, the benefit-risk balance for this study is considered positive.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the safety and tolerability of TAF 25 mg QD at Week 24

To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) 
at Week 24
The secondary objectives of this study are:

To evaluate the safety and tolerability of TAF 25 mg QD at Weeks 48 and 96

To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) 
at Weeks 48 and 96

To evaluate biochemical (ALT normal and ALT normalization) and serological (loss of 
HBeAg with seroconversion to anti-HBe in HBeAg-positive subjects and loss of HBsAg with 
seroconversion to anti-HBs) responses at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on renal parameters at Weeks 24, 48, and 96 in 
subjects with moderate or severe renal impairment and hepatically impaired subjects

To evaluate the safety of TAF 25 mg QD as determined by percentage change from Baseline 
in hip and spine bone mineral density (BMD) at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on fibrosis as assessed by Fibrotest® at 
Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on changes in Child-Pugh-Turcotte (CPT) and 
Model for End-stage Liver Disease (MELD) scores at Weeks 24, 48, and 96 in hepatically 
impaired subjects
The exploratory objectives of this study are as follows:
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3.
STUDY DESIGN
3.1.
Study Treatment Plan and Regimen
This is an open label, multi-center study to evaluate the safety and efficacy of switching to TAF 
25 mg QD from TDF and/or other OAV in virologically suppressed subjects who have CHB
with renal and/or hepatic impairment.
Approximately 120 subjects will be enrolled into the 2 Parts of the study:
Part A (Renally Impaired subjects):
Approximately 90 subjects will be enrolled into 2 cohorts and stratified by the level of renal 
impairment. Approximately 50% of subjects (target n = 42 to 46) enrolled into Part A should be 
virologically suppressed (HBV DNA < LLOQ) for at least 6 months on TDF or a 
TDF-containing anti-HBV regimen for CHB at time of Screening.
Cohort 1: Moderate or Severe renal impairment

Moderate renal impairment (30 mL/min ≤eGFRCG ≤59 mL/min)

Severe renal impairment (15 mL/min ≤eGFRCG < 30 mL/min)
eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
Cohort 2: ESRD (eGFR < 15 mL/min) and maintained on HD
Approximately 20% of subjects (target n = 16 to 18) enrolled into Part A will be enrolled into
Cohort 2.
Part B (Hepatically Impaired Subjects):
Approximately 30 subjects, all of whom are virologically suppressed (HBV DNA < LLOQ) for 
at least 6 months on TDF, or a TDF-containing anti-HBV regimen, or other OAV(s) for CHB at 
time of Screening will be enrolled with:

Moderate hepatic impairment (CPT [Appendix 7] Class B; Score of 7-9 inclusive) OR

Severe hepatic impairment (CPT Class C; Score of 10-12 inclusive) 


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Figure 3-1. 
Study Design Schematic 
Primary 
endpoint 
Week24 Week 48 
v 
Week 96 
v 
v 
Cohort 1 
PART A 
Moderate-Severe Renal Impairment 
N=90 
(aooroximatlev 80%) 
(TAF25mg) 
Cohort 2 
ESRD (approximately 20%} 
PARTS 
N= 30 
Moderate - Severe Hepatic Impairment 
(TAF25mg) 
, .. ···-·-· -· 
... 
... 
--
The duration of study drng treatment for all subjects is 96 weeks. 
Final 
Amendment 1 
Subjects in Prut A (renally impaired) with HBsAg loss with confmned seroconversion to 
anti-HBs should discontinue study drng within 3-6 months following confinnation of 
seroconversion to anti-HBs. Subjects with HBsAg loss with confirmed seroconversion prior to 
Week 24 are not permitted to discontinue study drng prior to the Week 24 visit. Subjects with 
HBsAg loss with confumed seroconversion will be followed off treatment every 4 weeks for 
12 weeks and then per the study visit schedule (Appendix 2) thrnugh Week 96/Early 
Discontinuation (ED). Discontinuation of study drng for subjects experiencing HBsAg loss with 
confinned seroconversion, who have known bridging fibrosis or compensated ci1Thosis, should 
be considered on a case by case basis. 
Subjects with moderate or severe hepatic impai.J.ment (Pa1i B) who experience HBsAg loss and 
seroconversion to anti-HBs should not discontinue study drug. 
Subjects in Prut A (renally impaired) who pennanently discontinue study drug (either 
prematurely or after completing 96 weeks of treatment) for reasons other than HBsAg loss with 
confumed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks off treatment 
or until initiation of appropriate, alternative HBV therapy, whichever occurs first. Use of 
appropriate, alternative HBV therapy is strongly encouraged. 
For subjects in Prui B (hepatic impai1ment) who pe1manently discontinue study mug, immediate 
initiation of appropriate, alternative HBV therapy is strongly recommended. 
A data monitoring committee (DMC) will review the progress of the study and perfo1m review 
of safety data after 30 subjects have completed 12 weeks of treatment. However, Gilead will 
defer to the DMC for any decision to convene eru·lier or more frequently. The DMC will examine 
the safety results of the trial and also focus on logistical issues such as accrnal, retention, quality 
of clinical and laboratory data, and implications of results of external studies. No formal stopping 
rnles will be used by the DMC for safety outcomes. Rather, a clinical assessment will be made to 
dete1mine if the nature, frequency, and severity of adverse effects associated with study 
treatment waITant the early te1mination of the study to be in the best interests of the pa1ticipants. 
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3.2.
Biomarker Testing
3.2.1.
Biomarker Samples to Address the Study Objectives
The following biological specimens will be collected in this study and will be used to evaluate 
the association of biomarkers with study drug response, including efficacy and/or adverse events 
and to increase knowledge and understanding of the biology of chronic hepatitis B and related 
diseases. The specific analyses will include, but will not be limited to, the biomarkers listed 
below. Because biomarker science is a rapidly evolving area of investigation, and adverse events 
in particular are difficult to predict, it is not possible to specify prospectively all tests that will be 
done on the specimens provided. The testing outlined below is based upon the current state of 
scientific knowledge. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests based upon the growing state of art knowledge.

Urine Biomarkers including, but not limited to, retinol binding protein (RBP) and 
beta-2 microglobulin (for all subjects in Part A except Cohort 2 (ESRD subjects on HD) and 
all subjects in Part B [hepatic impairment])

Serum Bone Biomarkers including, but not limited to, C-type collagen sequence (CTX) and 
procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected in a fasted state at Baseline and Weeks 4, 12, 24, 48, 72, and 
96/ED. Samples may be stored by Gilead Sciences for a period of up to 15 years at the end of the 
study.
3.2.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
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3.2.3.
Biomarker Samples for Optional Pharmacogenomic Research
 
 
 
 
 
 
 
 
 
 
 
3.3.
End of Study
The end of the study will be the last subjects’ last observation or visit.
3.4.
Post Study Care
Once a subject has completed their study participation, the long-term care of the participant will 
return to the responsibility of their primary treating physicians.
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 120 subjects will be enrolled into Part A (renal impairment) and Part B (hepatic 
impairment). In Part A, approximately 90 subjects will be enrolled with approximately 50% of 
subjects (target n = 42 to 46) virologically suppressed (HBV DNA < LLOQ) for at least 
6 months on TDF or a TDF-containing anti-HBV regimen for CHB at time of Screening, and 
with approximately 20% of subjects (target n = 16 to 18) having ESRD and maintained on HD at 
time of Screening. In Part B, approximately 30 subjects will be enrolled, all of whom should be 
virologically suppressed (HBV DNA < LLOQ) for at least 6 months on TDF, or a 
TDF-containing anti-HBV regimen, or other OAV(s) for CHB at time of Screening and have 
moderate or severe hepatic impairment.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible to participate in this 
study.
All Subjects (Parts A and B):
1) Must have the ability to understand and sign a written informed consent form; consent must 
be obtained prior to initiation of study procedures
2) Adult male or non-pregnant female subjects, ≥18 years of age based on the date of the 
Screening visit. A negative serum pregnancy test at Screening is required for female subjects 
of childbearing potential (as defined in Appendix 5)
3) Documented evidence of chronic HBV infection previously (e.g., documented HBsAg 
positive for ≥6 months)
4) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
5) ALT ≤10 × ULN at Screening by central laboratory
6) Must be willing and able to comply with all study requirements
Part A Only (renal impairment):
1) Maintained on TDF and/or other OAV treatment(s) for CHB for at least 48 weeks and with
viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to Screening 

All subjects must have HBV DNA < 20 IU/mL at Screening by central laboratory

Both HBeAg positive and negative subjects are eligible to participate


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2) Moderate renal impairment ( 30 mL/min ≤eGFRCG ≤59 mL/min), severe renal impairment 
(15 mL/min ≤eGFRCG < 30 mL/min) using the Cockcroft-Gault equation {Cockcroft 1976}, 
or ESRD (eGFR < 15 mL/min) maintained on HD

eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)

Stable renal function (for subjects with moderate or severe impairment): serum creatinine 
measured at least once within three months prior to Screening. The measurement 
difference between the value measured within three months prior to Screening versus the 
Screening value must be ≤25% of the Screening value
Part B Only (hepatic impairment): 
1) Maintained on TDF and/or other OAV treatment(s) for CHB for at least 48 weeks and with
viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to Screening

All subjects must have HBV DNA < 20 IU/mL at Screening by central laboratory

Both HBeAg positive and negative subjects are eligible to participate
2) CPT score (Appendix 7) of 7-12 (inclusive) OR a past history of CPT score ≥ 7 and any CPT 
score ≤ 12 at Screening
3) eGFRCG ≥30 mL/min using the Cockcroft-Gault equation {Cockcroft 1976}:

eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible to participate in the 
study:
All Subjects (Parts A & B):
1) Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study
2) Males and females of reproductive potential who are unwilling to use an “effective”, 
protocol-specified method(s) of contraception during the study (Appendix 5)


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3) Co-infection with HCV, HIV, or HDV

Subjects who are HCV positive, but have a documented negative HCV RNA, are eligible
4) Prior IFN use within 6 months of Screening
5) Evidence of hepatocellular carcinoma (i.e. evidenced by imaging within 6 months of 
Screening)
6) Received solid organ or bone marrow transplant
7) Significant cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator
8) Malignancy within 5 years prior to Screening, with the exception of specific cancers that are 
cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible
9) Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic 
agents, or agents capable of modifying renal excretion
10) Known hypersensitivity to study drugs, metabolites, or formulation excipients
11) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
12) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
13) Use of investigational agents within 3 months of Screening, unless allowed by the Sponsor
14) Use of any prohibited medication as described in Section 5.3.
Part A Only (renal impairment):
1) Current or historical evidence of clinical hepatic decompensation (e.g., ascites, 
encephalopathy or variceal hemorrhage)
2) Abnormal hematological and biochemical parameters, including:

Hemoglobin < 9 g/dL

Absolute neutrophil count < 750/mm3

Platelets ≤ 50,000/mm3

AST > 10 × ULN


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
Albumin < 3.0 g/dL

Total bilirubin > 2.5 × ULN

INR > 1.5 × ULN (unless stable on anticoagulant regimen)
3) Subjects with ESRD (i.e. eGFR < 15 mL/min) not on HD, or those on other forms of renal 
replacement therapy (i.e. peritoneal dialysis)
Part B Only (hepatic impairment): 
1) Active variceal bleeding within 6 months or prior placement of a portosystemic shunt 
(such as transjugular intrahepatic portosystemic shunt [TIPS])
2) History of hepatorenal syndrome, hepatopulmonary syndrome, Grade 3 or Grade 4 hepatic 
encephalopathy, or spontaneous bacterial peritonitis within 6 months of Screening
3) Grade 2 hepatic encephalopathy at Screening
4) MELD score ≥30
5) Abnormal hematological and biochemical parameters, including:

Absolute neutrophil count < 750/mm3

Platelets < 30,000/mm3

Hemoglobin < 8.0 g/dL


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of TAF
5.1.1.
Formulation
5.1.1.1.
TAF Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of TAF. The tablets are yellow, round-shaped, and film-coated. The tablets are debossed 
with “GSI” on one side and “25” on the other side. In addition to the active ingredient, each 
film-coated tablet contains the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.1.2.
Packaging and Labeling
TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets and a silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner. Study drug(s) to be distributed to centers in the US 
and other participating countries shall be labeled to meet applicable requirements of the 
United States Food and Drug Administration. (FDA), EU Guideline to Good Manufacturing 
Practice − Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.1.3.
Storage and Handling
TAF tablets should be stored at controlled room temperature of 25°C (77°F); excursions are 
permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. 
Until dispensed to the subjects, all bottles of study drugs should be stored in a securely locked 
area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug(s) should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure when handling.
5.2.
Dosage and Administration of Tenofovir Alafenamide (TAF)
All subjects will receive TAF 25 mg QD. It is preferred that subjects take their study drug 
according to a morning dosing schedule; however, evening dosing is allowable.
All study drugs should be taken at approximately the same time each day with food.
Study drug should be administered after assessing adverse events and concomitant medication(s).


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On the day of hemodialysis, study drug should not be administered to subjects until after 
the completion of hemodialysis and collection of any required post-hemodialysis samples 
for Part A, Cohort 2.
 
5.3.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of Screening, up to and including the 
date of the last study visit, need to be recorded in the source documents and eCRFs.
The following medications are excluded while subjects are participating in the study. These 
medications are prohibited during the Screening period and for a minimum of 30 days prior 
to the Baseline/Day 1 visit through the end of treatment:

Investigational agents or devices for any indication

Nephrotoxic agents (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir [except for short term (< 2 weeks) acute treatment], valacyclovir
[except for short term (< 2 weeks) acute treatment], ganciclovir, valganciclovir, and multiple 
or high dose nonsteroidal antiinflammatory agents [NSAIDs])

Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or immunomodulating 
agents
Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e., P-glycoprotein [P-gp]) with TAF may decrease TAF plasma concentrations, 
which may lead to loss of therapeutic effect.
Examples of representative medications which are prohibited from 21 days prior to Day 1 
through the end of treatment are listed below:
Table 5-1.
Disallowed Concomitant Medications
Medication Class
Prohibited Medications
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
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Drugs that strongly inhibit P-gp and BCRP activity may increase TAF plasma concentrations. 
(USPI Vemlidy® {VEMLIDY® 2016}). In accordance with the EU SmPC for TAF, the use of 
strong P-gp inhibitors is not recommended {Vemlidy 2017}.
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
including herbal/natural products/therapies, and over the counter medications, the 
Gilead Sciences Medical Monitor must be consulted prior to initiation of the new medication. In 
instances where an excluded medication is initiated prior to discussion with the Sponsor, the 
investigator must notify Gilead Sciences as soon as he/she is aware of the use of the excluded 
medication.
5.4.
Accountability for Tenofovir Alafenamide (TAF)
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product (IMP) bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP bottles dispensed to subjects must be returned to the site.
Investigational product accountability records will be provided to each study site to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP bottles returned, along with the initials of 
the person recording the information.
5.4.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for drug 
destruction, arrangements will be made between the site and Gilead Sciences (or Gilead Sciences’ 
representative) for return of unused study drug supplies. A copy of the site’s SOP will be obtained 
for central files. Where possible, study drug will be destroyed at the site. Upon study completion, 
a copy of the Investigational Drug Accountability records must be filed at the site. Another copy 
will be returned to Gilead Sciences. If drug is destroyed on site, the investigator must maintain 
accurate records for all study drug bottles destroyed. Records must show the identification and 
quantity of each unit destroyed, the method of destruction, and person who disposed of the drug. 
All study drug records must be maintained at the site and copies must be submitted to 
Gilead Sciences at the end of the study.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment. Once consent has been obtained, all screening tests and procedures 
have been completed, and study eligibility has been confirmed, subjects will begin study 
treatment within 45 days at the Baseline visit.
Candidates who fail to meet eligibility criteria by screening evaluations may be re-screened once 
after the initial screen if there is a reasonable expectation that the candidate will be eligible after 
repeat screening.
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principal Investigator’s opinion, the retest value will be within accepted parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample); or due to an extenuating circumstance.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 45 days before randomization to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment history)

Review concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature), body weight, and height

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)


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
DXA scan of hip and spine. The Baseline DXA scan can be performed at any time during the 
Screening period, but should be conducted at least 14 days prior to the first dose of study 
drug to ensure an acceptable pre-dose DXA scan.

Obtain blood samples for: 
plasma HBV DNA (must be < 20 IU/mL by central laboratory at time of Screening to be 
eligible)
Serum chemistry and liver function tests (including PT/INR), hematology (including 
ALT [must be ≤10 times ULN by central laboratory]), serum HBsAg (quantitative), 
HBV serology (qualitative HBsAg and HBeAg), eGFRCG, HIV, HDV, HCV, serum 
pregnancy test (for females of child-bearing potential), α-fetoprotein (AFP). An AFP 
> 50 ng/mL at Screening must have an appropriate evaluation (e.g., CT scan if not 
performed within the previous 6 months) in order to rule out HCC prior to being 
permitted to enter the study.

Urine sample for urinalysis and drug screen for all subjects except only where available for 
subjects in Part A, Cohort 2 (ESRD subjects on HD)

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites assessment, 
and Hepatic encephalopathy assessment) for Part B subjects (hepatic impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/eCRF).
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history CRF/eCRF.
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Baseline Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug. Subjects screened within 45 days before Baseline will be eligible to participate in the 
study. Initiation of treatment with study drug should take place on the day of the Baseline visit. 
The following will be performed at the Baseline visit:

Review of inclusion/exclusion criteria and confirm medical history (including HBV disease 
and treatment history)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications


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
Review adverse events

Serum Cystatin C testing for eGFR by CKD-EPI [Chronic Kidney Disease Epidemiology 
Collaboration] (cystatin C)

Blood sample for Fibrotest®

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment) for Part B subjects 
(hepatic impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection

Complete the “Fracture Risk Assessment” (FRAX®) eCRF

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection

Blood sample for serum chemistry and liver function tests (including PT/INR), hematology, 
plasma HBV DNA level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and 
HBeAg), eGFRCG, virology (resistance surveillance), serum and plasma for storage, sparse 
plasma PK (all subjects except Part A, Cohort 2 [ESRD subjects on HD]), and vitamin D 
assessment

 
 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI, EQ-5D-3L)

Site-administered questions for Health Utilization Assessment to be completed

Dispense study drug; subjects should be reminded that dosing of study drug will occur
in-clinic at the next visit and/or (for Part A, Cohort 2 subjects [ESRD on HD]) after the 
hemodialysis at or following the next visit
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6.3.
Treatment Assessments
6.3.1.
Week 4 (Visit Window ± 3 days)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
level, eGFRCG, virology (resistance surveillance), and serum and plasma for storage

Blood samples for Sparse PK:
All subjects except Part A, Cohort 2 (ESRD subjects on HD)
■
Study drug administered in clinic and the single plasma PK sample collected between 
15 minutes and 4 hours post dose
Part A, Cohort 2 Subjects (ESRD subjects on HD at selected sites)
■
On the day of hemodialysis, 4 samples will be collected:
○
1 sample collected within 10 minutes before a hemodialysis session begins
○
1 sample each collected approximately 1 hour prior to conclusion of the 
hemodialysis session from both the arterial and venous sides of the dialyzer and
○
1 sample collected within 10 minutes after a hemodialysis session concludes
On the day of hemodialysis, study drug should not be administered to subjects 
until after the completion of hemodialysis and collection of any required 
post-hemodialysis samples for Part A, Cohort 2.

 for Optional Intensive PK substudy (separate consent required)
CCI
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
Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Fasting blood sample for serum bone biomarkers − no food or drinks, except water, at least 
8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 (ESRD 
subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood collection

Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense study drug; subjects should be reminded that dosing of study drug will occur 
in-clinic at the next visit and/or (for Part A, Cohort 2 subjects [ESRD on HD]) after the 
hemodialysis at or following the next visit
6.3.2.
Week 8 (Visit Window ± 3 days)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 
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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
level, eGFRCG, virology (resistance surveillance), and serum and plasma for storage

Blood samples for Sparse PK:
All subjects except Part A, Cohort 2 (ESRD subjects on HD)
■
Study drug administered in clinic and the single plasma PK sample collected between 
15 minutes and 4 hours post dose
Part A, Cohort 2 Subjects (ESRD subjects on HD at selected sites)
■
On the day of hemodialysis, 4 samples will be collected: 
○
1 sample collected within 10 minutes before a hemodialysis session begins
○
1 sample each collected approximately 1 hour prior to conclusion of the 
hemodialysis session from both the arterial and venous sides of the dialyzer and
○
1 sample collected within 10 minutes after a hemodialysis session concludes
On the day of hemodialysis, study drug should not be administered to subjects 
until after the completion of hemodialysis and collection of any required 
post-hemodialysis samples for Part A, Cohort 2.

 for Optional Intensive PK substudy (separate consent required)
CCI
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
Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense study drug; subjects should be reminded that dosing of study drug will occur
in-clinic at the next visit and/or (for Part A, Cohort 2 subjects [ESRD on HD]) after the 
hemodialysis at or following the next visit
6.3.3.
Week 12 (Visit Window ± 3 days)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA
level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
eGFRCG, virology (resistance surveillance), and serum and plasma for storage
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
Blood samples for Sparse PK:
All subjects except Part A, Cohort 2 (ESRD subjects on HD)
■
Study drug administered in clinic and the single plasma PK sample collected between 
15 minutes and 4 hours post dose
Part A, Cohort 2 Subjects (ESRD subjects on HD at selected sites)
■
On the day of hemodialysis, 4 samples will be collected: 
○
1 sample collected within 10 minutes before a hemodialysis session begins
○
1 sample each collected approximately 1 hour prior to conclusion of the 
hemodialysis session from both the arterial and venous sides of the dialyzer and
○
1 sample collected within 10 minutes after a hemodialysis session concludes
On the day of hemodialysis, study drug should not be administered to subjects 
until after the completion of hemodialysis and collection of any required 
post-hemodialysis samples for Part A, Cohort 2.

 for Optional Intensive PK substudy (separate consent required)
CCI
CCI


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
Fasting blood sample for serum bone biomarkers − no food or drinks, except water, at least 
8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense study drug; Part A, Cohort 2 subjects (ESRD on HD) should be reminded that 
dosing of study drug will occur after the hemodialysis at or following the next visit
6.3.4.
Week 24 (visit window is −7 days)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests (including PT/INR), hematology, 
plasma HBV DNA level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg 
and HBeAg), eGFRCG, virology (resistance surveillance), vitamin D assessment, and serum 
and plasma for storage
CCI


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
Blood samples for Sparse PK:
All subjects except Part A, Cohort 2 (ESRD subjects on HD)
■
Single plasma PK sample
Part A, Cohort 2 Subjects (ESRD subjects on HD at selected sites) 
■
On the day of hemodialysis, 4 samples will be collected: 
○
1 sample collected within 10 minutes before a hemodialysis session begins
○
1 sample each collected approximately 1 hour prior to conclusion of the 
hemodialysis session from both the arterial and venous sides of the dialyzer and
○
1 sample collected within 10 minutes after a hemodialysis session concludes
On the day of hemodialysis, study drug should not be administered to subjects 
until after the completion of hemodialysis and collection of any required
post-hemodialysis samples for Part A, Cohort 2.

Blood sample for Fibrotest®

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment) for Part B subjects 
(hepatic impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection

DXA scan of hip and spine (within −14 days of the expected visit date)

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI, EQ-5D-3L)

Site-administered questions for Health Utilization Assessment to be completed

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.


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
Perform study drug accountability

Dispense study drug
6.3.5.
Week 36 (Visit Window ± 14 days)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects except Part A, 
Cohort 2 subjects [ESRD subjects on HD]), and serum and plasma for storage

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense study drug
6.3.6.
Week 48 (Visit Window is −7 days)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests (including PT/INR), hematology, 
plasma HBV DNA level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg 
and HBeAg), eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects 
except Part A, Cohort 2 [ESRD subjects on HD]), vitamin D assessment, and serum and 
plasma for storage


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
Blood sample for Fibrotest®

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment) for Part B subjects 
(hepatic impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection

DXA scan of hip and spine (within −14 days of the expected visit date)

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI, EQ-5D-3L)

Site-administered questions for Health Utilization Assessment to be completed

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

Perform study drug accountability

Dispense study drug

 
6.3.7.
Week 60 (Visit Window ± 14 days)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications
CCI


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
Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects except Part A, 
Cohort 2 [ESRD subjects on HD]), and serum and plasma for storage

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense open label study drugs
6.3.8.
Week 72 (Visit Window ± 14 days)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects except Part A, 
Cohort 2 [ESRD subjects on HD]), and serum and plasma for storage

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 
(ESRD subjects on HD)− no food or drinks, except water, at least 8 hours prior to blood
collection

DXA scan of hip and spine (within ± 14 days of the expected visit date)

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.


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
Site-administered questions for Health Utilization Assessment to be completed

Perform study drug accountability

Dispense study drug
6.3.9.
Week 96 (Visit Window is −7 days)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

Blood sample for serum chemistry and liver function tests (including PT/INR), hematology, 
plasma HBV DNA level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg 
and HBeAg), eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects 
except Part A, Cohort 2 [ESRD subjects on HD]), and serum and plasma for storage

Blood sample for Fibrotest®

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment) for Part B subjects 
(hepatic impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers for all subjects except Part A, Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection

DXA scan of hip and spine (within - 14 days of the expected visit date)

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI, EQ-5D-3L)

Site-administered questions for Health Utilization Assessment to be completed


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
Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Perform study drug accountability

 
6.4.
Post-Treatment Assessments
6.4.1.
HBsAg Loss and Seroconversion Subjects
Subjects in Part A (renally impaired) who discontinue study drug due to HBsAg loss with 
confirmed seroconversion to anti-HBs on or after the Week 24 visit, will be followed off 
treatment every 4 weeks for 12 weeks and then per the original study visit schedule through 
Week 96/ED (excluding drug dispensation and accountability). Discontinuation of study drug for 
subjects experiencing HBsAg loss with confirmed seroconversion, who have known bridging 
fibrosis or compensated cirrhosis, should be considered on a case by case basis.
Subjects with moderate or severe hepatic impairment (Part B) who experience HBsAg loss and 
seroconversion to anti-HBs should not discontinue study drug.
6.4.2.
All Other Subjects Who Discontinue Study Drug
Subjects in Part A (renally impaired) who have received at least one dose of study drug and 
permanently discontinue study drug for reasons other than HBsAg loss with confirmed 
seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks off treatment or up to 
initiation of appropriate, alternative HBV therapy, whichever occurs first. Use of appropriate, 
alternative HBV therapy is strongly encouraged.
For subjects in Part B (hepatic impairment) who permanently discontinue study drug, immediate 
initiation of appropriate, alternative HBV therapy is strongly recommended.
6.4.3.
Treatment-Free Follow Up Visit Assessments (Part A Subjects)

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events
CCI


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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA 
levels, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
eGFRCG, and serum for storage

Urine for urinalysis
6.5.
Early Discontinuation (ED)/Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator.
The assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic rebound a serum blood sample for 
resistance testing must be collected.
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
The ED Visit should be performed within 72 hours (i.e., visit window is + 3 days) of the last 
study drug dose.

Complete physical exam with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to
the recording)

DXA scan of spine and hip to be performed within ± 14 days of the expected visit date and is 
done only if not done within the past 12 weeks of the ED visit

Review concomitant medications

Review adverse events 

Fasting blood sample for serum bone biomarkers and metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and triglycerides]) − no food or drinks, 
except water, at least 8 hours prior to blood collection (only collected if not done in the last 
12 weeks)

Fasting urine sample for renal biomarkers for all subjects except for Part A, Cohort 2 
(ESRD subjects on HD) − no food or drinks, except water, at least 8 hours prior to blood
collection(only collected if not done in the last 12 weeks)


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
Blood sample for serum chemistry and liver function tests (including PT/INR), hematology, 
plasma HBV DNA level, serum HBsAg (quantitative), HBV serology (qualitative HBsAg 
and HBeAg), eGFRCG, virology (resistance surveillance), sparse plasma PK (all subjects 
except Part A, Cohort 2 [ESRD subjects on HD]), and serum and plasma for storage

Blood sample for Fibrotest®

CPT ([Appendix 7] Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment) for Part B subjects (hepatic 
impairment) only

MELD Score (Assessment requires: total bilirubin, serum creatinine, serum sodium, and 
PT/INR) for Part B subjects (hepatic impairment) only

Urine sample (for all subjects except only where available for subjects in Part A, Cohort 2 
[ESRD subjects on HD]) for urinalysis, pregnancy test (for females of child-bearing 
potential; in case of a positive urine test, or if urine cannot be collected for subjects in Part A, 
Cohort 2 [ESRD subjects on HD], a serum pregnancy test will be done), and for storage.

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI, EQ-5D-3L) are 
done only if not done within the past 24 weeks of the ED visit

Site-administered questions for Health Utilization Assessment to be completed
6.6.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Therapeutic failure 

Part A (renally impaired) subjects only - HBsAg loss with seroconversion to anti-HBs. These 
subjects should discontinue study drug within 3-6 months following confirmation of 
seroconversion to anti-HBs. Subjects with HBsAg loss with confirmed seroconversion before
Week 24 are not permitted to discontinue study drug prior to the Week 24 visit. 

Discontinuation of study drug for subject experiencing HBsAg-loss with confirmed 
seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, should be 
considered on a case by case basis


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
Any subject with eGFRCG < 15 ml/min who does not initiate hemodialysis or initiates other 
forms of renal support (e.g. peritoneal dialysis) will be required to discontinue study 
treatment

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.7.
Other Evaluations
6.7.1.
Bone and Renal Markers
The following biological specimens will be collected in this study. The specific analyses will 
include, but will not be limited to, the biomarkers listed below.

Urine Biomarkers including, but not limited to, retinol binding protein (RBP) and 
beta-2 microglobulin (for all subjects except Part A, cohort 2 [ESRD subjects on HD])

Serum Bone Biomarkers including, but not limited to, C-type collagen sequence (CTX) and 
procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected in a fasted state at Baseline and Weeks 4, 12, 24, 48, 72, and 
96/ED. Samples may be stored by Gilead Sciences for a period of up to 15 years at the end of the 
study.
 
6.7.2.
Intensive Pharmacokinetic Substudy (Optional)
 
 
 
 
 
 
 
CCI
CCI
I 


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6.8.
Resistance Surveillance and Virologic Rebound Management
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for potential resistance
mutations may be attempted for any subject with HBV DNA ≥69 IU/mL at Baseline and for
subjects who experience viremia (HBV DNA ≥ 69 IU/mL) at Weeks 24, 48, and 96/ED.
Phenotypic analysis will be performed for subjects that are subjected to sequence analysis.
As it may not be known at the time of the visit whether a patient is viremic or if it will be their
last study visit, a separate serum sample for potential resistance surveillance will be collected at
each study visit.
In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be asked
to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound
occurring within the first 12 weeks of the study, the next scheduled visit will used for follow up.
For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit
within 2-3 weeks after the date of the original test that resulted with HBV DNA virologic
rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for
resistance testing will be obtained. For unscheduled visits, the subject will be required to bring 
their supply of study drug with them and be assessed for adherence by pill count, and if 
necessary, the subject will be re-counseled on adherence to study medication.
CCI


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and 
Serious Adverse Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
Severity of adverse events is to be determined based on GSI Grading Scale for Severity of
Adverse Events and Laboratory Abnormalities (Appendix 4). A distinction should be drawn
between seriousness and severity of AEs. An AE that is assessed as Grade 4 (potentially 
life-threatening) should not be confused with an SAE. Severity is a category utilized for rating
the intensity of an event: both AEs and SAEs can be assessed as Grade 4. An event is defined as
“serious” when it meets one of the predefined outcomes described above in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH:
Fax:
Email:
Medical Monitor:
Phone: 
Fax: 
Email: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
PPD
PPD
PPD
PPD
PPD
PPD


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 3.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Administration of study drug may be discontinued due to a clinical or laboratory event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.


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7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise, or 
triglyceride elevation that is non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
7.5.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in 
bone mineral density for chronic HBV-infected patients, Gilead recommends that any subject 
who has a DXA scan that demonstrates a decrease from baseline of > 5% in bone mineral density 
of the spine region or the hip region be followed per local medical practice at the discretion of 
the investigator.


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7.5.5.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × baseline 
value and > 10 × ULN, with or without associated symptoms
7.5.5.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT > 2 × baseline and > 10 × ULN, the following is 
recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after 
initial laboratory results were drawn). During the visit, a clinical assessment of the subject 
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
serum albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV, and 
HEV.
Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable Relative to Baseline Liver Function Tests
If ALT levels are elevated (i.e., > 2 × baseline and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to baseline, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or baseline level. 
During monitoring, if the ALT values remain persistently elevated, the investigator should 
discuss with the Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.


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Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × baseline and > 10 × ULN), and total bilirubin is confirmed 
to be 2 × baseline value, and INR is 0.5 above baseline, provided both are > ULN, the 
investigator should consider discontinuing study medication (upon discussion with the 
Gilead Medical Monitor, unless the safety of the subject is of immediate concern). 
The subject should be monitored weekly as long as ALT, total bilirubin, and INR values remain 
elevated or above baseline values.
During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
7.5.5.2.
Management of Exacerbation of Hepatitis in Subjects Who Have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation > 2 × baseline and > 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function 
(total bilirubin 2 × baseline, INR 0.5 above baseline, provided both are > ULN) and the subject is 
on no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, 
creatinine, sodium, and albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV and 
HEV. If Plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy. 

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or baseline up to a maximum of 6 months after the initial occurrence of the event. 


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7.5.6.
Management of Potential Nephrotoxicity
For subjects with moderate or severe renal impairment (Part A, Cohort 1), and subjects with 
hepatic impairment (Part B), eGFRCG will be followed post-baseline during the study. 
eGFRCG is calculated by:
(140 – age in years) (actual body weight [kg])
(72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
Any subject with a post baseline eGFRCG < 15 mL/min must have serum creatinine measured 
again within 3 calendar days of receipt of results. At the time of this repeat serum creatinine 
assessment, serum Cystatin C will also be measured and the eGFR by CKD-EPI (cystatin C) will 
be calculated and compared with the baseline measurement. Any subject who has an eGFRCG
< 15 mL/min who also experiences > 20% reduction in eGFR by CKD-EPI (cystatin C) from 
baseline or any subject who has other clinical and/or laboratory evidence of acute renal failure 
will be discussed with the Medical Monitor and may require discontinuation from study drugs. 
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499 × max (Scys/0.8, 1)−1.328 × 0.996Age
[× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of Scys/0.8 or 1, 
and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
If the eGRFCG is confirmed to be < 15 ml/min and hemodialysis is to be initiated, the subject can 
remain on study after discussion with the Medical Monitor. However, any subject with eGFR
< 15 mL/min who does not initiate hemodialysis, or those who initiate other forms of renal 
support (e.g. peritoneal dialysis) will be required to permanently discontinue study drug.
All subjects with moderate or severe renal impairment with a change from baseline serum 
creatinine of ≥ 0.4 mg/dL must have serum creatinine repeated, with a concurrent urinalysis and 
urine chemistry, within 2 weeks of receipt of results. If a subject has a confirmed change from 
baseline serum creatinine of ≥ 0.4 mg/dL, the Medical Monitor should be notified and a 
consultation with a nephrologist should be obtained.
All subjects with moderate or severe renal impairment with negative or trace proteinuria at
baseline that develop ≥1+ proteinuria on urinalysis are recommended to have a urinalysis 
repeated, with a concurrent urinalysis and urine chemistry, within 2 weeks of receipt of results. 
Any subject with ≥1+ proteinuria at baseline who develops a ≥1+ change from baseline should 
follow this same procedure. Upon confirmation of new proteinuria, subjects will be asked to 
return to the clinic for a scheduled or unscheduled follow up visit for evaluation. It is 
recommended that the Investigator contact the Gilead Medical Monitor to discuss if further 
consultation with a nephrologist is clinically warranted.


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7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, and 
pregnancy reports regardless of an associated AE and AE in an infant following exposure from
breastfeeding. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of
one’s professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: 
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
 or email 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.6.2 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this switch study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD at Week 24

To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) 
at Week 24
The secondary objectives of this switch study are as follows: 

To evaluate the safety and tolerability of TAF 25 mg QD at Weeks 48 and 96

To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) 
at Weeks 48 and 96

To evaluate biochemical (ALT normal and ALT normalization) and serological (loss of 
HBeAg with seroconversion to anti-HBe in HBeAg-positive subjects and loss of HBsAg with 
seroconversion to anti-HBs) responses at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on renal parameters at Weeks 24, 48, and 96 in 
subjects with moderate or severe renal impairment and hepatically impaired subjects

To evaluate the safety of TAF 25 mg QD as determined by percentage change in hip and 
spine bone mineral density (BMD) at Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on fibrosis as assessed by Fibrotest® at 
Weeks 24, 48, and 96

To evaluate the effect of TAF 25 mg QD on changes in Child-Pugh-Turcotte (CPT) and 
Model for End-stage Liver Disease (MELD) scores at Weeks 24, 48, and 96 in hepatically 
impaired subjects

To evaluate the pharmacokinetics of TAF and TFV
The exploratory objectives of this switch study are as follows:
CCI


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8.1.2.
Primary Endpoint

The primary safety endpoint is the incidence of graded adverse events and graded laboratory 
abnormalities at Week 24.

The primary efficacy endpoint is the proportion of subjects achieving virologic response 
(plasma HBV DNA < 20 IU/mL) at Week 24.
8.1.3.
Secondary Endpoint
The Secondary safety endpoints are:

Incidence of graded adverse events and graded laboratory abnormalities at Week 48 and 96

Change from baseline in eGFRCG at Weeks 24, 48, and 96 in subjects with moderate or 
severe renal impairment and hepatically impaired subjects

Percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24, 48, and 96
The Secondary efficacy endpoints are:

Proportion of subjects achieving virologic response (plasma HBV DNA < 20 IU/mL ) at 
Weeks 48 and 96

Proportion of subjects with plasma HBV DNA < 20 IU/mL and target detected/not detected 
(i.e. < LLOD) at Weeks 24, 48, and 96

Proportion of subjects with serological response (loss of HBsAg and seroconversion to 
anti-HBs, loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) at
Weeks 24, 48, and 96

Proportion of subjects with biochemical response (normal ALT and normalized ALT) at
Weeks 24, 48, and 96

Change in fibrosis as assessed by FibroTest® at Weeks 24, 48, and 96

Change from baseline in CPT score (Appendix 7) and MELD score at Weeks 24, 48, and 96
in hepatically impaired subjects
8.1.4.
Other Endpoints of Interest
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8.2.
Analysis Conventions
If not otherwise specified, subjects will be analyzed according to the Part (and Cohort, for 
Part A) they enrolled into. In addition, for Part A, overall summary of Cohort 1 and Cohort 2 
combined will also be provided. No combined summary of Part A and Part B will be provided.

Part A, Cohort 1: Moderate ( 30 mL/min ≤eGFRCG ≤59 mL/min) or severe 
(15 mL/min ≤eGFRCG < 30 mL/min) renal impairment

Part A, Cohort 2: ESRD (eGFR < 15 mL/min) maintained on HD

Part B: Moderate (CPT Class B [Appendix 7]; Score of 7-9 inclusive) or Severe 
(CPT Class C; Score of 10-12 inclusive) hepatic impairment
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is the Full Analysis Set (FAS), defined as all 
subjects who are enrolled and received at least one dose of study drug. 
8.2.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set, defined as all subjects 
who are enrolled and received at least one dose of study drug. 
All data collected during treatment will be included in the safety summaries.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who have received at least one dose of study 
medication and for whom concentration data of any analytes of interest are available. The PK 
analysis set will be used for analyses of concentration data.
 
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.
CCI
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8.2.1.5.
DEXA
8.2.1.5.1.
Hip DXA Analysis Set
The Hip DXA Analysis Set includes all subjects who were randomized and had received at least 
1 dose of study drug, and had nonmissing baseline hip BMD values. 
8.2.1.5.2.
Spine DXA Analysis Set
The Spine DXA Analysis Set includes all subjects who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline spine BMD values. 
8.3.
Data Handling Conventions
For categorical efficacy endpoints, missing data will be handled using a M = F approach.
Sensitivity analyses will be performed using a missing = excluded (M=E) approach.
For secondary safety endpoints of change from baseline in eGFRCG and percent change from 
baseline in hip and spine bone mineral density (BMD), an analysis will be performed using the 
last observation carried forward (LOCF) method to impute missing data.
For the remaining endpoints, values for missing data will not be imputed, unless specified 
otherwise.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, age, etc.
Baseline data will include a summary of body weight, height, body mass index (BMI), 
HBV DNA level, years positive for HBV, ALT level (≤ ULN, > ULN), previous TDF use and 
other oral nucleoside/nucleotide treatment experience, previous interferon experience, fibrotest 
score, CPT and MELD score, and HBV genotype by history, if available.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary analysis will be performed when the last subject has completed Week 24 
assessments or discontinued prematurely.
The proportion of subjects with plasma HBV DNA < 20 IU/mL will be summarized 
descriptively using an M = F approach.


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8.5.2.
Secondary Analyses
Continuous secondary endpoints will be summarized using conventional descriptive statistics 
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum). 
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint. Missing data will be handled by the M = F approach. Sensitivity analyses will 
be performed for the primary endpoint using M = E approach.
8.6.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the end of 
treatment will be summarized. Data for the pretreatment will be included in data listings. 
8.6.1.
Primary Safety Analysis
Incidence of graded adverse events and graded laboratory abnormalities will be summarized. For 
more details, please refer to Sections 8.6.3 and 8.6.4 below.
8.6.2.
Secondary Safety Analysis
The change from baseline in eGFRCG at Weeks 24, 48, and 96 in subjects with moderate or 
severe renal impairment will be summarized.
The percent change from baseline in hip and spine BMD at Weeks 24, 48, and 96 will be 
summarized.
8.6.3.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP administration data. 
Exposure data will be summarized.
8.6.4.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
IMP up to the date of last dose of IMP. Continuing adverse events diagnosed prior to the start of 
treatment and worsening in severity grade, or non-serious adverse events at baseline which 
become serious, or adverse events resulting in treatment discontinuation after the start of 
treatment will also be considered treatment-emergent. Summaries (number and percentage of 
subjects) of treatment-emergent adverse events (by SOC and PT) will be provided:

Treatment-emergent adverse events

Treatment-emergent study drug-related adverse events


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
Grade 3 or 4 treatment-emergent adverse event

Grade 3 or 4 treatment-emergent study drug-related adverse event

Grade 2, 3, or 4 treatment-emergent adverse event

Grade 2, 3, or 4 treatment-emergent study drug-related adverse event

AE that caused permanent discontinuation from study drug

AE that caused change in dose or temporary interruption of study drug

Treatment-emergent serious adverse event

Treatment-emergent study drug-related serious adverse event
8.6.5.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 4.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the end of treatment will be 
summarized.
Laboratory abnormalities that occur before the first dose of IMP or after the subject has been 
discontinued from treatment will be included in a data listing.
8.7.
Pharmacokinetic Analysis
In the PK analysis set, plasma concentrations of the study drug over time will be listed. Details 
of the analysis will be provided in the pharmacokinetic reporting and analysis plan.
In the intensive PK substudies, pharmacokinetic parameters will be listed and summarized for 
TAF and TFV using descriptive statistics (e.g., sample size, arithmetic mean, geometric mean,
% coefficient of variation, standard deviation, median, minimum, and maximum). Plasma
concentrations over time will be plotted in semi logarithmic and linear formats as 
mean ± standard deviation.
8.8.
Biomarker Analysis
Selected renal biomarkers, including retinol binding protein, beta-2 microglobulin, will be 
summarized for Part A, Cohort 1 (moderate or severe renal impairment) and Part B (moderate or 
severe hepatic impairment) by visit using descriptive statistics. 
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1 
N-terminal propeptide (P1NP), will be summarized by visit using descriptive statistics.


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8.9.
Sample Size
No formal sample size calculation was performed as this is an exploratory study. A sample size 
of 120 subjects is based on practical considerations and is considered sufficient to evaluate the 
primary objectives of the study.
8.10.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data after 30 subjects have completed 12 weeks of treatment. However, Gilead will 
defer to the DMC for any decision to convene earlier or more frequently. The DMC will examine 
the safety results of the trial and also focus on logistical issues such as accrual, retention, quality 
of clinical and laboratory data, and implications of results of external studies. No formal stopping 
rules will be used by the DMC for safety outcomes. Rather a clinical assessment will be made to 
determine if the nature, frequency, and severity of adverse effects associated with study 
treatment warrant the early termination of the study in the best interests of the participants.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, International Conference on Harmonisation (ICH) guidelines, or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC/EC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC/EC 
or local requirements. The consent form will inform subjects about pharmacogenomic testing 
and sample retention.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC/EC or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions for further details. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria (i.e., history, physical examination, and 
confirmation of diagnosis [to support inclusion and exclusion criteria]);


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
Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 


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verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
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Goyal SK, Dixit VK, Shukla SK, Ghosh J, Behera M, Tripathi M, et al. Prolonged use of 
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Kazancioglu R. Risk factors for chronic kidney disease: an update. Kidney Int Suppl (2011) 
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Kearney BP, Yale K, Shah J, Zhong L, Flaherty JF. Pharmacokinetics and dosing 
recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment. 
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resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with 
chronic hepatitis B. Hepatology 2014;59 (2):434-42.
Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. 
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entecavir in patients with decompensated chronic hepatitis B liver disease. 
Hepatology 2011;53:62-72.
Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, et al. No detectable resistance to 
tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic 
hepatitis B after 8 years of treatment. J Viral Hepat 2016.
Lok AS, McMahon BJ. AASLD Practice Guideline Update: Chronic hepatitis B: update 2009. 
Hepatology 2009;50 (3):661-2.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis 
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-
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Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet 
Infect Dis 2016;16 (1):43-52.
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Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus 
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Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, et al. Switching to Tenofovir 
Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in 
HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-
Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr 
2016;71 (5):530-7.
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Alafenamide as 10-Day Monotherapy in HIV-1-Positive Adults. J Acquir Immune 
Defic Syndr 2013;63 (4):449-55.
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guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.
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tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-
blind, phase 3, non-inferiority trials. Lancet 2015;385:2606-15.
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of chronic hepatitis B virus infection: a systematic review of data published 
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Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
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for treatment of chronic hepatitis B. Hepatology 2015.
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VEMLIDY®, Gilead Sciences Inc. VEMLIDY® (tenofovir alafenamide) tablets, for oral use. 
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Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Optional Intensive Pharmacokinetic Sub-study Recommended Meal Examples
Appendix 7.
Child-Pugh-Turcotte Score {Pugh 1973}


PPD
PPD
Tenofovir Alafenamide (TAF), GS-7340 
Protocol GS-US-320-4O35 
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Final 
Amendment I 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of Switching to 
Tenofovir Alafenamide (T AF) from Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral 
Antiviral Treatment (OA V) in Virologically Suppressed Chronic Hepatitis B Subjects with 
Renal and/or Hepatic Impairment 
GS-US-320-4035, Amendment 1, 23 May 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Medical Monitor 
Date 
o 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Jnc. l will discuss this material with them to ensure 
that they are fuily informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
-
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Study Procedures
Visit Windowsk
± 3 Days
± 14 Days
EDl
Follow Upm
Screening
(45 days)
Baseline
(Day 1)
Week
4
Week
8
Week
12
Week
24k
Week
36
Week
48k
Week
60
Week
72
Week
96k
Informed Consent
x
Inclusion/Exclusion Criteria
x
x
Medical History (including HBV disease 
and treatment history)
x
x
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete Physical Examination with 
weight and vital signsa
x
x
x
x
x
x
x
Height 
x
Body Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom driven Physical Examination
x
x
x
x
x
x
Health Related Quality of Life (CLDQ, 
SF-36, WPAI, EQ-5D-3L)b
x
x
x
x
x
Health Utilization Assessment
x
x
x
x
x
x
x
x
x
x
x
Serum Chemistry, Hematology, and Liver 
Function Testsc
x
x
x
x
x
x
x
x
x
x
x
x
x
Fasting Metabolic Assessmentd
x
x
x
x
x
x
Pregnancy testing (women of child-bearing 
potential only)
serum
urine (+ve test to be confirmed with serum; serum test will also be collected if urine cannot be 
collected for subjects in Part A, Cohort 2 [ESRD subjects on HD])
x
x
x
x
x
x
x
x
x
x
x
x
Estimated Glomerular Filtration Rate by 
Cockcroft-Gault method (eGFRCG)
x
x
x
x
x
x
x
x
x
x
x
x
x


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 114
23 May 2017
Study Procedures
Visit Windowsk
± 3 Days
± 14 Days
EDl
Follow Upm
Screening
(45 days)
Baseline
(Day 1)
Week
4
Week
8
Week
12
Week
24k
Week
36
Week
48k
Week
60
Week
72
Week
96k
HBV serology (qualitative HBsAg and 
HBeAg) and quantitative HBsAge
x
x
x
x
x
x
x
x
x
x
x
HCV, HDV, HIV Testing
x
α-fetoprotein (AFP)f
x
Urinalysisg
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine drug screeng
x
DXA scans (Hip & Spine)h
x
x
x
x
x
x
ECGi
x
x
x
x
Plasma HBV DNA level
x
x
x
x
x
x
x
x
x
x
x
x
x
FibroTest®
x
x
x
x
x
CPT and MELD Scores (Part B subjects 
[hepatic impairment] only)j
x
x
x
x
x
x
Serum Cystatin Cn
x
Fasting Blood for Bone Biomarkers, 
Fasting Urine for Renal Biomarkerso
x
x
x
x
x
x
x
x
Fracture Risk Assessment (FRAX)
x
Virology (Sequence analysis of HBV 
pol/RT for resistance surveillance)p
x
x
x
x
x
x
x
x
x
x
x
Vitamin D
x
x
x
Sparse Plasma PK (All subjects except 
Part A, Cohort 2 [ESRD subjects on HD])q
x
x
x
x
x
x
x
x
x
x
x
Sparse Plasma PK (Part A, Cohort 2 
[ESRD subjects on HD])r
x
x
x
x
CCI


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 115
23 May 2017
Study Procedures
Visit Windowsk
± 3 Days
± 14 Days
EDl
Follow Upm
Screening
(45 days)
Baseline
(Day 1)
Week
4
Week
8
Week
12
Week
24k
Week
36
Week
48k
Week
60
Week
72
Week
96k
Serum, plasma, and urineg for storage
x
x
x
x
x
x
x
x
x
x
x
x 
(serum only)
Study Drug Accountability
x
x
x
x
x
x
x
x
x
Study Drug Dispensation
x
x
x
x
x
x
x
x
x
In-clinic Dosingt
x
x
x
x
a
Vital signs include blood pressure, pulse, respiration rate and temperature.
b
Health Related Quality of Life surveys required for Early Discontinuation (ED) visit if not done within the last 24 weeks of the expected ED visit date.
c
Serum chemistry and Liver Function Tests: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects with total 
amylase > 1.5 × ULN), and PTH. PTH analyzed at all visits except for Screening. At Baseline, Weeks 24, 48, 72, and 96/ED, analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry panel. Liver Function Tests: PT/INR will be done at Screening, Baseline, and Weeks 24, 48, and 96/ED and then 
as a reflex only test for ALT flares.
d
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides).
e
HBeAb and HBsAb reflex testing will be performed as needed.
f
An AFP > 50 ng/mL at Screening must have an appropriate evaluation (e.g., CT scan if not performed within the previous 6 months) in order to rule out HCC prior to being 
permitted to enter the study.
g
Urine sample collection for all subjects except only where available for subjects in Part A, Cohort 2 (ESRD subjects on HD).
h
The Baseline DXA can be performed at any time during the Screening period, but should be completed at least 14 days prior to the first dose of study drug to ensure an 
acceptable pre-dose DXA scan. The Week 24, Week 48, and Week 96 DXA window is −14 days only. DXA required for Early Discontinuation (ED) visit if not done within 
the last 12 weeks and should be done within ± 14 days of the expected ED visit date.
i
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
j
CPT [Appendix 7] assessment requires: total bilirubin, albumin, PT/INR, Ascites assessment, and Hepatic encephalopathy assessment. MELD assessment requires total 
bilirubin, serum creatinine, PT/INR, and serum sodium.
k
The visit window for the Week 24, Week 48, and Week 96 visits is −7 days only. 
l
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
CCI


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 116
23 May 2017
m
Subjects in Part A (renally impaired) who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-HBs on or after the Week 24 visit, will be 
followed off treatment every 4 weeks for 12 weeks and then per the original study visit schedule through Week 96/ED. Subjects in Part A (renally impaired) who have 
received at least one dose of study drug and permanently discontinue study drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be 
followed every 4 weeks for 24 weeks off treatment or up to initiation of appropriate, alternative HBV therapy, whichever occurs first. Use of appropriate, alternative HBV 
therapy is strongly encouraged. For subjects in Part B (hepatic impairment) who permanently discontinue study drug, immediate initiation of appropriate, alternative HBV 
therapy is strongly recommended.
n
Any subject with a post baseline eGFRCG < 15 mL/min must have serum creatinine measured again within 3 calendar days of receipt of results. At the time of this repeat 
serum creatinine assessment, serum Cystatin C will also be measured and the eGFR by CKD-EPI (cystatin C) will be calculated and compared with the baseline measurement. 
Any subjects who have an eGFRCG < 15 mL/min that also experience > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline or who have other clinical and/or 
laboratory evidence of acute renal failure will be discussed with the Medical Monitor and may discontinue from study drugs.
o
Blood for selected bone biomarkers and urine for selected renal biomarkers will be collected in a fasted state. The fasting urine sample will be collected for all subjects except 
Part A, Cohort 2 (ESRD subjects on HD). Required for ED visit if the last sample was not collected within the last 12 weeks.
p
Resistance sequence analysis may be performed at Baseline for subjects with HBV DNA ≥ 69 IU/mL and may be attempted for viremic (HBV DNA ≥ 69 IU/mL) at 
Weeks 24, 48, and 96/ED. Phenotypic analysis will be performed for subjects that are subjected to sequence analysis. As it may not be known at the time of the visit whether a 
subject is viremic or if it will be their last study visit, a virology sample will be collected as each visit. In the event of unconfirmed virologic rebound (HBV DNA 
≥20 IU/mL), subjects will be asked to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound occurring within the first 12 weeks of the study, 
the next scheduled visit will used for follow up. For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 2-3 weeks after the date of the 
original test that resulted with HBV DNA virologic rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for resistance testing will be 
obtained. For unscheduled visits, the subject will be required to bring their supply of study drug with them and be assessed for adherence by pill count, and if necessary, the 
subject will be re-counseled on adherence to study medication.
q
For all subjects except Part A, Cohort 2 (ESRD subjects on HD): A single PK blood sample will be collected at Baseline and at each subsequent on treatment visit. At the 
Week 4, 8 and 12 visits, study drug will be administered in clinic, and the single PK blood sample will be collected between 15 minutes and 4 hours post dose. 
r
For Part A, Cohort 2 (ESRD subjects on HD at selected sites): 4 PK blood samples total will be collected at each of 4 hemodialysis sessions between Weeks 4 and Week 24, 
inclusive: one sample collected within 10 minutes before a hemodialysis session begins, one sample each collected approximately 1 hour prior to conclusion of the 
hemodialysis session from both the arterial and venous sides of the dialyzer, and one sample collected within 10 minutes after a hemodialysis session concludes. On the day 
of hemodialysis, study drug should not be administered to subjects until after the completion of hemodialysis and collection of any required post-hemodialysis 
samples for Part A, Cohort 2.
s
 
 
 
 
 
 
 
 
t
Dosing of study drug will occur in-clinic at the Weeks 4, 8, and 12 visits for subjects in Part A, Cohort 1 (moderate or severe renal impairment) and Part B (hepatic 
impairment).
 
CCI
CCI


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 117
23 May 2017
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
If confirmed and possibly and/or probably related to 
investigational medicinal products:
1.
Withhold investigational medicinal products until Grade 2
2.
Restart all investigational medicinal products at full dose
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator
.______I I 
11 .______ 
i 
----+ 
,. 
,i, 
l 
I 
I 
l 
r----------,1 r-----1 -~ 


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 118
23 May 2017
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 119
23 May 2017
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized 
Ratio of prothrombin time 
(INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time 
(APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 120
23 May 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmol/L
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmol/L
2.0 mEq/L                         
<2.0 mmol/L
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 121
23 May 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                       
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmol/L
6.1 to  <7.0 mg/dL                     
1.51 to < 1.74 mmol/L
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric 7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4035
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 122
23 May 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-urgent 
medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant 
acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening 
consequences (eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years 
(with repeat testing at same 
visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences (eg, malignant 
hypertension) OR
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV block 
OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Embolic event 
(eg, pulmonary embolism, 
life-threatening thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced 
to 70% to 80%
FEV1 or peak flow 50% to 
69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak 
flow 25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social 
& functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse 
oximetry 90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in 
affected eye(s) 
Visual Changes 
(from baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing 
greater than minimal 
interference with usual social 
& functional activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in 
affected eye(s)


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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by study 
participant or  caregiver (for 
disabled adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited number of 
bullae OR Superficial 
ulcerations of mucous 
membrane limited to one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two or 
more distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis 
(itching – no skin lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or minimal 
interference with usual social 
& functional activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight 
loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated 
[eg, tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated (eg, 
diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis 
(functional- symptomatic)
Also see Mucositis/Stomatitis 
for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability 
to perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences 
(eg, hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood 
(eg, agitation, anxiety, 
depression, mania, psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater 
than minimal interference 
with usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others 
(eg, suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, 
OR coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability 
to perform usual social & 
functional activities
Symptoms causing inability 
to perform basic self-care 
functions OR Hospitalization 
indicated (other than ER 
visit) OR Headache with 
significant impairment of 
alertness or other neurologic 
function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic 
self-care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & functional 
activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic 
self-care functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase from 
Previous Level of Control to 
Any of These Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated with 
a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater 
than minimal interference 
with usual social & functional 
activities
Joint pain causing inability to 
perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing greater than minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score
–2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater 
than minimal interference 
with usual social & functional 
activities
Muscle pain causing inability 
to perform usual social & 
functional activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND 
No operative intervention 
indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic 
self-care functions


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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR laryngeal 
edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities 
Symptoms causing inability 
to perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability 
to perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site Pain, 
Headache, Arthralgia, and 
Myalgia
Pain causing no or minimal 
interference with usual social 
& functional activities
Pain causing greater than 
minimal interference with 
usual social & functional 
activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than 
ER visit) indicated
Unintentional Weight Loss
NA
5% to 9% loss in body weight 
from baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  
Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]


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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain 
(pain without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no or 
minimal limitation of use of 
limb
Pain/tenderness limiting use 
of limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than 
ER visit) indicated for 
management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm 
(or 2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (eg, upper 
arm/thigh)
Erythema OR Induration OR 
Edema involving 50% 
surface area of the extremity 
segment (eg, upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile abscess 
OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 48 h 
treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h 
treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back of 
neck, breasts, abdomen)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to 
initiate medication OR 
Modification of current meds 
to regain glucose control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & functional 
activities OR Thyroid 
suppression therapy indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & functional 
activities OR Thyroid 
replacement therapy indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences
(eg, myxedema coma)
Lipoatrophy (eg, fat loss from 
the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding 
greater in duration or amount 
than usual menstrual cycle
Hemorrhage with 
life-threatening hypotension 
OR Operative intervention 
indicated
Urinary Tract obstruction 
(eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other than 
HIV infection)
Localized, no systemic 
antiμbial treatment indicated 
AND Symptoms causing no 
or minimal interference with 
usual social & functional 
activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than 
simple incision and drainage) 
indicated
Life-threatening 
consequences 
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of TAF have demonstrated that there is no
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies in
animals (rats and rabbits) of TAF have demonstrated no adverse effect on fertility or
embryo-fetal development. However, there are no clinical studies of TAF in pregnant women.
Please refer to the latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable
effective contraceptive measure. They must have a negative serum pregnancy test at Screening
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. At minimum, a
pregnancy test will be performed at the end of relevant systemic exposure. In the event of a
delayed menstrual period (over one month between menstruations), a pregnancy test must be
performed to rule out pregnancy. This is even true for women of childbearing potential with
infrequent or irregular periods. They must also agree to one of the following from Screening
until the end of relevant systemic exposure.


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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable
method of contraception only when it is in line with the subject’s preferred and usual
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of < 1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use
condoms when engaging in intercourse of reproductive potential.


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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.6.2.1.


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Appendix 6.
Optional Intensive Pharmacokinetic Sub-study Recommended Meal 
Examples
CCI


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Appendix 7.
Child-Pugh-Turcotte Score {Pugh 1973}
Parameter
Points Assigned
1
2
3
Albumin
> 3.5 g/dL (35 g/liter)
2.8 - 3.5 g/dL (28 to 35 g/liter)
< 2.8 g/dL ( < 28 g/liter)
Ascites
Absent
Slight
Moderate to Severe
Bilirubin
< 2 mg/dL
( < 34.2 micromol/liter)
2 - 3 mg/dL
(34.2 to 51.3 micromol/liter)
> 3 mg/dL
( > 51.3 micromol/liter)
Encephalopathy
None
Grade 1 – 2
Grade 3 - 4
Prothrombin time
Seconds over control
< 4
4 – 6
> 6
INR
< 1.7
1.7 – 2.3
> 2.3
Modified Child-Pugh-Turcotte classification of the Severity of Liver Disease
Class A
Class B
Class C
Total Points
5-6
7-9
10-15
Severity of Hepatic Cirrhosis
Well-compensated
Significant Functional Compromise
Decompensated 
1- and 2- year survival
100% and 85%
80% and 60%
45% and 35%