Clinical trial NCT02862548
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2016-09-16; Completion date: 2021-05-05
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF)-containing regimens at Week 24 in participants with chronic hepatitis B virus (HBV) infection and Stage 2 or greater chronic kidney disease who have received a liver transplant.

Detailed description:

Arms: arm 1: TAF 25 mg once daily for 48 weeks arm 2: TDF alone or in combination with other approved antivirals per local practice for 48 weeks arm 3: After Week 48, participants will be eligible to receive TAF 25 mg once daily for an additional 144 weeks.
Interventions: intervention 1: TAF intervention 2: TDF intervention 3: Other approved antivirals
Intervention descriptions: intervention 1: Tablet administered orally intervention 2: Tablet administered orally intervention 3: Other approved antivirals (such as lamivudine, entecavir, or immunoglobulin antihepatitis B) administered per local practice

Protocol documents:
SAP_006.pdf: 
~ GILEAU 
STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety ofTenofovir Alafenamide (fAF) versus 
Tenofovir Disoproxil Fumarate (fDF)-containing Regimens in 
Subjects with Chmnic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant 
Name of Test Drug: 
Tenofovir Alafenamide (fAF) 
Study Number: 
GS-US-320-3912 
Protocol Version (Date): 
Amendment 2 (28 March 2017) 
Analysis Type: 
Week 24 
Analysis Plan Version: 
Version 1.0 
Analysis Plan Date: 
19 March 2018 
Analysis Plan Author(s): 
PD 
..._ ______ ...... 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Data Monitoring Committee (DMC) Analysis.......................................................................................11
2.2.
Week 24 Analysis (Primary Analysis) ...................................................................................................11
2.3.
Week 48 Analysis ..................................................................................................................................11
2.4.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
Randomized Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set (FAS) .......................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Serologically Evaluable Full Analysis Set for HBsAg 
Loss/Seroconversion ............................................................................................................13
3.1.5.
Serologically Evaluable Full Analysis Set for HBeAg 
Loss/Seroconversion ............................................................................................................13
3.1.6.
DXA Analysis Set ................................................................................................................13
3.1.7.
Pharmacokinetic Analysis Set..............................................................................................13
3.1.8.
Pharmacokinetic Substudy Analysis Set ..............................................................................13
3.2.
Subject Grouping ...................................................................................................................................13
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subgroups........................................................................................................14
3.5.
Missing Data and Outliers......................................................................................................................14
3.5.1.
Missing Data ........................................................................................................................14
3.5.2.
Outliers.................................................................................................................................14
3.6.
Data Handling Conventions and Transformations .................................................................................14
3.7.
Analysis Visit Windows.........................................................................................................................15
3.7.1.
Definition of Study Day .......................................................................................................15
3.7.2.
Analysis Visit Windows.......................................................................................................17
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment and Disposition.......................................................................................................22
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................22
4.2.1.
Duration of Exposure to Study Drug....................................................................................23
4.2.2.
Adherence to Study Drug.....................................................................................................23
4.3.
Protocol Deviations................................................................................................................................24
5.
BASELINE CHARACTERISTICS....................................................................................................................25
5.1.
Demographics ........................................................................................................................................25
5.2.
Other Baseline Characteristics ...............................................................................................................25
5.3.
Medical History......................................................................................................................................26


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6.
EFFICACY ANALYSES ...................................................................................................................................27
6.1.
Primary Efficacy Endpoints ...................................................................................................................27
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................27
6.1.2.
Analysis of the Primary Efficacy Endpoint..........................................................................27
6.1.3.
Secondary Analysis for the Primary Efficacy Endpoint.......................................................27
6.2.
Other Efficacy Endpoints.......................................................................................................................27
6.2.1.
Definition of Secondary and Other Efficacy Endpoints.......................................................27
6.2.2.
Analysis Methods for Secondary and Other Efficacy Endpoints .........................................28
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................29
7.
SAFETY ANALYSES........................................................................................................................................30
7.1.
Adverse Events and Deaths....................................................................................................................30
7.1.1.
Adverse Event Dictionary ....................................................................................................30
7.1.2.
Adverse Event Severity........................................................................................................30
7.1.3.
Relationship of AEs to Study Drug......................................................................................30
7.1.4.
Relationship of AEs to Study Procedure..............................................................................30
7.1.5.
Serious Adverse Events........................................................................................................30
7.1.6.
Treatment-Emergent Adverse Events...................................................................................31
7.1.7.
Summaries of Adverse Events and Deaths...........................................................................33
7.2.
Laboratory Evaluations ..........................................................................................................................34
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................34
7.2.2.
Graded Laboratory Values ...................................................................................................35
7.2.3.
ALT Elevation......................................................................................................................36
7.3.
Bone Safety Analysis .............................................................................................................................37
7.3.1.
Bone Mineral Density (BMD)..............................................................................................37
7.3.2.
Bone Biomarkers..................................................................................................................38
7.3.3.
Fracture Events.....................................................................................................................38
7.3.4.
Assessment of Fracture Probability......................................................................................38
7.3.5.
Bone Events .........................................................................................................................39
7.4.
Renal Safety Analysis ............................................................................................................................39
7.4.1.
Confirmed Renal Abnormalities...........................................................................................39
7.4.2.
Serum Creatinine..................................................................................................................39
7.4.3.
Estimated Glomerular Filtration Rate ..................................................................................39
7.4.4.
Treatment-emergent Proteinuria (Dipstick)..........................................................................40
7.4.5.
Urine RBP to Creatinine Ratio and Beta 2 Microglobulin to Creatinine 
Ratio.....................................................................................................................................40
7.4.6.
Proteinuria by Quantitative Assessment...............................................................................40
7.4.7.
Other Renal Biomarkers.......................................................................................................41
7.5.
Body Weight ..........................................................................................................................................42
7.6.
Prior Hepatitis B Medications................................................................................................................42
7.7.
Concomitant Medications ......................................................................................................................42
7.8.
Other Safety Measures ...........................................................................................................................43
7.9.
Changes From Protocol-Specified Safety Analyses...............................................................................43
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................44
8.1.
PK Sample Collection............................................................................................................................44
8.2.
Estimation of PK Parameters .................................................................................................................44
8.3.
Statistical Analysis Methods ..................................................................................................................45
9.
REFERENCES ...................................................................................................................................................47
10.
SOFTWARE.......................................................................................................................................................48
11.
SAP REVISION..................................................................................................................................................49


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12.
APPENDICES ....................................................................................................................................................50
Appendix 1.
Fracture Events.......................................................................................................................51
Appendix 2.
Bone Events............................................................................................................................53
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HBV DNA, Hematology, Serum Chemistry and Liver 
Function Tests, eGFR (by CG and CKD-EPI), UACR, UPCR, Non-fasting Glucose, 
Weight, and Vital Sign Assessments......................................................................................18
Table 3-2.
Analysis Visit Windows for Fasting Glucose.........................................................................18
Table 3-3.
Analysis Visit Windows for BMD Results from DXA, Fibrotest, Lipid Panel and 
HBV Serology........................................................................................................................19
Table 3-4.
Analysis Visit Windows for Cr EDTA Renal Scan.................................................................19
Table 3-5.
Analysis Visit Windows for Renal and Bone Biomarkers......................................................19
Table 3-6.
Analysis Visit Windows for Post Treatment Assessments.....................................................20
Table 7-1.
Normal, Osteopenia, and Osteoporosis as Defined by T-score ..............................................37
Table 8-1.
PK Parameters ........................................................................................................................45


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LIST OF ABBREVIATIONS
AASLD
American Association for the Study of Liver Diseases
AE
adverse event
ALT
alanine aminotransferase (SGPT)
Anti-HBe
antibody to HBeAg
Anti-HBs
antibody to HBsAg
AST
aspartate aminotransferase (SGOT)
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration 
AUCtau
area under the concentration versus time curve over the dosing interval
BLQ
below the limit of quantitation
BMD
bone mineral density
BMI
body mass index
bsAP
bone specific alkaline phosphatase
CDER
Center for Drug Evaluation and Research
CG
Cockcroft-Gault
CHB
chronic hepatitis B
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration formula for calculating 
glomerular filtration rate
Clast
last observed quantifiable concentration of the drug 
CLCr
creatinine clearance
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau, where “Dose” is the dose of the drug
Cmax
maximum observed concentration of drug 
CMH
Cochran-Mantel-Haenszel 
CRF
case report form
Ctau
observed drug concentration at the end of the dosing interval
CTX
c-type collagen sequence
CV
coefficient of variation
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ESDD
early study drug discontinuation
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEPO4
fractional excretion of filtered phosphate


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FEUA
fractional excretion of uric acid
GFR
glomerular filtration rate
Gilead
Gilead Sciences, Inc.
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high density lipoprotein
HDV
hepatitis D virus
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IVRS
interactive voice response system
IWRS
interactive web response system
LDL
low density lipoprotein
LLN
lower limit of the normal range
LLT
lower-level term
LOCF
last observation carried forward
M = E
Missing = Excluded
M = F
Missing = Failure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mantel-Haenszel 
OC
osteocalcin
P1NP
procollagen type 1 N-terminal propeptide
PBMC
peripheral blood mononuclear cell
PK
pharmacokinetic
pol/RT
polymerase/reverse transcriptase
PP
per protocol
PT
preferred term
Q
quartile
Q1
first quartile
Q3
third quartile
RBP
retinol binding protein
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class


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t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log 
of 2 by the terminal elimination rate constant (z)
TAF
tenofovir alafenamide 
TDF
tenofovir disoproxil fumarate (Viread®)
TFLs
tables, figures, and listings
TFV
tenofovir
TFV-DP
tenofovir-diphosphate
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve
TmP
tubular maximum reabsorption rate of phosphate
UACR
urine albumin to creatinine ratio
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio
WHO
World Health Organization


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Statistical Analysis Plan- Week 24 Analysis 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for the Week 24 Analysis for 
Study GS-US-320-3912. This SAP is based on the study protocol amendment 2 dated 
28 March 2017 and the electronic case report form ( eCRF). The SAP will be finalized before 
database finalization. 
1.1. 
Study Objectives 
The primary objectives ofthis study are as follows: 
• 
To evaluate the safety and tolerability of TAF 25 mg once daily (QD) versus TDF-containing 
regimens as determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are as follows: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
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1.2. 
Study Design 
This is a randomized, open-label, single center Phase 2 study to evaluate the safety and efficacy 
of TAP 25 mg QD versus TDF in adult chronic hepatitis B (CHB) infection subjects with Stage 2 
or greater chronic kidney disease and have received a liver transplant. 
Approximately 50 subjects will be randomized in a 1: 1 ratio to either continue cunent treatment 
regimen with TDF alone or in combination with other approved antivirals or to receive TAP 
25 mg per os (PO) daily. Approximately 40 of 50 subjects will be emolled with eGFRam-EPI 
< 60 ml/min/1. 73m2. Randomization will be stratified by baseline renal fimction ( eGFRcKD-EPI 
< 50 mlfmin/1. 73m2 and ~ 50 ml/min/1. 73m2) 
• 
Treatment Ann A: approximately 25 subjects administered TAP 25 mg oral daily 
• 
Treatment Aim B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals as per local practice 
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to Screening, subjects will be randomized to receive TAP or TDF alone or in 
combination with approved antivirals per local practice. 
PPD 
If subjects choose PPD 
~~~~~~ 
---~·~-~~---~---~~----~--~-~~~~--------~--
discontinue TAP prematmely, they will be followed for 24 weeks after the discontinuation of 
TAP (i.e., Treatment Free Follow-Up, TFFU) or lmtil an altemative CHB treatment is started, 
whichever occurs first. In this SAP, the first 48 weeks of study treatment is refened to as 
randomized phase, PPD 
----------------------------------------------------
The end of the study will be the last subjects' last observation or visit. 
Laborat01y analyses (sennn chemistly, liver tests, hematology, plasma HBV DNA levels, 
pregnancy testing [for females of childbearing potential]), body weight, vital signs, adverse 
events (AEs ), and concomitant medications will be perf01med at screening, baseline, week 4, 8, 
12, 20, 24, evety 12 weeks thereafter through Week 72, and eve1y 24 weeks through 
PO 
/ED visit. 
HBV serology ualitative HBsAg and HBeAg) will be perf01med at screening, baseline, 
Weeks 24, 48, PPD 
and ED. HBeAb and HBsAb testing will be perf01med as reflex 
testing as needed. Bone and renal biomarker testing will be perf01med at baseline and then at 
defmed intervals throughout the study. Vitamin D assessments, FibroTest® and fasting metabolic 
assessments (fasting glucose and lipid panel) will be perf01med at baseline, Weeks 24, 48, PPD 
andPP ED visit. Cr EDTA renal scan will be perf01med at baseline, Week 48 PPD 
visit. 
....._ ___ _. 
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Complete E!!_ysical examinations will be performed at screening, baseline, and Weeks 12, 24, 48, 
PPD 
ED visit. Symptom directed physical examinations including body weight 
assessment will be conducted at all other visits. Dual energy x-ray absorptiometry (DXA) scans 
ofthe hip and spine should be performed during Screening and should be completed at least 
14 days prior to the first dose of study drug, and will be conducted at Weeks 24, 48, PPD 
and 
the ED visit if not done within the last 24 weeks ofthis visit. Plasma, serum, and urine will be 
collected at baseline and at every visit thereafter for storage. 
Follow-up assessments will occur every 4 weeks for 24 weeks and include the following: vital 
signs, hematolo , serum chemistry, liver function tests, and plasma HBV DNA. PPD 
1.3. 
Sample Size and Power 
This is an exploratory study. No formal sample size calculation was performed. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee (DMC) Analysis
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data once after 30 subjects have completed 12 weeks of treatment, and provide 
recommendation to Gilead whether 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, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design. 
Subsequent meetings will be held on an ad hoc basis. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule. More details are documented in the 
independent DMC charter.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study. 
2.2.
Week 24 Analysis (Primary Analysis)
The Week 24 analysis will be conducted after the last subject completes the Week 24 visit or 
prematurely discontinues study drug.
2.3.
Week 48 Analysis
The Week 48 analysis will be conducted after the last subject completes the Week 48 visit or 
prematurely discontinues study drug.
2.4.
Final Analysis
The final statistical analysis for the study will be conducted after all subjects complete the study 
or prematurely discontinue study.
This statistical analysis plan (SAP) describes the analysis plan for the Week 24 analysis. 


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), 
third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Randomized Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as 
AEs, will be presented in chronological order within the subject. The treatment group to which 
subjects were randomized will be used in the listings. Age, sex at birth, race, and ethnicity will 
be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
Randomized Analysis Set
Randomized Analysis Set includes all subjects who were randomized in the study. This is the 
primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set (FAS)
The FAS will include all randomized subjects who have received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment to which they were randomized. This is the 
primary analysis set for efficacy analyses. 
3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who have received at least 1 dose 
of study drug. Subjects will be analyzed according to the treatment they actually received during 
the randomized phase. The actual treatment received will differ from the randomized treatment 
only when their actual treatment differs from randomized treatment for the entire treatment 
duration. This is the primary analysis set for safety analyses.


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3.1.4. 
Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion 
The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drug, and with HBsAg 
positive and HBsAb negative or missing at baseline. Subjects will be analyzed according to the 
treatment they were randomized to. 
3.1.5. 
Serologically Evaluable Full Analysis Set for HBeAg Loss/Seroconversion 
The Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drug, and with HBeAg 
positive and HBeAb negative or missing at baseline. Subjects will be analyzed according to the 
treatment they were randomized to. 
3.1.6. 
DXA Analysis Set 
3.1.6.1. 
Hip DXA Analysis Set 
The Hip DXA Analysis Set will include all subjects who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline hip BMD values. Subjects will be 
analyzed according to the treatment they actually received during the randomized phase. 
3.1.6.2. 
Spine DXA Analysis Set 
The Spine DXA Analysis Set will include all subjects who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline spine BMD values. Subjects will be 
analyzed according to the treatment they actually received during the randomized phase. 
3.1.7. 
Phannacokinetic Analysis Set 
The PK Analysis Set will include all randomized subjects who took at least 1 dose of study drug 
and have at least 1 nonmissing postdose concentration value reported by the PK laboratory. This 
is the primary analysis set for sparse PK analyses. 
PPD 
3.2. 
Subject Grouping 
For efficacy analysis using FAS, subjects will be analyzed by randomized treatment. For safety 
analysis using the Safety Analysis Set, subjects will be analyzed by actual treatment received 
during the randomized phase. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received. 
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3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive voice or web response 
system (IXRS) in a 1:1 ratio using a stratified randomization schedule. Stratification will be 
based on the following variables:

Screening renal function (eGFRCKD-EPI < 50 mL/ min/1.73m2 and ≥ 50 mL/ min/1.73m2)
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for efficacy and safety analysis.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for
prior [disease-specific prior] and concomitant medications in Section 7.7.
3.5.2.
Outliers
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes, unless 
specified otherwise. All data will be included in the analysis. 
3.6.
Data Handling Conventions and Transformations
Logarithm (base 10) will be used to transform HBV DNA data. 
Natural logarithm transformation will be applied to PK concentrations and PK parameters such 
as Cmax, Ctau, and AUCtau for PK analysis. 
PK concentration values below the limit of quantitation (BLQ) will be treated as 0 for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ”. If more than 50% of the subjects have a concentration data value 
BLQ for the time point, the minimum and median values will be displayed as “BLQ”. If all 
subjects have concentration data values BLQ for all the time points, all order statistics 
(minimum, first quartile [Q1], median, third quartile [Q3], and maximum) will be displayed as 
“BLQ”. 


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Data that are continuous in nature but aTe below the lower limit of quantitation or above the 
upper limit of quantitation will be imputed as follows except for direct bilirubin, urine creatinine, 
and sennn cystatin C: 
• 
A value that is 1 tmit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is repmted in the fmm of"< x" (x is considered as the 
limit of quantitation). For example, if the values are repo1ted as < 50 and < 5.0, then values 
of 49 and 4.9 will be used for calculation of summruy statistics, respectively. 
• 
A value that is 1 tmit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is repmted in the fmm of"> x" (xis considered as the 
limit of quantitation). Values with decimal points will follow the same logic as stated above. 
• 
The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the fom1 of"::; x" or"~ x" (xis considered as the limit of quantitation). 
For direct bilnubin, a value of"< 0.1" is imputed as 0.09. For urine creatinine, a value of"< 1" is 
handled as a missing value in its summruy and the calculation of related ratios. For sennn 
cystatn1 C, a value of"< 0.1 0" is handled as a missing value in the calculation of estiinated 
glomerular filtration rate ( eGFR). 
For HBV DNA, if the value in IU/mL (AMPLIPREP TAQM) is above the upper limit of 
quantification, the conesponding diluted value (AMPLIPREP TAQ), if available, will be used. 
3.7. 
Analysis Visit Windows 
3.7.1. 
Definition of Study Day 
Study Day 1 is defined as the day when the fn·st dose of study drug was taken, as recorded on 
the Study Drug Administration eCRF form. 
Since the TDF group subjects ru·e to continue administration of TDF alone or in combination 
with other approved antivn·als as per local practice, for the TDF group the Study Day 1 is defmed 
as: the first actual dose date on or after the latest lab or PK visit date with Baseline/Day 1 visit. 
PPD 
Study days are calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1 date, study days are calculated as (visit date- Study Day 1 + 1). For events that 
occmTed prior to Study Day 1, study days are calculated as (visit date- Study Day 1). 
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Statistical Analysis Plan- Week 24 Analysis 
Version 1.0 
- PD 
Follow-up days are for visits occUlTed dming 24-week treatment-free follow-up period and 
calculated as (visit date -last dose date). 
Last Dose Date of Randomized Drug is the latest non-missing end date of randomized dmg, 
recorded on the Study Dmg Administration eCRF fonn with "Study Drug Petmanently 
Discontinued" box checked for subjects who prematmely discontinued randomized dmg or who 
completed randomized dmg according to the Randomized Study Dmg Completion eCRF. If the 
last dose date of randomized dmg is missing (e.g., due to lost to follow up) for subjects who 
prematmely discontinued randomized dmg, or for subjects who are still on randomized dmg, the 
latest of non-missing randomized study dmg start dates and end dates, the clinical visit dates and 
the laborat01y visit dates excluding the dates ofPPD 
24-week 
treatment-free follow-up visits will be used to impute tlie last dose date of randomized dmg. 
For subjects who prematmely discontinued randomized study dmg or who completed 
randomized study dmg but did not enter optional treatment extension phase, the Last Dose Date 
is the same as Last Dose Date of Randomized Study Dmg. 
PD 
Last Study Date is the latest of non-missing study dmg (randomized PPD 
phase) start 
dates and end dates, the clinic visit, the laborat01y visit and DXA visit dates including the 
24-week treatment-free follow-up visit date for subjects who prematmely discontinued study or 
who completed study according to Study Completion eCRF. 
Baseline value for the randomized phase (except DXA BMD) is defined as the last 
non-missing value obtained on or prior to Study Day 1. For DXA BMD, the baseline value is 
defined as the last non-missing value on or prior to Study Day 14. 
PPD 
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Statistical Analysis Plan- Week 24 Analysis 
Version 1.0 
3.7.2. 
Analysis Visit Windows 
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. 
The following windows (Table 3-1 to Table 3-5) apply to baseline and on-treatment assessments 
only. For summaries and analysis, assessments will first be categorized into baseline and 
on-treatment assessments occmTing dming the randomized PO 
phase, before applying 
analysis windows. 
For subjects who prematmely discontinued the randomized study drug PPD 
, laboratmy assess,_m_e_n-:-ts_u_p_t-:-o-an
- d' fficluding 
~~--~--~--~~~--~~~~--~~--~~ 
the last dose date of the randomized study chug + 3 days, and DXA assessments up to and 
including the last dose date of the randomized study drug + 14 days, will be considered as 
baseline or on-treatment dming the randomized phase. 
PPD 
For subjects who have not discontinued the randomized study ch·ug pe1mauently, data collected 
up to database fmalization date will be considered as baseline or on-treatment of the randomized 
phase. 
PD 
For subjects who discontinue study ch11g early due to HBsAg loss with confumed 
seroconversion, all efficacy data including data collected after the last dose date of the study chug 
will be reassigned analysis visits using the on-treatment assessment windows (Table 3-1, 
Table 3-2, and Table 3-4). 
The analysis windows for HBV DNA, hematology, senun chemisfly and liver function tests, 
eGFR (by CG and Clu·onic Kidney Disease Epidemiology Collaboration [CKD-EPI]), renal 
biomarkers mine albmnin to creatinine ratio (UACR), mine protein to creatinine ratio (UPCR), 
non-fasting glucose, weight, and vital sign assessments are provided in Table 3-1. 
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Statistical Analysis Plan- Week 24 Analysis 
Version 1.0 
Table 3-1. 
Nominal Visit 
Baseline 
Week4 
WeekS 
Week 12 
Week20 
Week24 
Week 36 
Week 48 
Analysis Visit Windows for HBV DNA, Hematology, Serum 
Chemistry and Liver Function Tests, eGFR (by CG and CKD-EPI), 
UACR, UPCR, Non-fasting Glucose, Weight, and Vital Sign 
Assessments 
Nominal Study Day 
Lower Limit 
Upper Limit 
28 
2 
41 
56 
42 
69 
84 
70 
111 
140 
112 
153 
168 
154 
209 
252 
210 
293 
336 
294 
377 
The analysis window for Fasting Glucose is in Table 3-2. 
Table 3-2. 
Analysis Visit Windows for Fasting Glucose 
Nominal Visit 
Nominal Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
Week4 
28 
2 
55 
Week 12 
84 
56 
125 
Week24 
168 
126 
251 
Week 48 
336 
252 
419 
PPD 
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Statistical Analysis Plan- Week 24 Analysis 
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The analysis windows for BMD results from DXA, fasting and non-fasting lipid panel including 
direct low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol to 
HDL ratio, Fibrotest and HBV serology are presented in Table 3-3. 
Table 3-3. 
Nominal Visit 
Baseline 
Week24 
Week 48 
PPD 
Analysis Visit Windows for BMD Results from DXA, Fibrotest, Lipid 
Panel and HBV Serology 
Nominal Study Day 
Lower Limit 
Upper Limit 
1(14a) 
168 
2(15a) 
251 
336 
252 
503 
a 
This applies to DXA only. Upper limit for baseline DXA BMD is Day 14 and lower limit for Week 24 DXA BMD is 
Day 15. 
The analysis windows for Cr EDTA renal scan are presented in Table 3-4. 
Table 3-4. 
Analysis Visit Windows for Cr EDTA Renal Scan 
Nominal Visit 
Nominal Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
Week 48 
336 
2 
503 
FPD 
The analysis windows for renal biomarkers including urine retinol binding protein (RBP) to 
creatinine ratio, urine beta-2-microglobulin to creatinine ratio, and bone biomarkers including 
serum parathyroid hormone (PTH), C-type collagen sequence (CTX), procollagen type 1 
N-terminal propeptide (PlNP), osteocalcin (OC), and bone specific alkaline phosphatase (bsAP) 
are presented in Table 3-5. 
Table 3-5. 
Analysis Visit Windows for Renal and Bone Biomarkers 
Nominal Visit 
Nominal Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
Week4 
28 
2 
55 
Week 12 
84 
56 
125 
Week24 
168 
126 
251 
Week 48 
336 
252 
419 
PPD 
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Data collected after the last dose date will be considered as post-treatment visits. The analysis 
windows for post-treatment assessments are presented in Table 3-6.
Table 3-6.
Analysis Visit Windows for Post Treatment Assessments
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Follow-Up Week 4
28
1
41
Follow-Up Week 8
56
42
69
Follow-Up Week 12
84
70
97
Follow-Up Week 16
112
98
125
Follow-Up Week 20
140
126
153
Follow-Up Week 24
168
154
181
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values are required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rule(s) will be used. 
For baseline of the randomized phase, the last available record on or prior to the first dose of 
study drug will be selected. For DXA BMD, it is defined as the last value on or prior to Study 
Day 14. If there are multiple records with the same time or no time recorded on the same day for 
numeric observations, average will be computed for that day. If there are multiple records with 
the same time or no time recorded on the same day for categorical observations, the most 
conservative value will be taken, e.g., negative will be selected over positive for HBeAg and 
HBsAg, and positive will be selected over negative for HBeAb and HBsAb.
The following specified rules will be used for postbaseline visits:

ALT: The largest value will be included in the analysis when 2 or more ALT values occur 
within the same visit window.

BMD: The latest record in the window will be selected.

HBV DNA (IU/mL): The record closest to the nominal day for that visit will be selected. If 
there are 2 records equidistant from the nominal day, the latest will be selected. If there is 
more than 1 record on the selected day, the geometric mean will be taken.

Serology: For HBeAg, HBeAb, HBsAg, and HBsAb, the record closest to the nominal day 
for that visit will be selected. If there are 2 records equidistant from the nominal day, the 
latest will be selected. If there is more than 1 record on the selected day, the most 
conservative value will be taken, ie, positive will be selected over negative for HBeAg and 
HBsAg, and negative will be selected over positive for HBeAb and HBsAb.


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For all other laboratory parameters: 

If multiple valid non-missing numeric observations exist in a window, then records will be 
chosen as follows:
The record closest to the nominal day for that visit will be selected. If there are 2 records 
equidistant from the nominal day, the latest will be selected. If there is more than 1 record 
on the selected day, the average will be taken.

If multiple valid non-missing categorical observations (eg, safety ECG results) exist in a 
window, then records will be chosen as follows:
The most conservative value (eg, abnormal will be selected over normal for safety ECG) 
within the window will be selected. In the event that 2 values within a window are of 
equal abnormality, the value collected nearest to the nominal date will be used.


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Statistical Analysis Plan- Week 24 Analysis 
4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
Version 1.0 
The number and percentage of subjects enrolled in each randomization stratum will be 
summarized based on interactive voice response system/web response system (IXRS) data. If 
there are discrepancies between IXRS and screening laboratory data with regard to stratum 
assignment, a listing of the discrepancies will be provided. 
The summary of subject disposition will be provided by treatment group and overall. This 
summary will include the number of subjects screened, screen failure subjects who were not 
randomized, subjects who met all eligibility criteria and were not randomized, subjects in the 
Randomized Analysis Set, subjects randomized but not treated, and subjects in the 
Safety Analysis Set. 
In addition, the number and percentage ofthe subjects in the following categories will be 
summarized using the Safety Analysis Set: 
Study Drug Completion 
• 
Remaining on randomized study treatment 
• 
Prematurely discontinued randomized study treatment (with summary of reasons for 
discontinuing treatment) 
• 
Completed randomized study treatment 
• PPD 
Study Completion 
• 
Entered 24-week treatment-free follow-up period 
• 
Remaining on study 
• 
Prematurely discontinued study (with summary of reasons for discontinuing study) 
• 
Completed protocol-planned duration of the study 
No inferential statistics will be generated. A data listing of reasons for premature study 
drug/study discontinuation will be provided. 
4.2. 
Extent of Study Drug Exposure and Adherence 
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol. 
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Statistical Analysis Plan- Week 24 Analysis 
4.2.1. 
Duration of Exposure to Study Drug 
Version 1.0 
Duration of exposure to randomized study drug will be defined as (last dose date of randomized 
study drug- first dose date of randomized study drug+ 1), regardless oftemporary interruptions 
in study drug administration, and will be expressed in weeks (recorded to 1 decimal place, 
e.g., 4.5 weeks). If subjects are still on randomized study drug, the latest of randomized study 
drug start and end dates, and the clinic and laboratory visit dates (excluding the PPD 
?---~--~--~---~--~~ treatment-free follow-up visit dates) will be used to impute the 
last dose date of randomized study drug for calculating the duration of randomized study drug 
exposure. 
Duration of exposure to randomized study drug will be summarized using descriptive statistics 
(sample size, mean, standard deviation [SD], median, Q1, Q3, minimum, and maximum) and as 
the number and percentage of subjects exposed for specified periods, e.g., 2' 4 weeks (28 days), 
2' 8 weeks (56 days), etc. 
Summaries will be provided by treatment group for subjects in the Safety Analysis Set. 
No inferential statistics will be provided. 
4.2.2. 
Adherence to Study Drug 
Study drug regimen adherence will be computed based on tablet counts for the T AF group only. 
The numbers of tablets of study drug dispensed and returned are captured on study drug 
accountability forms. 
Adherence(%) of study drug regimen will be calculated as follows: 
Adh 
(0 1 ) 
100 
Number of tablets taken 
erence / o = 
x ------------
Number of tablets prescribed 
L No. of tablets taken at each dispensing period [1] 
= 100 X--=--------------------
L No. of tablets prescribed at each dispensing period [2] 
[1] Number oftablets taken at a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number 
of tablets prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same 
dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number of 
tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable 
dispensing periods. 
[2] Number oftablets prescribed at a distinct dispensing period for a study drug is calculated as the daily number of tablets 
prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. 
Total number of tablets prescribed is determined by summing the number oftablets prescribed from all evaluable dispensing 
periods. 
The duration of treatment at a dispensing period for a study drug is calculated as the 
minimum of (a) the last returned date of the same dispensing period for the study drug, 
(b) date of premature discontinuation of the study drug, and (c) next dispensing date of the 
study drug, minus dispensing date of the study drug. 
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The next dispensing date is the following dispensing date of the study drug regardless of the 
bottle return date. 
For a record where the number of tablets returned was missing (with “Yes” answered for 
“Was bottle returned?” question), it is assumed the number of tablets returned was 0. If the 
number of tablets dispensed was missing or any study drug bottle was not returned or the bottle 
return status was unknown for the same dispensing date, then all records for the same dispensing 
date for that study drug will be excluded from both denominator and numerator calculation.
Adherence up to Week 24 visit will be calculated for each subject for the entire randomized
dosing period up to the date of permanent discontinuation of the randomized study drug for 
subjects who prematurely discontinued randomized study drug or completed randomized study 
drug or using all data available for subjects remaining on randomized study drug.
The number and percentage of subjects who return at least 1 bottle and have calculable 
adherence during the study, descriptive statistics for adherence up to Week 24 visit for a study 
drug regimen (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) along with the 
number and percentage of subjects belonging to adherence categories (eg, < 80%, ≥ 80% to 
< 90%, ≥ 90% to < 95%, ≥ 95%) will be provided by treatment group for the Safety Analysis 
Set. No inferential statistics will be provided.
4.3.
Protocol Deviations
A listing will be provided for subjects in the Randomized Analysis Set who violated at least 
1 inclusion or exclusion criterion. The listing will include the unmet criteria. A listing of subjects 
who received the wrong study treatment will also be provided.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason will be summarized by treatment group for the Randomized Analysis Set. 
A by-subject listing will be provided for those subjects with important protocol deviations.


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Version 1.0
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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic data (e.g., age, sex, race, and ethnicity) and baseline characteristics 
(e.g., body weight, height, and body mass index [BMI]) will be summarized by treatment group 
and overall using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and 
maximum) for continuous data and by the number and percentage of subjects for categorical 
data. Age is calculated as age in years at the first dose of study drug. The summaries of 
demographic data and baseline subject characteristics will be provided for the Safety Analysis 
Set.
5.2.
Other Baseline Characteristics

BMI categories (< 18.5 kg/m2 [underweight], ≥ 18.5 - 25.0 kg/m2 [normal], 
≥25.0 - 30.0 kg/m2 [overweight], and ≥30.0 kg/m2 [obese])

HBV DNA (IU/mL)

ALT (U/L)

ALT level based on central laboratory normal range (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN – 10 × ULN, > 10 ULN)

ALT level based on American Association for the Study of Liver Diseases (AASLD) normal 
range with the ULN as 19 U/L for female and 30 U/L for male (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN - 10 × ULN, > 10 ULN)

Estimated GFR by CG, CKD-EPI creatinine, and CKD-EPI Cystatin C methods

HBeAg status (positive, negative)

HBeAb status (positive, negative)

Years positive for HBV 

Years of liver transplant

Fibrotest score

Fibrosis stage by fibrotest score (0 - 0.48, 0.49 - 0.74, 0.75 - 1)

Proteinuria by urinalysis (dipstick) (Grade 0, Grade 1, Grade 2, Grade 3)

Vitamin D 


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
Clinical BMD status (normal, osteopenia, osteoporosis)

Hip fracture and major osteoporotic fracture probabilities estimated using FRAX®
(see Section 7.3.4)
5.3.
Medical History
A listing of medical history data will be provided for the Randomized Analysis Set.


TAF 
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Statistical Analysis Plan- Week 24 Analysis 
6. 
EFFICACY ANALYSES 
Version 1.0 
For Week 24 analyses, efficacy data will be summarized for the randomized phase (ie, up to 
Week 48), with the exception that summaries using M = F approach will be presented up to 
Week 24 onl . All efficacy data up to the Week 24 data-cut including data collected during 
PD 
treatment-free follow-up period will be listed. 
6.1. 
Primary Efficacy End points 
6.1.1. 
Defmition ofthe Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with HBV DNA < 20 IU/mL at 
Week24. 
6.1.2. 
Analysis of the Primary Efficacy End point 
The primary efficacy analysis will be conducted after the last randomized subject reaches 
Week 24 or discontinues study drug prematurely. An M = F approach will be employed. In this 
approach, all missing data will be treated as not achieving the primary endpoint 
(i.e., having HBV DNA ~ 20 IU/mL). 
6.1.3. 
Secondary Analysis for the Primary Efficacy Endpoint 
Sensitivity analyses will be performed for the primary endpoint using Missing = Excluded 
(M = E) approach. In this approach, all missing data will be excluded in the computation 
(ie, missing data points will be excluded from both the numerator and denominator in proportion 
computation). 
6.2. 
Other Efficacy Endpoints 
6.2.1. 
Defmition of Secondary and Other Efficacy Endpoints 
The secondary efficacy endpoint is: 
• 
The proportion of subjects with plasma HBV DNA < 20 IU/mL at Weeks 48 
Other efficacy endpoints include: 
• 
The proportion of subjects with normal ALT (by central laboratory and AASLD criteria) at 
Weeks 24 and 48 
• 
The proportion of subjects with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 24 and 48 
• 
The proportion of subjects with HBsAg loss at Weeks 24 and 48 
• 
The proportion of subjects with HBeAg loss at Weeks 24 and 48 
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
The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 24 and 48

The proportion of subjects with HBeAg seroconversion to anti-HBe at Weeks 24 and 48

The change from baseline in ALT at Weeks 24 and 48
The secondary endpoints at Weeks 48 will not be summarized using the primary analysis method 
(M=F) for the Week 24 analysis. Instead, they will be summarized at the next interim analyses at 
Weeks 48. 
For the Week 24 analysis, the following definitions will be used:

HBsAg loss is defined as HBsAg test result changes from HBsAg positive at baseline to 
HBsAg negative at a postbaseline visit with baseline HBsAb negative or missing

HBeAg loss is defined as HBeAg test result changes from HBeAg positive at baseline to 
HBeAg negative at a postbaseline visit with baseline HBeAb negative or missing

HBsAg seroconversion is defined as HBsAg loss and HBsAb test result changes from 
HBsAb negative or missing at baseline to HBsAb positive at a postbaseline visit 

HBeAg seroconversion is defined as HBeAg loss and HBeAb test result changes from 
HBeAb negative or missing at baseline to HBeAb positive at a postbaseline visit

ALT normalization is defined as ALT > ULN (by central laboratory normal range or AASLD 
normal range) at baseline but within normal range at a postbaseline visit
Both baseline and postbaseline borderline serology results will be imputed using the following 
rules:

HBsAg and HBeAg borderline will be considered as HBsAg positive and HBeAg positive

HBsAb and HBeAb borderline will be considered as HBsAb negative and HBeAb negative
6.2.2.
Analysis Methods for Secondary and Other Efficacy Endpoints
All the secondary and other efficacy endpoints involving proportions will be analyzed using the 
same statistical method (M = F) applied to the analysis of the primary efficacy endpoint. 
Sensitivity analyses will be performed using the M = E approach as well. 
The change from baseline in ALT will be summarized by visit using observed data 
(ie, missing will be excluded). 
In addition, the proportion of subjects with HBV DNA < 20 IU/mL and the proportion of 
subjects with normal ALT (by central laboratory and AASLD criteria, M = F) will be plotted 
with 95% CI over time for FAS. Median (Q1, Q3) and mean (95% CI) of change from baseline 
in ALT (U/L) will also be plotted over time using observed data for FAS.


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6.3.
Changes From Protocol-Specified Efficacy Analyses
Change from baseline in ALT was added in the SAP as other efficacy endpoints to fully explore 
the treatment effect of TAF versus TDF. Proportion of normal ALT and ALT normalization by 
visit evaluated using central laboratory and AASLD ULN, and proportion of subjects with 
HBsAg loss, HBeAg loss, HBsAg seroconversion and HBeAg seroconversion were also added. 
All Randomized Analysis Set was not defined in the protocol but is added in the SAP.


TAF 
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Statistical Analysis Plan- Week 24 Analysis 
7. 
SAFETY ANALYSES 
Version 1.0 
For Week 24 analysis, safety data will be summarized for the randomized phase only 
~ to Week 48). All safety data u to the Week 24 data-cut including data collected during 
PPD 
24-week treatment-free follow-up period will be included 
in data listings. 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
AEs 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. 
7.1.2. 
Adverse Event Severity 
AEs are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or 
Grade 4 (life threatening) according to toxicity criteria specified in Appendix 5 of the clinical 
study protocol. The severity grade of events for which the investigator did not record severity 
will be categorized as "missing" for tabular summaries and data listings, and will be considered 
the least severe for the purposes of sorting for data presentation. 
7.1.3. 
Relationship of AEs to Study Drug 
Related AEs are those for which the investigator answers "Yes" to the question "Related to 
Study Treatment?" in the eCRF. Events for which the investigator did not record relationship to 
study drug will be considered related to study drug for summary purpose. Data listings will show 
relationship as missing. 
7.1.4. 
Relationship of AEs to Study Procedure 
AEs for which 'Yes' is marked for question 'Related to Study Procedures?' in the eCRF will be 
identified and included in AE listing. 
7.1.5. 
Serious Adverse Events 
Serious AEs are those identified as serious in the eCRF, where 'Yes' was marked for 'AE 
serious'. The clinical database will be reconciled with the serious AE database (from the 
Drug Safety and Public Health Department) before database finalization. 
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Statistical Analysis Plan- Week 24 Analysis 
Version 1.0 
7.1.6. 
Treatment-Emergent Adverse Events 
7.1.6.1. 
Definition of Treatment-Emergent Adverse Events 
Treatment-emergent AEs will be defined for the randomized phase and the extension phase 
separately. 
Treatment-emergent AEs occuning during the randomized phase are defmed as follows: 
• 
Any AE with onset date on or after the randomized study dmg stait date and no later than the 
minimum of the randomized study dmg stop date + 3 days PPD 
, for those who discontinued randomized stud'_y_di,_u_g_p_e_rm_ an_e_n""':"t'ly, or 
• 
Any AE with onset date on or after the randomized study di11g strut date for those who ru·e 
still on the randomized study di11g, or 
• 
Any AE leading to randomized study dmg discontinuation. 
PD 
I 
I 
I 
7.1.6.2. 
Incomplete Dates 
If an AE onset date is incomplete or completely missing, the following mles will be used to 
define treatment-emergent AE: 
Events with Missing Onset Day and/or Month 
The event is treatment-emergent during the randomized phase if the following criteria are met: 
• 
The month and year (or yeru") of onset date is the same as or after the month and yeru· 
(or year) of the first dose of the randomized study diug, and 
• 
For those who discontinued the randomized study di11g pennanently only: the month and 
year (or year) of onset date is the same as or before the month and ear ~year) of the 
minimum of the randomized study diug stop date + 3 days PPD 
and 
""------------
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Statistical Analysis Plan- Week 24 Analysis 
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• 
AE End date is as follows: 
-
The (complete) end date is on or after the ftrst dose date of the randomized study dmg, or 
-
The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of randomized study drug, or 
-
End date is completely missing 
PPD 
I 
I 
I 
I 
I 
• 
Events with Completely Missing Onset Date 
An AE with a completely missing onset date is defmed as treatment-emergent AE during the 
randomized phase if end date is as follows: 
• 
The (complete) end date is on or after the first dose date of the randomized study dmg, or 
• 
The month and year (or year) of end date is the same or after the month and year (or year) of 
the first dose of the randomized study dmg, or 
• 
End date is completely missing 
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7.1.7. 
Summaries of Adverse Events and Deaths 
A brief summruy of AEs (i.e., the number and percentage of subjects) will be presented by 
treatment group for the following: (1) any treatment-emergent AE, (2) any Grade 3 or 4 
treatment-emergent AE, (3) any Grade 2, 3 or 4 treatment-emergent AE, (4) any treatment-emergent 
study dmg-related AE, (5) any Grade 3 or 4 treatment-emergent study <hug-related AE, 
(6) any Grade 2, 3 or 4 treatment-emergent study drug-related AE, (7) any treatment-emergent 
serious adverse event (SAE), (8) any treatment-emergent study <hug-related SAE, 
(9) any treatment-emergent AE leading to premature study <h·ug discontinuation, 
(1 0) any treatment-emergent AE leading to dose modification or study <h11g intenuption, and 
(11) ru1y death. 
Treatment-emergent death dming the randomized phase refers to death that occms between the 
first dose date of the randomized study <hu and the minimum of the last dose date of the 
rru1domized study <h11g + 3 daysE PD 
, for those 
who discontinued randomized study di11g.Petmanent~~PP D 
Summaries (number and percentage of subjects) of AEs (by SOC, HL T [if specified below], 
and PT) will be provided by treatment group and overall using the Safety Analysis Set for the 
randomized phase as follows: 
• 
All treatment-emergent AEs s1.11nmru·ized by SOC, HLT, and PT 
• 
Any Grade 3 or 4 treatment-emergent AEs 
• 
Any Grade 2, 3, or 4 treatment-emergent AEs 
• 
All treatment-emergent nonserious AEs occuning in at least 5% of subjects in any 
treatment group (this summaty is generated per requirement for repmting in 
ClinicalTrials.gov) 
• 
All treatment-emergent study <hug-related AE summmi.zed by SOC, HLT, and PT 
• 
Any Grade 3 or 4 treatment-emergent study <hug-related AEs 
• 
Any Grade 2, 3, or 4 treatment-emergent study <hug-related AEs 
• 
All treatment-emergent SAEs 
• 
All treatment-emergent study <hug-related SAEs 
• 
All treatment-emergent AEs leading to prematme discontinuation from study <h11g 
• 
All treatment-emergent AEs leading to dose modification or study <hug inte1mption 
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Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC (and HLT) will be ordered alphabetically, with PT sorted by decreasing total frequency. 
For summaries by severity grade, the most severe event will be selected. 
In addition to the by-treatment summaries, data listings will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Study drug-related SAEs

Deaths

AEs leading to premature discontinuation of study drug

AEs leading to dose modification or study drug interruption
7.2.
Laboratory Evaluations
Summaries of laboratory data will be provided for the randomized phase based on Safety 
Analysis Set. Analysis will be based on values reported in conventional units. No formal 
statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each laboratory test specified in the 
study protocol as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window

Percentage change from baseline to each postbaseline analysis window (if specified) 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.
7.2.1.1.
Metabolic Assessments
Fasting lipid panel and fasting glucose measurements will not be summarized for the Week 24 
analysis.


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7.2.1.2. 
Calcium Conelated for Albumin 
Calcium conected for albumin will be calculated and summaTized. The following fmmula will 
be used when both senun calcium and albumin results for a given blood draw are available and 
sennn albmnin value is < 4.0 g/dL. 
Calcilnn conected for albmnin (mg/dL) = sennn calcium (mg/dL) + 0.8 x (4.0- albmnin (g/dL)). 
When albumin value is~ 4.0 g/dL, the actual calcium results will be used. Toxicity grading for 
calcium will be applied based on the conected values. 
7.2.2. 
Graded Laboratory Values 
The criteria specified in the protocol will be used to grade laboratmy results as Grade 0, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life-threatening). Grade 0 
includes all values that do not meet criteria for an abnmmality of at least Grade 1. Some 
laboratmy tests have criteria for both increased and decreased levels; analysis for each direction 
(i.e., increased, decreased) will be presented sepaTately. 
For triglycerides, LDL, and total cholesterol, the protocol-specified toxicity grade scale is for 
fasting test values; non-fasting lipid results (or lipid results without known fasting status) will not 
be graded or smnmarized by toxicity grades. 
If any laboratmy toxicity grading scale overlaps with nmmal reference ranges (e.g., Grade 1 
scale overlaps with nmmal reference ranges), laboratmy values within nonnal range will not be 
graded except for lipid tests. 
7.2.2.1. 
Treatment-Emergent Laboratory Abnmmalities 
Treatment-emergent laboratory abnmmalities occmTing in the randomized phase are defined as 
values that increase by at least 1 toxicity grade from baseline at any postbaseline visit up to and I 
including the minimum of the randomized study dmg stop date + 3 days PPD 
, for those who discontinued randomized study dmg prematmely, or values 
-.-....... --~-~ 
that increase by at least 1 toxicity grade from baseline at any postbaseline visit for those who are 
still on the randomized study dmg. If the relevant baseline laboratmy data are missing, any 
laboratmy abnonnality of at least Grade 1 will be considered treatment-emergent. 
PPD 
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Fasting glucose and nonfasting glucose aTe graded based on different grading scales. 
Treatment-emergent laboratmy abnmmalities will be summarized for fasting glucose and 
nonfasting glucose separately. 
7.2.2.2. 
Treatment-Emergent Marked Laboratmy Abnormalities 
Treatment-emergent marked laboratoty abnonnalities occmTing in the randomized phase are 
defined as values that worsen by at least 3 grades from baseline at any postbaseline visit uJ to 
and including the miuimmn of the randomized study dmg stop date + 3 days PPD 
'-.------:-1 
for those who discontinued randomized study dmg prematmely, 
or values that worsen b-y-a~t:-.-ea-st 3 grades from baseline at any postbaseline visit for those who 
are still on randomized study drug. If relevant baseline laboratmy data are missing, any 
laboratoty abnmmalities of at least Grade 3 or 4 will be considered as treatment-emergent 
marked laboratmy abnmmalities. 
PPD 
7.2.2.3. 
SUlllillaries of Laboratmy Abnormalities 
The following Slllllillaries (number and percentage of subjects) of laboratory abnmmalities will 
be provided by treatment group (subjects categorized according to most severe abnormality 
grade) for the randomized phase: 
• 
Treatment-emergent laboratmy abnmmalities 
• 
Treatment-emergent Grade 3 and 4laboratmy abnmmalities 
• 
Treatment-emergent marked laboratory abnmmalities 
For all slllllillaries of laboratmy abnmmalities, the denominator is the number of subjects with 
any non-missing postbaseline value in the given study period. A listing of treatment-emergent 
Grade 3 or 4 laboratmy abnmmalities will be provided. 
7.2.3. 
ALT Elevation 
An AL T elevation is defmed as sennn AL T > 2 x baseline value and > 10 x ULN, with or 
without associated symptoms. Confltmed AL T elevation (ALT flare) is defmed as AL T 
elevations at 2 consecutive postbaseline visits. All treatment-emergent AL T elevations including 
confumed AL T elevations will be stnnmarized for the randomized phase. All treatment-emergent 
and nontreatment-emergent ALT elevations will be included in a listing. 
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If the first of two consecutive results is in the randomized phase and the second is out of the 
randomized phase (ie, in the PPD 
TFFU phase), then the result will be considered to be 
confirmed in the randomized phase (assuming both values meet the criterion). And ifthe 
criterion is met by the last value in the randomized phase and no assessments are available after 
due to the subject exiting the study or data not yet available, then the result will also be 
considered to be confirmed. 
7.3. 
Bone Safety Analysis 
7.3.1. 
Bone Mineral Density (BMD) 
Percentage change from baseline in hip BMD and spine BMD will be summarized by treatment 
group and visit using descriptive statistics for subjects in the Hip and Spine DXA Analysis Sets, 
respectively. 
Observed BMD values will be used for all the analyses described below. 
For each subject and each visit, the clinical BMD status will be defined for hip and spine BMD 
based on the corrected t-score in Table 7-1. 
Table 7-1. 
Nonnal, Osteopenia, and Osteoporosis as Defined by T -score 
Clinical Status 
BMD T-score 
Nonnal 
t-score 2 -1.0 
Osteopenia 
-2.5 ::; t-score < -1.0 
Osteoporosis 
t-score < -2.5 
The number and percentage of subjects in each clinical BMD status (normal, osteopenia, and 
osteoporosis) will be summarized by visit and by baseline clinical status for both hip and spine. 
The number and percentage of subjects in each category based on percentage change from 
baseline in hip BMD and spine BMD (> 7% decrease, > 5% to S 7% decrease, > 3% to S 5% 
decrease, > 1% to S 3% decrease, > 0 to S 1% decrease, 0 to S 1% increase, > 1% to S 3% 
increase, > 3% to S 5% increase, > 5% to S 7% increase, > 7% increase) will be summarized by 
treatment group and visit. 
Median (Q1, Q3) and mean (95% CI) of percentage change from baseline in observed hip and 
spine BMD over time will be plotted by treatment group for the randomized phase. Listings of 
hip and spine DXA results will be provided. 
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7.3.2.
Bone Biomarkers
Bone biomarkers include serum CTX, P1NP, PTH, OC, and bsAP.
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone 
biomarkers will be summarized by treatment group and visit using descriptive statistics. 
Median (Q1, Q3) percentage change from baseline in bone biomarkers over time will be plotted 
by treatment group. A listing of bone biomarker data will be provided.
7.3.3.
Fracture Events
The PTs for fracture events were defined based on both Standardized MedDRA Query (SMQ) of 
Osteoporosis/Osteopenia and HLGT of Fractures from MedDRA 20.0 (see Appendix 1). 
Treatment-emergent fracture events will be summarized based on the identified PTs from SMQ 
alone and both SMQ and HLGT combined. The number and percentage of subjects who 
experienced fracture events will be summarized by treatment group for the randomized phase. 
A data listing of fracture events will be provided.
7.3.4.
Assessment of Fracture Probability
Fracture probabilities will be assessed using FRAX®, a computer based algorithm developed by 
the World Health Organization (WHO; http://www.shef.ac.uk/FRAX).
The FRAX algorithm is based on individual patient models that integrate the risks associated 
with clinical risk factors as well as BMD at the femoral neck. The algorithm provides both the 
10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture 
(clinical spine, forearm, hip, or shoulder fracture).
The FRAX model is constructed from real data in population-based cohorts around the world 
that have a limited age range. For an age below 40 or above 90 years, the tool will calculate the 
probability of fracture at the age of 40 or 90 years, respectively. Due to the age limitation, 
2 sets of analyses of fracture probabilities will be performed.
In the first set of analysis, summaries of baseline and change from baseline in the 10-year 
probabilities of hip fracture, as well as major osteoporotic fracture will be presented by treatment 
group and visit for subjects aged between 40 and 90 years for the randomized phase. 
In the second set of analysis, the above-specified analysis will be performed to include all 
subjects, where subjects with an age below 40 or above 90 years will be treated as having an age 
of 40 or 90 years, respectively, in computing their fracture probabilities.
Data listings of fracture risk assessment questionnaire and FRAX fracture probabilities will be 
provided.


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7.3.5. 
Bone Events 
Version 1.0 
The PTs for bone events were defined by selecting relevant bone PTs based on MedDRA 20.1 
(see Appendix 2). The number and percentage of subjects who experienced treatment-emergent 
bone events will be summarized by treatment group for the randomized phase. A data listing of 
bone events will be provided. 
7.4. 
Renal Safety Analysis 
7.4.1. 
Confirmed Renal Abnormalities 
Confirmed renal abnormalities are defined as follows: 
• 
Confirmed increase from baseline in creatinine of at least 0. 5 mg/dL or 
• 
Baseline eGFRCKD-EPI :2 50 mL/min/1.73 m2 and confirmed postbaseline eGFRcKD-EPI 
< 50 mL/min/1.73 m2 or 
• 
Confirmed phosphorous < 2 mg/dL 
Treatment-emergent confirmed renal abnormalities will be summarized for randomized 
All confirmed renal abnormalities including those occurred during PPD 
-
24-week treatment-free follow-up period will be listed . ....._ _________ ___. 
7.4.2. 
Serum Creatinine 
The baseline and change from baseline in serum creatinine at Week 24 will be summarized using 
descriptive statistics. Change from baseline in observed serum creatinine by visit will be 
analyzed similarly. 
Median (Q1, Q3) and mean (95% CI) of change from baseline in observed serum creatinine over 
time will be plotted by treatment group. 
7.4.3. 
Estimated Glomerular Filtration Rate 
The following formulae will be used to calculate eGFR: 
• 
CG: 
eGFRca (mL/min) = [(140- age (yrs)) x weight (kg) x (0.85 if female)] I (SCr 
(mg/dL) x 72), 
where weight is actual total body mass in kilograms, and SCr is serum creatinine. 
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
CKD-EPI Creatinine Based:
eGFRCKD-EPI, creatinine (mL/min/1.73 m2) = 141 × min(SCr/κ,1)α × max(SCr/κ,1)-1.209 × 0.993Age
× 1.018 (if female) × 1.159 (if black),
where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, 
min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1
{Levey 2009}.

CKD-EPI Cystatin C based:
eGFRCKD-EPI, cysC (mL/min/1.73 m2) = 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.
Change from baseline in eGFRCG and eGFRCKD-EPI, creatinine at each postbaseline visit will also be 
provided during the randomized phase. 
The number and proportion of subjects with decrease from baseline of ≥ 25% and ≥ 50% in 
eGFRCG and eGFRCKD-EPI, creatinine will be summarized by treatment groups for the randomized
phase.
The baseline and postbaseline eGFRCKD-EPI, cysC with percentage change from baseline will be 
listed.
Median (Q1, Q3) change from baseline in eGFRCG and eGFRCKD-EPI, creatinine over time will be 
plotted for the randomized phase.
7.4.4.
Treatment-emergent Proteinuria (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) will be summarized by treatment group 
for the randomized phase. A listing of subjects with treatment-emergent proteinuria will be 
provided.
7.4.5.
Urine RBP to Creatinine Ratio and Beta 2 Microglobulin to Creatinine Ratio
Baseline, postbaseline, change from baseline and percentage change from baseline in urine RBP 
to creatinine ratio and beta-2-microglobulin to creatinine ratio will be summarized by treatment 
group and visit using descriptive statistics. Median (Q1, Q3) percentage change from baseline 
over time will be plotted by treatment group for the randomized phase.
7.4.6.
Proteinuria by Quantitative Assessment
Baseline, postbaseline, changes from baseline, and percentage change from baseline in UPCR 
and UACR will be summarized by treatment group and visit using descriptive statistics, for the 
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The number and proportion of subjects with UPCR ≤ 200 mg/g versus > 200 mg/g will be 
summarized by baseline category for each postbaseline visit during the randomized phase 
{KDIGO Guideline Development Staff 2013}.
The number and proportion of subjects with UACR < 30 mg/g versus ≥30 mg/g will be 
summarized by baseline category for each postbaseline visit during the randomized phase
{KDIGO Guideline Development Staff 2013}.
Median (Q1, Q3) percentage change from baseline over time will be plotted by treatment group 
for the randomized phase.
7.4.7.
Other Renal Biomarkers
Other renal biomarkers include TmP/GFR, FEPO4, and FEUA.
TmP/GFR based on serum creatinine {Barth 2000} will be calculated as follows:


86
.0
)
8.0
(
1
/
3.0
/
86
.0
/
4
4









TRP
if
SPO
TRP
TRP
GFR
TmP
TRP
if
SPO
TRP
GFR
TmP
where TRP (tubular reabsoprtion of phosphate) is calculated by:
UCr
SCr
SPO
UPO
TRP



4
4
1
where SCr is serum creatinine concentration (mg/dL), UPO4 is urine phosphate concentration 
(mg/dL), SPO4 is serum phosphate concentration, and UCr is urine creatinine concentration 
(mg/dL).
Urine FEPO4 will be calculated as follows:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Urine FEUA will be calculated as follows:
FEUA (%) = (SCr × UUa) / (SUa × UCr) × 100 (%)
where UUa and SUa are urine and serum uric acid (mg/dL), respectively. 
The baseline, postbaseline, and change from baseline in TmP/GFR, FEPO4, and FEUA will be 
summarized by treatment group and visit using descriptive statistics during the randomized
phase. 
In addition, the baseline, postbaseline, and change from baseline of corrected surface area value 
from EDTA renal scan will be summarized by treatment group and visit using descriptive 
statistics during the randomized phase.


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7.5. 
Body Weight 
Body weight at each visit and change from baseline in body weight will be summarized using 
descriptive statistics (sample size, mean, SD, median, Ql, Q3, minimum, and maximum) by 
treatment group for each postbaseline analysis window. In the case of multiple values in an 
analysis window, data will be selected for analysis as described in Section 3.7.3. 
7.6. 
Prior Hepatitis B Medications 
Prior HBV medications will be smmnarized by treatment group. No inferential statistics will be 
computed. A listing of prior HBV medications will also be provided. 
7.7. 
Concomitant Medications 
Concomitant medications (ie, medications other than study dmg that are taken while receiving 
study dmg) will be coded using the WHO Dmg Dictionruy. 
For the Week 24 analysis, smnmaries of concomitant medications using the number and 
percentage of subjects for each treatment group will be provided for the randomized phase based 
on the Safety Analysis Set and by WHO generic name. Subject will be counted only once for 
each generic name. The sulllillaiy will be ordered by overall frequency. For drugs with the same 
frequency, s01ting will be done alphabetically. 
If the strut or stop date of concomitant medications is incomplete, the month and year 
(or yeru· alone if month is not recorded) of strut or stop date will be used to determine if the 
medications are concomitant as follows. 
The medication is concomitant for the randomized phase if the month and year of strut or stop 
(or yeru· of the strut or stop) of the medication do not meet any of following criteria: 
• 
The month and yeru· of strut of the medication is after the date of the last dose of randomized 
study drug 
• 
The month and yeru· of stop of the medication is before the date of the first dose of 
randomized study dmg 
PPD 
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If the stali and stop date of the medications are not missing, and the sta1i date is not after the last 
dose date of the randomized study dmg and the stop date is not before the first dose date of the 
randomized study dmg, or the medications are mru·ked as ongoing and stmt date is on or before 
the last dose date of the randomized study dmg, the medications are considered concomitant 
dming the randomized phase. 
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PD 
No inferential statistics will be provided. Subjects with any concomitant medication use will also 
be listed. 
7.8. 
Other Safety Measures 
A data listing will be provided for subjects experiencing pregnancy during the study. 
7.9. 
Changes From Protocol-Specified Safety Analyses 
Treatment-emergent AE and lab abnmmality in randomized phase was defmed as any AE or lab 
abnormality that begins on or after the first dose date of study drug up to the last dose date in the 
protocol, and is updated in this SAP. Treatment-emergent AE occmTing in the randomized phase 
is defmed as any AE with onset date on or after the first dose date of the randomized study and 
no later than the minimum of the randomized study dmg stop date + 3 days PD 
....... --~~ 
if applicable for the randomized phase. Treatment-emergent laboratmy 
'a6iiO:nnali1tie;;;o()cc:<c:Umirlr1ing m the randomized phase are defmed as values that increase by at least 
1 toxicity grade from baseline at any postbaseline visit u to and including the minimum of the 
randomized study dmg stop date + 3 days PPD 
=-oJ for the 
randomized phase. This change was made as labs performed 1-2 days after study chug stopped 
were being excluded causing the measurement for the timepoint to be missed, even though 
protocol specified visit windows allowed for labs to be perfmmed in a shmt period after the 
study ch11g was stopped. 
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8. 
PHARMACOKINETIC (PK) ANALYSES 
8.1. 
PK Sample Collection 
A single PK blood sample will be collected at any time dming each On-Treatment Visit for all 
subjects up to week 48 to measme T AF and TFV concentrations 
PPD 
8.2. 
Estimation of PK Parameters 
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompatimental methods. The linear/log trapezoidalmle will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and conesponding real-time values, based on drug dosing times whenever 
possible. 
All predose sample times (elapsed time) before time-zero will be convetted to 0. 
For ru·ea lmder the cmve (AUC), samples BLQ of the bioanalytical assays occmTing prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AU C. Post dose samples that ru·e BLQ will be imputed at 
one-half of the lower limit of quantitation (LLOQ). The nominal time point for a key event or 
dosing intetval (t) may be used to pemlit direct calculation of AUC over specific time intervals. 
The appropriateness of tllis approach will be assessed by the PK scientist on a profile-by-profile 
basis. 
Phannacokinetic pru·ameters such as AUC~au, "-z. and t112 are dependent on an accmate estimation 
of the temlinal elimination phase of dmg. The appropriateness of calculating these pru·ameters 
will be evaluated upon inspection ofPK data on a profile-by-profile basis by the PK scientist. 
PK parameters that may be estimated in this substudy ru·e listed and defmed in Table 8-1. 
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Table 8-1.
PK Parameters
Parameter
Description
AUClast
The area under the concentration versus time curve from time 0 to the last quantifiable concentration
AUCtau
The area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
CL/F
apparent oral clearance after administration of the drug:
at steady state: CL/F = Dose/AUCtau, where “Dose” is the dose of the drug
T1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
Vz/F
apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the plasma concentration of drug versus time curve
8.3.
Statistical Analysis Methods
Individual subject plasma concentration data and individual subject PK parameter will be listed 
and summarized using descriptive statistics. The descriptive statistics (sample size, mean, SD, 
coefficient of variation [% CV], minimum, median, maximum, Q1, Q3, geometric mean, and its 
95% CI, will be presented for plasma concentration data and individual PK parameters. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
zero at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points.
For some PK parameter data (ie, Cmax, Ctau, Clast, AUCtau and AUClast), the geometric mean, its 
95% CI, and the mean and SD of the natural-log transformed values will be presented in addition 
to the summaries mentioned above.
The following TFLs will be provided for analytes for intensive PK analysis at the Week 4 or 
Week 8 visits (summarization is for PK Substudy Analysis Set):

Table with individual subject concentration data and summary statistics at each time point for 
each analyte

Table with individual subject PK parameters and summary statistics for each analyte (for PK 
Substudy Analysis Sets only)


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
Mean (SD) concentration vs time figures – linear and semi-log plots for TAF and TFV (for 
PK Substudy Analysis Sets only)

Median (Q1, Q3) concentration vs time figures – linear and semi-log plots for TAF and TFV 
(for PK Substudy Analysis Sets only)
The following TFLs will be provided for analytes for sparse PK from Week 4 through Week 24
visits (summarization is for PK Analysis Set):

Table with individual subject concentration data and summary statistics at each visit for each 
analyte.

Mean (SD) concentration vs visit figures – linear and semi-log plots for TAF and TFV (for 
PK Analysis Sets only).
The following listings will be provided for general PK analysis from Week 4 through Week 48 
for the randomized analysis set:

Listing of PK sampling details 

Listing of study drug administration record for PK dosing
The listings of PK sample details and study drug administration record for the intensive PK 
substudy and single PK samples will be combined for presentation.


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19 March 2018
9.
REFERENCES
Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the 
algorithm performs better than the nomogram. Ann Clin Biochem 2000;37 ( Pt 
1):79-81.
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the 
Evaluation and Management of Chronic Kidney Disease. Kidney international. 
Supplement 2013;3 (1):v-150.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150 (9):604-
12.


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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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10.
SOFTWARE
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, 
listings, and figures.
Phoenix WinNonlin® (Pharsight Corporation Version 7.0, Mountain View, CA) is to be used for 
all PK analyses.
FRAX® (WHO Collaborating Center for Metabolic Bone Disease, University of Sheffield, UK) 
is to be used for the 10-year probabilities of hip fracture or a major osteoporotic fracture.


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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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19 March 2018
11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 50
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12.
APPENDICES
Appendix 1.
Fracture Events
Appendix 2.
Bone Events


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 51
19 March 2018
Appendix 1.
Fracture Events
The selected PTs of fracture events from SMQ of Osteoporosis/Osteopenia and HLGT of 
Fractures are listed as follows:
Selected Preferred Terms
Selection Type
1
Acetabulum fracture
cSMQ+cHLGT 
2
Ankle fracture
cHLGT
3
Atypical femur fracture
cSMQ+cHLGT 
4
Atypical fracture
cHLGT
5
Avulsion fracture
cHLGT
6
Bone fissure
cHLGT
7
Bone fragmentation
cHLGT
8
Cervical vertebral fracture
cSMQ+cHLGT 
9
Chance fracture
cHLGT
10
Clavicle fracture
cHLGT
11
Closed fracture manipulation
cSMQ
12
Comminuted fracture
cHLGT
13
Complicated fracture
cHLGT
14
Compression fracture
cHLGT
15
Craniofacial fracture
cHLGT
16
Epiphyseal fracture
cHLGT
17
External fixation of fracture
cSMQ
18
Facial bones fracture
cHLGT
19
Femoral neck fracture
cSMQ+cHLGT 
20
Femur fracture
cSMQ+cHLGT 
21
Fibula fracture
cHLGT
22
Flail chest
cHLGT
23
Foot fracture
cHLGT
24
Forearm fracture
cSMQ+cHLGT 
25
Fracture
cSMQ+cHLGT 
26
Fracture displacement
cHLGT
27
Fracture of clavicle due to birth trauma
cHLGT
28
Fracture treatment
cSMQ
29
Fractured coccyx
cHLGT
30
Fractured ischium
cSMQ+cHLGT 
31
Fractured sacrum
cSMQ+cHLGT 
32
Fractured skull depressed
cHLGT
33
Greenstick fracture
cHLGT
34
Hand fracture
cHLGT
35
Hip fracture
cSMQ+cHLGT 
36
Humerus fracture
cHLGT
37
Ilium fracture
cSMQ+cHLGT 
38
Impacted fracture
cHLGT


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 52
19 March 2018
Selected Preferred Terms
Selection Type
39
Internal fixation of fracture
cSMQ
40
Jaw fracture
cHLGT
41
Limb fracture
cHLGT
42
Lisfranc fracture
cHLGT
43
Lower limb fracture
cHLGT
44
Lumbar vertebral fracture
cSMQ+cHLGT 
45
Multiple fractures
cSMQ+cHLGT 
46
Open fracture
cHLGT
47
Open reduction of fracture
cSMQ
48
Open reduction of spinal fracture
cSMQ
49
Osteochondral fracture
cHLGT
50
Osteoporotic fracture
cSMQ+cHLGT 
51
Patella fracture
cHLGT
52
Pathological fracture
cSMQ+cHLGT 
53
Pelvic fracture
cSMQ+cHLGT 
54
Periprosthetic fracture
cHLGT
55
Pubis fracture
cSMQ+cHLGT 
56
Radius fracture
cSMQ+cHLGT 
57
Rib fracture
cSMQ+cHLGT 
58
Sacroiliac fracture
cSMQ+cHLGT 
59
Scapula fracture
cHLGT
60
Scapulothoracic dissociation
cHLGT
61
Skull fracture
cHLGT
62
Skull fractured base
cHLGT
63
Spinal compression fracture
cSMQ+cHLGT 
64
Spinal fracture
cSMQ+cHLGT 
65
Sternal fracture
cHLGT
66
Stress fracture
cHLGT
67
Tartrate-resistant acid phosphatase decreased
cSMQ
68
Thoracic vertebral fracture
cSMQ+cHLGT 
69
Tibia fracture
cHLGT
70
Torus fracture
cHLGT
71
Traumatic fracture
cHLGT
72
Ulna fracture
cHLGT
73
Upper limb fracture
cHLGT
74
Vertebroplasty
cSMQ
75
Wrist fracture
cSMQ+cHLGT 
76
Vertebral body replacement
cSMQ


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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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19 March 2018
Appendix 2.
Bone Events
The selected PTs of bone events based on MedDRA 20.1 are listed as follows:
Selected Preferred Terms
1
Subchondral insufficiency fracture
2
Metaphyseal corner fracture
3
Fracture infection
4
Acetabulum fracture
5
Ankle fracture
6
Atypical femur fracture
7
Atypical fracture
8
Avulsion fracture
9
Bone fissure
10
Bone fragmentation
11
Cervical vertebral fracture
12
Chance fracture
13
Clavicle fracture
14
Comminuted fracture
15
Complicated fracture
16
Compression fracture
17
Costal cartilage fracture
18
Craniofacial fracture
19
Epiphyseal fracture
20
Facial bones fracture
21
Femoral neck fracture
22
Femur fracture
23
Fibula fracture
24
Flail chest
25
Foot fracture
26
Forearm fracture
27
Fracture
28
Fracture blisters
29
Fracture delayed union
30
Fracture displacement


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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19 March 2018
Selected Preferred Terms
31
Fracture malunion
32
Fracture nonunion
33
Fracture of clavicle due to birth trauma
34
Fractured coccyx
35
Fractured ischium
36
Fractured sacrum
37
Fractured skull depressed
38
Greenstick fracture
39
Hand fracture
40
Hip fracture
41
Humerus fracture
42
Ilium fracture
43
Impacted fracture
44
Jaw fracture
45
Limb fracture
46
Lisfranc fracture
47
Lower limb fracture
48
Lumbar vertebral fracture
49
Multiple fractures
50
Open fracture
51
Osteochondral fracture
52
Osteoporotic fracture
53
Patella fracture
54
Pathological fracture
55
Pelvic fracture
56
Periprosthetic fracture
57
Pseudarthrosis
58
Pubis fracture
59
Radius fracture
60
Rib fracture
61
Sacroiliac fracture
62
Scapula fracture
63
Scapulothoracic dissociation


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 55
19 March 2018
Selected Preferred Terms
64
Skull fracture
65
Skull fractured base
66
Spinal compression fracture
67
Spinal fracture
68
Spinal fusion fracture
69
Sternal fracture
70
Stress fracture
71
Thoracic vertebral fracture
72
Tibia fracture
73
Torus fracture
74
Traumatic fracture
75
Ulna fracture
76
Upper limb fracture
77
Wrist fracture
78
Bone formation test
79
Bone formation test abnormal
80
Bone metabolism biochemical marker increased
81
Bone resorption test
82
Bone resorption test abnormal
83
C-telopeptide
84
C-telopeptide increased
85
Deoxypyridinoline urine
86
Deoxypyridinoline urine increased
87
N-telopeptide
88
N-telopeptide urine
89
N-telopeptide urine abnormal
90
N-telopeptide urine decreased
91
N-telopeptide urine increased
92
N-telopeptide urine normal
93
Osteocalcin
94
Osteocalcin decreased
95
Osteocalcin increased
96
Osteoprotegerin


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19 March 2018
Selected Preferred Terms
97
Osteoprotegerin decreased
98
Osteoprotegerin increased
99
Osteoprotegerin ligand
100
Osteoprotegerin ligand decreased
101
Pyridinoline urine
102
Pyridinoline urine decreased
103
Pyridinoline urine increased
104
Tartrate-resistant acid phosphatase
105
Tartrate-resistant acid phosphatase decreased
106
Alveolar osteitis
107
Aneurysmal bone cyst
108
Bone callus excessive
109
Bone contusion
110
Bone cyst
111
Bone development abnormal
112
Bone disorder
113
Bone erosion
114
Bone fistula
115
Bone formation decreased
116
Bone formation increased
117
Bone hyperpigmentation
118
Bone infarction
119
Bone lesion
120
Bone loss
121
Callus formation delayed
122
Cemento osseous dysplasia
123
Cystic angiomatosis
124
Dental alveolar anomaly
125
Dental cyst
126
Enostosis
127
Erdheim-Chester disease
128
Exostosis
129
Exostosis of external ear canal


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Statistical Analysis Plan – Week 24 Analysis
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CONFIDENTIAL
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19 March 2018
Selected Preferred Terms
130
Exostosis of jaw
131
Exposed bone in jaw
132
Extraskeletal ossification
133
Hyperphosphatasaemia
134
Hypertrophic osteoarthropathy
135
Inadequate osteointegration
136
Jaw cyst
137
Jaw disorder
138
Jaw fistula
139
Medial tibial stress syndrome
140
Melorheostosis
141
Osteitis
142
Osteitis condensans
143
Osteitis deformans
144
Osteonecrosis
145
Osteonecrosis of external auditory canal
146
Osteonecrosis of jaw
147
Osteoradionecrosis
148
Osteorrhagia
149
Osteosclerosis
150
Osteosis
151
Periosteal haematoma
152
Periostitis
153
Periostitis hypertrophic
154
Periostosis
155
Periprosthetic osteolysis
156
Post transplant distal limb syndrome
157
Post-traumatic osteoporosis
158
Primary sequestrum
159
Radiation osteitis
160
Secondary sequestrum
161
Skeletal injury
162
Spinal column injury


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 58
19 March 2018
Selected Preferred Terms
163
Spinal disorder
164
Sternal injury
165
Tertiary sequestrum
166
Vertebral column mass
167
Vertebral lesion
168
Vertebral wedging
169
Bone atrophy
170
Itai-itai disease
171
Bone decalcification
172
Bone metabolism disorder
173
Brown tumour
174
Chronic kidney disease-mineral and bone disorder
175
Craniotabes
176
Gorham's disease
177
Hereditary hypophosphataemic rickets
178
High turnover osteopathy
179
Hungry bone syndrome
180
Hypochondroplasia
181
Hypophosphataemic rickets
182
Low turnover osteopathy
183
Oncogenic osteomalacia
184
Osteolysis
185
Osteomalacia
186
Osteopenia
187
Osteoporosis
188
Osteoporosis circumscripta cranii
189
Osteoporosis postmenopausal
190
Osteoporotic fracture
191
Rachitic rosary
192
Resorption bone decreased
193
Resorption bone increased
194
Rickets
195
Senile osteoporosis


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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19 March 2018
Selected Preferred Terms
196
Spinal compression fracture
197
Bone marrow oedema
198
Bone marrow oedema syndrome
199
Bone pain
200
Bone swelling
201
Coccydynia
202
Eagle's syndrome
203
Metatarsalgia
204
Os trigonum syndrome
205
Pain in jaw
206
Pubic pain
207
Spinal pain
208
Astragalectomy
209
Bone cyst excision
210
Bone debridement
211
Bone electrostimulation therapy
212
Bone graft
213
Bone graft removal
214
Bone lesion excision
215
Bone operation
216
Bone prosthesis insertion
217
Bone trimming
218
Cementoplasty
219
Epiphyseal surgery
220
Epiphysiodesis
221
Orthopaedic procedure
222
Ostectomy
223
Osteomyelitis drainage
224
Osteopathic treatment
225
Osteosynthesis
226
Osteotomy
227
Removal of epiphyseal fixation
228
Removal of internal fixation


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Statistical Analysis Plan – Week 24 Analysis
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CONFIDENTIAL
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19 March 2018
Selected Preferred Terms
229
Sequestrectomy
230
Calcification metastatic
231
Parathyroid hyperplasia
232
Gastric mucosal calcinosis
233
Calciphylaxis
234
Calcium deficiency
235
Calcium intoxication
236
Calcium metabolism disorder
237
Chondrocalcinosis pyrophosphate
238
Chvostek's sign
239
Dent's disease
240
Familial hypocalciuric hypercalcaemia
241
Hypercalcaemia
242
Hypercalcaemia of malignancy
243
Hypercalcaemic nephropathy
244
Hypercalcitoninaemia
245
Hypercalciuria
246
Hypocalcaemia
247
Hypocalcaemic seizure
248
Hypocalciuria
249
Hypoparathyroidism
250
Hypoparathyroidism secondary
251
Latent tetany
252
Neonatal hypocalcaemia
253
Periarthritis calcarea
254
Primary familial brain calcification
255
Primary hypoparathyroidism
256
Pseudohypercalcaemia
257
Pseudohypoparathyroidism
258
Tetany
259
Tooth demineralisation
260
Trousseau's sign
261
Williams syndrome


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 61
19 March 2018
Selected Preferred Terms
262
Congenital syphilitic osteochondritis
263
Epiphyseal disorder
264
Epiphyseal injury
265
Epiphyses delayed fusion
266
Epiphyses premature fusion
267
Epiphysiolysis
268
Epiphysitis
269
Closed fracture manipulation
270
External fixation of fracture
271
Fracture debridement
272
Fracture reduction
273
Fracture treatment
274
Fractured maxilla elevation
275
Fractured zygomatic arch elevation
276
Internal fixation of fracture
277
Intramedullary rod insertion
278
Open reduction of fracture
279
Skeletal traction
280
Surgical fixation of rib fracture
281
Ankle fracture
282
Atypical femur fracture
283
Clavicle fracture
284
Epiphyseal fracture
285
Femoral neck fracture
286
Femur fracture
287
Fibula fracture
288
Foot fracture
289
Forearm fracture
290
Fracture of clavicle due to birth trauma
291
Greenstick fracture
292
Hand fracture
293
Hip fracture
294
Humerus fracture


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 62
19 March 2018
Selected Preferred Terms
295
Limb fracture
296
Lisfranc fracture
297
Lower limb fracture
298
Osteochondral fracture
299
Patella fracture
300
Radial head dislocation
301
Radius fracture
302
Scapula fracture
303
Scapulothoracic dissociation
304
Tibia fracture
305
Torus fracture
306
Ulna fracture
307
Upper limb fracture
308
Wrist fracture
309
Amputation
310
Arm amputation
311
Calcanectomy
312
Finger amputation
313
Finger repair operation
314
Foot amputation
315
Foot operation
316
Gluteoplasty
317
Hand amputation
318
Hand repair operation
319
Hip disarticulation
320
Interscapulothoracic amputation
321
Leg amputation
322
Limb amputation
323
Limb immobilisation
324
Limb operation
325
Limb reattachment surgery
326
Limb reconstructive surgery
327
Metacarpal excision


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 63
19 March 2018
Selected Preferred Terms
328
Metatarsal excision
329
Microsurgery to hand
330
Rotationplasty
331
Talipes correction
332
Toe amputation
333
Toe operation
334
Trapeziectomy
335
Alveolar bone resorption
336
Itai-itai disease
337
Bone atrophy
338
Bone decalcification
339
Bone metabolism disorder
340
Brown tumour
341
Chronic kidney disease-mineral and bone disorder
342
Dwarfism
343
High turnover osteopathy
344
Hungry bone syndrome
345
Low turnover osteopathy
346
Oncogenic osteomalacia
347
Osteodystrophy
348
Osteolysis
349
Osteomalacia
350
Osteopenia
351
Osteoporosis
352
Osteoporosis circumscripta cranii
353
Osteoporosis postmenopausal
354
Renal rickets
355
Resorption bone decreased
356
Resorption bone increased
357
Rickets
358
Senile osteoporosis
359
Aspiration bursa
360
Aspiration bursa abnormal


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GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 64
19 March 2018
Selected Preferred Terms
361
Aspiration bursa normal
362
Aspiration joint
363
Aspiration joint abnormal
364
Aspiration joint normal
365
Biopsy abdominal wall
366
Biopsy abdominal wall abnormal
367
Biopsy abdominal wall normal
368
Biopsy bone
369
Biopsy bone abnormal
370
Biopsy bone normal
371
Biopsy cartilage
372
Biopsy cartilage abnormal
373
Biopsy cartilage normal
374
Biopsy chest wall
375
Biopsy chest wall abnormal
376
Biopsy chest wall normal
377
Biopsy ligament
378
Biopsy ligament abnormal
379
Biopsy ligament normal
380
Biopsy muscle
381
Biopsy muscle abnormal
382
Biopsy muscle normal
383
Biopsy soft tissue
384
Biopsy tendon
385
Biopsy tendon abnormal
386
Biopsy tendon normal
387
Intervertebral disc biopsy
388
Synovial biopsy
389
Synovial biopsy abnormal
390
Synovial fluid cell count
391
Synovial fluid crystal
392
Synovial fluid crystal present
393
Synovial fluid red blood cells


TAF
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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 65
19 March 2018
Selected Preferred Terms
394
Synovial fluid red blood cells positive
395
Synovial fluid white blood cells
396
Synovial fluid white blood cells positive
397
Arthrogram
398
Arthrogram abnormal
399
Arthrogram normal
400
Arthroscopy
401
Arthroscopy abnormal
402
Arthroscopy normal
403
Bone densitometry
404
Bone density abnormal
405
Bone density decreased
406
Bone density increased
407
Bone scan
408
Bone scan abnormal
409
Bone scan normal
410
Discogram
411
Discogram abnormal
412
Discogram normal
413
Face and mouth X-ray
414
Face and mouth X-ray abnormal
415
Face and mouth X-ray normal
416
Orthoroentgenogram
417
Skeletal survey
418
Skeletal survey abnormal
419
Skeletal survey normal
420
Skull X-ray
421
Skull X-ray abnormal
422
Skull X-ray normal
423
Spinal X-ray
424
Spinal X-ray abnormal
425
Spinal X-ray normal
426
Ultrasound joint


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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 66
19 March 2018
Selected Preferred Terms
427
X-ray limb
428
X-ray limb abnormal
429
X-ray limb normal
430
X-ray of pelvis and hip
431
X-ray of pelvis and hip abnormal
432
X-ray of pelvis and hip normal
433
Acetabulum fracture
434
Fractured ischium
435
Ilium fracture
436
Pelvic fracture
437
Pubis fracture
438
Sacroiliac fracture
439
Acute phosphate nephropathy
440
Hyperphosphataemia
441
Hyperphosphaturia
442
Hypophosphataemia
443
Phosphorus metabolism disorder
444
Pseudohyperphosphataemia
445
Renal rickets
446
Craniofacial fracture
447
Facial bones fracture
448
Fractured skull depressed
449
Jaw fracture
450
Skull fracture
451
Skull fractured base
452
Cervical vertebral fracture
453
Chance fracture
454
Dislocation of vertebra
455
Fractured coccyx
456
Fractured sacrum
457
Intervertebral disc injury
458
Lumbar vertebral fracture
459
Spinal compression fracture


TAF
GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 67
19 March 2018
Selected Preferred Terms
460
Spinal fracture
461
Spinal fusion fracture
462
Thoracic vertebral fracture
463
Atypical femur fracture
464
X-ray dental abnormal
465
Carpal collapse
466
Osteonecrosis
467
Osteonecrosis of external auditory canal
468
Osteonecrosis of jaw
469
Osteoradionecrosis
470
Abscess jaw
471
Abscess oral
472
Alveolar osteitis
473
Arthrodesis
474
Biopsy bone abnormal
475
Bone abscess
476
Bone debridement
477
Bone graft
478
Bone infarction
479
Bone loss
480
Bone pain
481
Bone scan abnormal
482
Candida osteomyelitis
483
Chronic recurrent multifocal osteomyelitis
484
Dental necrosis
485
Exposed bone in jaw
486
Face and mouth X-ray abnormal
487
Groin pain
488
Hip arthroplasty
489
Hip surgery
490
Jaw fistula
491
Jaw lesion excision
492
Jaw operation


TAF
GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 68
19 March 2018
Selected Preferred Terms
493
Joint arthroplasty
494
Joint prosthesis user
495
Joint resurfacing surgery
496
Maxillofacial operation
497
Oral surgery
498
Oroantral fistula
499
Osteitis
500
Osteoarthropathy
501
Osteomyelitis
502
Osteomyelitis acute
503
Osteomyelitis bacterial
504
Osteomyelitis blastomyces
505
Osteomyelitis chronic
506
Osteomyelitis drainage
507
Osteomyelitis fungal
508
Osteomyelitis salmonella
509
Osteomyelitis viral
510
Osteotomy
511
Pain in jaw
512
Periodontal destruction
513
Primary sequestrum
514
Resorption bone increased
515
Secondary sequestrum
516
Sequestrectomy
517
Staphylococcal osteomyelitis
518
Subperiosteal abscess
519
Tertiary sequestrum
520
Tooth abscess
521
Tooth infection
522
X-ray limb abnormal
523
X-ray of pelvis and hip abnormal
524
Bone density decreased
525
Serum procollagen type I N-terminal propeptide decreased


TAF
GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 69
19 March 2018
Selected Preferred Terms
526
Subchondral insufficiency fracture
527
Bone formation decreased
528
Bone loss
529
Bone marrow oedema syndrome
530
Osteopenia
531
Osteoporosis
532
Osteoporosis postmenopausal
533
Osteoporotic fracture
534
Resorption bone increased
535
Senile osteoporosis
536
Acetabulum fracture
537
Atypical femur fracture
538
Body height abnormal
539
Body height below normal
540
Body height decreased
541
Bone density abnormal
542
Bone formation test abnormal
543
Bone metabolism biochemical marker increased
544
Bone metabolism disorder
545
Bone resorption test abnormal
546
Cervical vertebral fracture
547
Closed fracture manipulation
548
C-telopeptide increased
549
Deoxypyridinoline urine increased
550
External fixation of fracture
551
Femoral neck fracture
552
Femur fracture
553
Forearm fracture
554
Fracture
555
Fracture treatment
556
Fractured ischium
557
Fractured sacrum
558
Hip arthroplasty


TAF
GS-US-320-3912
Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
Page 70
19 March 2018
Selected Preferred Terms
559
Hip fracture
560
Hip surgery
561
Ilium fracture
562
Internal fixation of fracture
563
Kyphoscoliosis
564
Kyphosis
565
Lumbar vertebral fracture
566
Multiple fractures
567
N-telopeptide urine increased
568
Open reduction of fracture
569
Open reduction of spinal fracture
570
Osteocalcin increased
571
Osteoporosis prophylaxis
572
Pathological fracture
573
Pelvic fracture
574
Post-traumatic osteoporosis
575
Pubis fracture
576
Pyridinoline urine increased
577
Radius fracture
578
Rib fracture
579
Sacroiliac fracture
580
Spinal compression fracture
581
Spinal deformity
582
Spinal fracture
583
Tartrate-resistant acid phosphatase decreased
584
Thoracic vertebral fracture
585
Vertebral body replacement
586
Vertebroplasty
587
Wrist fracture
588
Wrist surgery
589
Ankle arthroplasty
590
Ankle operation
591
Arthrectomy


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Statistical Analysis Plan – Week 24 Analysis
Version 1.0
CONFIDENTIAL
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Selected Preferred Terms
592
Arthrolysis
593
Arthroscopic surgery
594
Arthrotomy
595
Baker's cyst excision
596
Bone groove deepening
597
Bunion operation
598
Capsulorrhaphy
599
Delayed spinal fusion
600
Elbow operation
601
Epiphyseal injury
602
Flail chest
603
Incomplete spinal fusion
604
Knee arthroplasty
605
Knee operation
606
Ligament operation
607
Maxillonasal dysplasia
608
Meniscus operation
609
Meniscus removal
610
Patella replacement
611
Patellectomy
612
Radiolucency around implant
613
Radiotherapy to joint
614
Removal of foreign body from joint
615
Rheumatoid nodule removal
616
Rotator cuff repair
617
Shoulder arthroplasty
618
Shoulder operation
619
Synovectomy
620
Synoviorthesis
621
Temporomandibular joint surgery
622
Tophus removal operation

Prot_005.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety of Tenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Indication:
Chronic Hepatitis B
Protocol ID:
GS-US-320-3912
Gilead Study Director:
Name:
Telephone:
Fax:
Name:
Telephone:
Fax:
Protocol Version/Date:
Original:
07 June 2016
Amendment 1:
22 November 2016
Amendment 2:
28 March 2017
Amendment 3:           18 June 2019
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
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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....................................................................15
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................21
1.2.1.
General Information .............................................................................................................21
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................24
1.3.
Rationale and Risk/Benefit Assessment for this Study ..........................................................................42
1.4.
Rationale for Dose Selection..................................................................................................................43
1.5.
Compliance ............................................................................................................................................43
2.
OBJECTIVES.....................................................................................................................................................44
3.
STUDY DESIGN................................................................................................................................................45
3.1.
Endpoints ...............................................................................................................................................45
3.1.1.
Primary Endpoints................................................................................................................45
3.1.2.
Secondary Endpoints............................................................................................................45
3.1.3.
Other Endpoints of Interest ..................................................................................................45
3.2.
Study Design..........................................................................................................................................46
3.3.
Study Treatments ...................................................................................................................................47
3.4.
Duration of Treatment............................................................................................................................47
3.5.
End of Study...........................................................................................................................................47
3.6.
Biomarker Testing..................................................................................................................................47
3.6.1.
Biomarker Samples to Address the Study Objectives ..........................................................47
3.6.2.
Biomarker Samples for Optional Future Research...............................................................48
3.6.3.
48
3.6.4.
48
4.
SUBJECT POPULATION..................................................................................................................................49
4.1.
Number of Subjects and Subject Selection ............................................................................................49
4.2.
Inclusion Criteria....................................................................................................................................49
4.3.
Exclusion Criteria...................................................................................................................................50
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................52
5.1.
Randomization, and Treatment Codes ...................................................................................................52
5.2.
Description and Handling of Tenofovir Alafenamide (TAF).................................................................52
5.2.1.
Formulation..........................................................................................................................52
5.2.2.
Packaging and Labeling .......................................................................................................52
5.2.3.
Storage and Handling...........................................................................................................52
5.3.
Dosage and Administration of TAF.......................................................................................................53
5.4.
Prior and Concomitant Medications.......................................................................................................53
5.5.
Accountability for Tenofovir Alafenamide (TAF).................................................................................54
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................55
6.
STUDY PROCEDURES ....................................................................................................................................56
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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................56
6.2.
Pretreatment Assessments......................................................................................................................56
6.2.1.
Screening Visit (Day −45 to Day 1 of Treatment) ...............................................................56
6.2.2.
Baseline Assessments (Day 1)..............................................................................................58
6.3.
Treatment Assessments..........................................................................................................................59
6.3.1.
Study Week Assessments (Weeks 4-48) ..............................................................................59
6.3.2.
.61
6.3.3.
Early Discontinuation (ED) Visit .........................................................................................62
6.4.
Post-Treatment Assessments..................................................................................................................64
6.4.1.
All Other Subjects Who Discontinue TAF...........................................................................64
6.5.
Assessments for Premature Discontinuation from Study.......................................................................64
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................65
6.7.
.65
6.8.
66
6.9.
Resistance Surveillance..........................................................................................................................66
6.10.
End of Study...........................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69
7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Toxicity Management ............................................................................................................................71
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................72
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................72
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.5.4.
Management of Bone Evaluation.........................................................................................72
7.5.5.
Management of Potential Nephrotoxicity.............................................................................73
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................74
7.5.7.
Management of Ocular Safety..............................................................................................76
7.6.
Special Situations Reports......................................................................................................................76
7.6.1.
Definitions of Special Situations..........................................................................................76
7.6.2.
Instructions for Reporting Special Situations.......................................................................77
8.
STATISTICAL CONSIDERATIONS................................................................................................................79
8.1.
Analysis Objectives and Endpoints........................................................................................................79
8.1.1.
Analysis Objectives..............................................................................................................79
8.1.2.
Primary Endpoint .................................................................................................................80
8.1.3.
Secondary Endpoint .............................................................................................................80
8.1.4.
Other Endpoints of Interest ..................................................................................................80
8.2.
Analysis Conventions.............................................................................................................................81
8.2.1.
Analysis Sets ........................................................................................................................81
8.3.
Data Handling Conventions ...................................................................................................................81
8.4.
Demographic Data and Baseline Characteristics ...................................................................................82
8.5.
Efficacy Analysis ...................................................................................................................................82
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8.5.1.
Primary Analysis..................................................................................................................82
8.5.2.
Secondary Analyses .............................................................................................................82
8.6.
Safety Analysis.......................................................................................................................................82
8.6.1.
Primary Safety Analysis.......................................................................................................82
8.6.2.
Secondary Safety Analyses ..................................................................................................82
8.6.3.
Extent of Exposure...............................................................................................................83
8.6.4.
Adverse Events.....................................................................................................................83
8.6.5.
Laboratory Evaluations ........................................................................................................83
8.7.
Pharmacokinetic Analysis......................................................................................................................83
8.8.
Biomarker Analysis................................................................................................................................84
8.9.
Sample Size............................................................................................................................................84
8.10.
Data Monitoring Committee ..................................................................................................................84
9.
RESPONSIBILITIES..........................................................................................................................................85
9.1.
Investigator Responsibilities ..................................................................................................................85
9.1.1.
Good Clinical Practice..........................................................................................................85
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................85
9.1.3.
Informed Consent.................................................................................................................85
9.1.4.
Confidentiality......................................................................................................................86
9.1.5.
Study Files and Retention of Records ..................................................................................86
9.1.6.
Case Report Forms...............................................................................................................87
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................88
9.1.8.
Inspections............................................................................................................................88
9.1.9.
Protocol Compliance............................................................................................................88
9.2.
Sponsor Responsibilities ........................................................................................................................88
9.2.1.
Protocol Modifications.........................................................................................................88
9.2.2.
Study Report and Publications .............................................................................................89
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................89
9.3.1.
Payment Reporting...............................................................................................................89
9.3.2.
Access to Information for Monitoring..................................................................................89
9.3.3.
Access to Information for Auditing or Inspections ..............................................................90
9.3.4.
Study Discontinuation..........................................................................................................90
10.
REFERENCES ...................................................................................................................................................91
11.
APPENDICES ....................................................................................................................................................94
Appendix 1.
Investigator Signature Page....................................................................................................95
Appendix 2.
Study Procedures Table..........................................................................................................96
Appendix 3.
100
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................101
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............102
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................124
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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................27
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) ........................................28
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) ...................................................................................................................................29
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) .............................30
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set)...........................................................32
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................33
Table 1-7.
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)...........................................................................................................................34
Table 1-8.
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)...........35
Table 1-9.
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) ..........................................37
Table 1-10.
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)...................38
Table 1-11.
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) .........................40
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution.....................................54
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................46


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy 
and Safety of Tenofovir Alafenamide (TAF) versus Tenofovir 
Disoproxil Fumarate (TDF)–containing Regimens in Subjects with 
Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant
Clinical Trials.gov 
Identifier:
NCT02862548
Study Centers Planned:
Approximately 1 center in New Zealand
Objectives:
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at 
Week 24
The secondary objectives of this study are as follows: 

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the percent change 
from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 48

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at
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The exploratory objectives of this study are as follows:
 
 
 
 
 
Study Design:
This is a randomized, open-label, single center Phase 2 study to 
evaluate the safety and efficacy of TAF 25 mg QD versus TDF in 
adult chronic hepatitis B infection (CHB) subjects with Stage 2 or 
greater chronic kidney disease and have received a liver transplant.
Approximately 50 subjects will be randomized in a 1:1 ratio to 
either continue current treatment regimen with TDF alone or in 
combination with other approved antivirals or to receive TAF 
25 mg PO daily. Approximately 40 of 50 subjects will be enrolled 
with eGFRCKD-EPI < 60 ml/min/1.73m2. 
Randomization will be stratified by baseline renal function 
(eGFRCKD-EPI < 50 ml/min/1.73m2 and ≥50 ml/min/1.73m2) 

Treatment Arm A: approximately 25 subjects administered 
TAF 25 mg oral daily

Treatment Arm B: approximately 25 subjects to continue 
administration of TDF alone or in combination with other 
approved antivirals as per local practice
 
 
 
 
 
The primary analysis will occur at Week 24 with the primary 
efficacy endpoint being the maintenance of viral suppression 
(HBV DNA < 20 IU/mL).
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Number of Subjects 
Planned:
Approximately 50
Target Population:
Adult subjects with CHB who are currently virally suppressed, 
receiving TDF alone or in combination with other approved 
antivirals as per local practice, with Stage 2 or greater chronic 
kidney disease and have received a liver transplant.
Duration of Treatment:
TAF will be administered orally once daily for 48 weeks for 
subjects in Treatment Arm A. Subjects in Treatment Arm B will 
continue on TDF alone or in combination with other approved 
antivirals. 
 
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be 
eligible to participate in the study:
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, over 18 years of 
age based on the date of the screening visit
3) Documented evidence of chronic HBV infection prior to 
transplantation 
4) Primary or secondary (re-transplant), liver alone or liver and
kidney transplant recipient from deceased or living donor 
5) Liver Transplant ≥ 12 weeks prior to screening
6) Maintained on TDF alone or in combination with other 
approved antivirals for HBV prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 
12 weeks post-transplant prior to screening, with 
HBV DNA < LLOQ at screening
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8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) 
must have a negative serum pregnancy test at Screening and a 
negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible to participate in the study:
1) Multi-organ transplant that includes heart or lung recipient 
(subjects who have their liver transplant as part of a 
liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular 
carcinoma (HCC) post-transplant and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic 
encephalopathy, hepatorenal syndrome, hepatopulmonary 
syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at 
screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on 
anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection 
requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 
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10) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g., basal cell skin cancer, etc.) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not 
eligible
11) Significant cardiovascular, pulmonary, or neurological disease
12) Use of investigational agents within 3 months of screening, 
unless allowed by the Sponsor
13) Use of any prohibited medications as described in Table 5-1
14) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
15) Known hypersensitivity to study drugs, metabolites or 
formulation excipients
16) Lactating females or those who may wish to become pregnant 
during the course of the study
Study Procedures/
Frequency:

Screening Visit

Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 20, 
24, 36, and 48
 
Screening assessments include:

Safety laboratory tests (chemistry, hematology, and 
coagulation) 

HBV DNA levels 

HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed)

HCV, HDV and HIV testing

Alpha-fetoprotein (AFP)

eGFRCKD-EPI

Hip and Spine DXA Scan

Urinalysis, urine drug screen

Serum beta human chorionic gonadotropin (β-hCG, for all 
female subjects of child-bearing potential)

Physical examination (with height and body weight), 
medical history, vital signs, concomitant medications, and 
adverse events
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On-treatment assessments include:

Safety laboratory tests (chemistry, hematology, and 
coagulation),urine pregnancy tests (for all female subjects of 
child-bearing potential), urinalysis, physical examination 
(with weight), vital signs, concomitant medications, and 
adverse events

Serum Renal Biomarkers including phosphate, Cystatin C at 
Baseline, Weeks 4, 12, 24, 48 , Early Discontinuation (ED),
 
 

Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobulin, uric acid and phosphate 
at Baseline, Weeks 4, 12, 24, 48, ED, 
 
nd ED 
Cr EDTA Renal Scan at Baseline, Week 48, 
 
 

Serum Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-terminal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathyroid hormone at 
Baseline, Weeks 4, 12, 24, 48, ED, 
 
and ED 
Hip and Spine DXA Scan at Screening, Weeks 24, 48, ED,
 
 

Fracture Risk Assessment will be evaluated at Baseline

HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed) 
at Baseline and Weeks 24, 48, ED, 
 

HBV DNA levels at Baseline and at each study visit thereafter, 

PBMC specimens are collected at Baseline, Weeks 24, and 48

Fibrotest® and vitamin D assessments at Baseline, 
Weeks 24, 48, ED,
 
 

Serum storage for potential resistance testing (sequencing and 
phenotypic analyses) at Baseline and at each study visit 
thereafter, 
 
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
Health Related Quality of Life (HRQoL) Surveys (SF-36, 
CLDQ, and WPAI) at Baseline, Weeks 24, 48, ED,
 
 

Single plasma PK samples at Baseline and at treatment visits 
through Week 48
 
 
 
 
 
See Section 6 for further information.
Test Product, Dose, and 
Mode of Administration:
Open label TAF will be supplied as 25 mg tablets for daily oral 
administration with food
Reference Therapy, 
Dose, and Mode of 
Administration:
Open-label TDF alone or in combination with or without other 
antivirals administered per local practice
Criteria for Evaluation:
Safety:
Adverse events (AEs) and clinical laboratory tests will be collected 
at every visit throughout the study, 
 
he proportion of subjects in 
each treatment arm with an AE leading to early discontinuation of 
study drug(s) and proportion of subjects with serious adverse events 
will be summarized through Weeks 24, 48, 
 
The primary safety endpoint is:

Change from baseline in eGFRCKD-EPI of TAF 25 mg QD versus 
TDF-containing regimens at Week 24 
The secondary safety endpoints are:

Percent change from baseline in hip and spine bone mineral 
density (BMD) of TAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48

Change from baseline in serum creatinine of TAF 25 mg QD 
versus TDF-containing regimens at Weeks 24 and 48

Change from baseline in eGFRCKD-EPI of TAF 25 mg QD versus 
TDF-containing regimens at Week 48
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Efficacy:
The primary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
The secondary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 48
Exploratory endpoints:
 
 
 
 
 
 
 
Pharmacokinetics:
All subjects will have single plasma PK samples drawn at each 
treatment visit through Week 48. At Weeks 8 and 24 the PK sample 
should be collected between 15 minutes and 4 hours post-dose.
 
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Statistical Methods:
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. The 
response rate for each treatment arm will be summarized.
A two-sided 95% confidence interval adjusted for the 
randomization stratification factor (the adjusted Mantel-Haenszel 
proportions), for the difference (TAF − TDF) in the proportion of 
subjects who maintained viral suppression (HBV DNA< 20 IU/mL) 
at Weeks 24, and 48 will be constructed. 
The change from baseline in eGFRCKD-EPI at Weeks 24, 48, 
will be summarized. 
The percent change from baseline in hip and spine BMD at 
Weeks 24, 48, 
 will be summarized. The change 
from baseline in serum creatinine at Weeks 24, 48, 
will be summarized. 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:
This is an exploratory study. No formal sample size calculation was 
performed.
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
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
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)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI/C
Cobicistat
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
DNA
Deoxyribonucleic acid
DXA
Dual energy x-ray absorptiometry
E2
Estradiol
EC
Ethics Committee


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E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)
IRB
Institutional review board
IV
Intravenous
IVRS
Interactive voice response system


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IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
PVE
Prothrombin time/ International normalized ratio
Pharmacovigilance and Epidemiology
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction


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TAF
tenofovir alafenamide
TAF Fumarate
tenofovir alafenamide fumarate, GS-7340-03
TDF
tenofovir disoproxil fumarate
TFFU
Treatment Free Follow-Up
TFV
tenofovir
TFV-DP
tenofovir diphosphate
TLOVR
Time to loss of virologic response
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
TSH
Thyroid stimulating hormone
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


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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}. Importantly, not all subjects will experience all phases of 
infection {Terrault 2015}. 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 


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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 
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 develop in the precore or core promoter region 
of the virus {Sarin 2015}. HBeAg-negative CHB affects about 10% of pediatric subjects 
{Sokal 2013}. The goal of anti-HBV therapy, in children as in adults, is to improve long-term 
survival and quality of life by reducing disease progression to cirrhosis, decompensated liver 
disease, and HCC {Sarin 2015, Sokal 2013}. As seroclearance of HBsAg is a rare spontaneous 
occurrence in children with CHB, durable anti-HBe seroconversion in HBeAg-positive subjects 
is considered a good 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}. As in adults, reduction 
of viremia to levels below assay detection can lead to reduced inflammation and slowing or 
reversal of fibrosis {Marcellin 2013, Sokal 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) 2012, Liaw 2012}. Additionally, while 
development of resistance to entecavir (ETV) is low in treatment-naive 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 6 years of use {Kitrinos 2014}.
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) 2012, Liaw 2012, 
Lok 2009}. Although highly effective, use of TDF is associated with nephrotoxicity and 
bone-related toxicity in some subjects.


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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 {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 the 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}. 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. A New Drug 
Application (NDA) for TAF 25 mg tablets was filed on 11-January, 2016 for the treatment of 
CHB in adults.
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 next generation 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 (GS-7340), in blood and biological 
fluids.
For further information on TAF (GS-7340), refer to the current investigator’s brochure for TAF.
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. 


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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 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, (GS-7340), 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.
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.


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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 tenofovir in the cells of the lymphoreticular system. The 
primary route of elimination of tenofovir 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. Tenofovir was the major 
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of 
tenofovir in dogs and fecal elimination of tenofovir in rats and dogs are negligible.
Tenofovir 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. 
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 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. 


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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, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program
for CHB includes 2 ongoing Phase 3 studies in hepatitis B e antigen (HBeAg)-negative and
HBeAg-positive subjects with CHB, a Phase 1b antiviral activity and safety/tolerability study in
subjects with CHB, as well as several Phase 1 safety, PK/pharmacodynamics (PD), and drug
interaction studies in healthy subjects (including Chinese and Japanese subjects) and in subjects
with impaired renal or hepatic function. 
In some studies, TAF was administered as a single agent or as part of the F/TAF,
FTC/RPV/TAF, or E/C/F/TAF FDC tablets. 
TAF clinical studies are listed below: 

GS-US-320-0101, a Phase 1b study to evaluate the pharmacokinetics, safety, viral kinetics,
and anti-HBV activity of TAF in treatment-naive adults with CHB (completed)
{Agarwal 2015}

GS-US-320-1228, a Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability
of TAF in healthy Japanese and non-Japanese subjects (completed)


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
GS-US-320-1229, a Phase 1 study to evaluate the pharmacokinetics of a single dose and
repeat doses of TAF 25 mg in healthy Chinese subjects (completed; data analysis is 
completed)

GS-US-320-1382, a Phase 1 study to evaluate the effect of food on a single dose of 
TAF 25 mg in healthy subjects (completed)

GS-US-320-1615, a Phase 1 study to evaluate the pharmacokinetics of a single dose of 
TAF 25 mg in subjects with severe hepatic impairment and subjects with normal liver 
function (completed)

GS-US-320-0108, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg 
once daily versus TDF 300 mg once daily for the treatment of HBeAg-negative subjects with 
CHB (ongoing)

GS-US-320-0110, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg
once daily versus TDF 300 mg once daily for the treatment of HBeAg-positive subjects with
CHB (ongoing)

GS-US-120-0108, a Phase 1, open-label, parallel-design study to evaluate the
pharmacokinetics of TAF in subjects with severe renal impairment (completed)

GS-US-120-0109, a Phase 1 mass balance study to evaluate the pharmacokinetics,
metabolism and excretion of TAF in healthy subjects (completed)

GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with
normal, mild, and moderately impaired hepatic function (completed)

GS-US-120-1538, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and MDZ (oral and intravenous) in healthy subjects (completed)

GS-US-120-1554, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and RPV in healthy subjects (completed)

GS-US-311-1386, a Phase 1 study that evaluated the effect of food on the PK of TAF and
FTC when administered as an F/TAF fixed-dose combination tablet in healthy subjects
(completed)

GS-US-311-1387, a Phase 1 study that evaluated the drug-drug interaction (DDI) potential
between CBZ and TAF administered as F/TAF in healthy subjects (completed)

GS-US-311-1790, a Phase 1 study that evaluated the DDI potential between F/TAF or
GS-9883 and norgestimate/ethinyl estradiol in healthy female subjects (completed)


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
GS-US-320-4018, a Phase 3, randomized (1:1), double-blind, multicenter, active-controlled 
study to evaluate the safety and efficacy of TAF 25 mg every day (QD) in virologically 
suppressed subjects who switch from TDF to TAF compared to continued TDF treatment 
(ongoing)

GS-US-320-4035, a Phase 2, open label, multi-center, single-arm study to evaluate the 
safety, tolerability, and efficacy of switching to TAF 25 mg QD in virologically suppressed 
subjects with CHB and renal impairment (moderate or severe renal impairment, or those with 
end-stage renal disease (ESRD) maintained on hemodialysis), and/or hepatic impairment 
(Child-Pugh-Turcotte Class B and C) (ongoing)

GS-US-320-1092, A Randomized, Double-Blind Evaluation of the Pharmacokinetics, Safety, 
and Antiviral Efficacy of Tenofovir Alafenamide (TAF) in Children and Adolescent Subjects 
with Chronic Hepatitis B Virus Infection (ongoing)

GS-US-320-1196, A Phase 1, Single-Dose, Cross-Over Study Evaluating the Relative 
Bioavailability of a Pediatric Oral Granule Formulation of Tenofovir Alafenamide in Healthy 
Adults (planned)
Please refer to the latest version of the investigator’s brochure for additional information.
An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below 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, subjects 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 are 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) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase 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 Subjectsa)
Data Presented
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 and GS-US-320-0110 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
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 (upper limit of normal 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 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 all time points from Week 8 onward using the 
M = F method.
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 at all time points from 
Weeks 8 through 48 using the M = F method.


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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. 
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.


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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 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 polymorphic site substitutions, and 
2 had a conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated 
with resistance to TFV were detected 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.
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; 


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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).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures 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.


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Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set)
Duration of Exposure to Study Regimen (Weeks)
GS-US-320-0108 and GS-US-320-0110
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
N
866
432
Mean (SD)
58.9 (14.71)
59.0 (15.58)
Median
56.1
56.1
Q1, Q3
48.1, 64.4
48.1, 64.7
Min, Max
0.1, 96.3
0.1, 96.3
Total Exposure to Study Drug n(%)
≥ 4 Weeks [28 days]
860 (99.3%)
426 (98.6%)
≥ 8 weeks [56 days]
858 (99.1%)
426 (98.6%)
≥ 12weeks [84 days]
854 (98.6%)
423 (97.9%)
≥ 16 Weeks [112 days]
851 (98.3%)
422 (97.7%)
≥ 20 Weeks [140 days]
851 (98.3%)
422 (97.7%)
≥ 24 Weeks [168 days]
851 (98.3%)
419 (97.0%)
≥ 28 Weeks [196 days]
849 (98.0%)
418 (96.8%)
≥ 32 Weeks [224 days]
843 (97.3%)
418 (96.8%)
≥ 36 Weeks [252 days]
838 (96.8%)
418 (96.8%)
≥ 40 Weeks [280 days]
835 (96.4%)
418 (96.8%)
≥ 44 Weeks [308 days]
832 (96.1%)
418 (96.8%)
≥ 48 Weeks [336 days]
669 (77.3%)
346 (80.1%)
Duration of exposure to blinded study drug was the number of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date of blinded study drug.
Source: TAF Week 48 ISS, Table 4
CCI


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Adverse Events for the TAF Phase 3 Safety Population (Week 48)
Summary of Adverse Events
Table 1-6 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).
Table 1-6.
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


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Common Adverse Events
Table 1-7 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)
Table 1-7.
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.


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Serious Adverse Events
Table 1-8 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.
Table 1-8.
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.


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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 %)
Table 1-9 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.


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Table 1-9.
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
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 


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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 1-10 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 was 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).
Table 1-10.
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


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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 1-11 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 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 1-11.
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


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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 (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:


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
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

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.
1.3.
Rationale and Risk/Benefit Assessment for this Study
While the number of liver transplants for CHB consequences is low in the United States 
(~350/year), in countries with high prevalence of CHB, HBV remains the most important cause 
of liver transplantation {Lee 2015}. Without prophylaxis, patients with CHB receiving a liver 
transplant have near universal re-infection of the graft {Samuel 1993}. Current practice is to treat
prior and post-transplant patients with oral nucleos(t)ide polymerase inhibitors and Hepatitis B 
Immunoglobulin (HBIG) to prevent infection of the new liver. Study 203-0107 demonstrated in a 
small group of post-liver transplant patients that treatment with TDF/FTC alone was equivalent 
to TDF/FTC + HBIG after 72 weeks of follow-up {Teperman 2013}.With these interventions, 
infection of the graft has been reduced to < 10% {Katz 2010}. While practice patterns for 
continuation of HBIG can vary by center, all patients must remain on lifelong nucleos(t)ide 
analog treatment. 
After receiving a liver transplant, the majority of patients develop some degree of chronic kidney 
disease, with over 18% having a GFR< 30 ml/min within 5 years of transplant mainly as a result 
of the use of calcineurin inhibitors (CNI) {Lucey 2013, Ojo 2003}. CNIs are a mainstay of 
immunosuppression immediately after transplantation and can lead to acute or chronic kidney 
injury through hemodynamic changes or direct nephrotoxic effects. While some centers reduce 
or eliminate CNIs from immunosuppressive regimens over time, many continue patients lifelong 
on CNIs. Even in those patients who stop CNIs, the renal effects are often not reversible. This 
persistent renal dysfunction, therefore, can complicate antiviral treatment with medications such 
as TDF. 


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For these patients who have received a liver transplant and have renal insufficiency, TAF may 
provide an alternative to currently used treatments by achieving viral suppression while resulting 
in improved safety of bone and renal parameters compared to TDF-based regimens.
1.4.
Rationale for Dose Selection
A 25-mg dose of TAF was selected for use in the Phase 3 non-inferiority studies based upon the 
magnitude of HBV DNA decline, systemic TFV exposure, and the safety profile. In
Study GS-US-320-0101, the magnitude of HBV DNA decreases observed over 28 days in
subjects with CHB given TAF at doses of 8, 25, 40, and 120 mg were similar indicating a lack of 
dose effect; these decreases were also comparable with the TDF 300-mg dose, which is the dose 
of TDF approved for treatment of CHB. In subjects who received TAF 25 mg, reduced systemic 
TFV exposures (approximately 92%) were observed relative to those who received the TDF 
300-mg dose, which is consistent with data in HIV-infected subjects who received TAF 25 mg as 
a single agent in Study GS-US-120-0104.
The selection of 25 mg TAF dose in this study is further supported by the results from the 
dedicated severe renal impairment study (GS-US-120-0108). In that study, plasma TAF exposure 
in subjects with severe renal impairment was less than 2-fold higher than TAF exposure in 
matched controls with normal renal function. For TFV, mean AUC was ~6-fold higher in renally 
impaired subjects as compared to matched controls. Importantly, TFV exposure was within the 
range of TFV exposures achieved following administration of a TDF-containing regimen in 
subjects with normal renal function. As such, dose adjustment of TAF in severe renal impairment 
was not warranted.
The PK/PD relationship between TAF plasma exposure and efficacy was also explored using 
data from the Phase 3 Studies GS-US-320-0108 and GS-US-320-0110. Importantly, in both 
studies virologic suppression (HBV DNA < 29 IU/mL) was uniform across the categories of 
TAF exposures, with no trends in exposure-response relationship observed.
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 versus TDF-containing regimens as 
determined by the change from baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus TDF-containing regimens in maintaining
viral suppression at Week 24
The secondary objectives of this study are:

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the change from baseline in eGFRCKD-EPI at Week 48

To evaluate the efficacy of TAF 25 mg QD versus TDF-containing regimens in maintaining
viral suppression at Week 48
The exploratory objectives of this study are:
 
 
 
CCI


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3.
STUDY DESIGN
3.1.
Endpoints
3.1.1.
Primary Endpoints
The primary safety endpoint is:

Change from baseline in eGFRCKD-EPI of TAF 25 mg QD versus TDF-containing regimens at 
Week 24
The primary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 24
3.1.2.
Secondary Endpoints
The secondary safety endpoints are:

Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48

Change from baseline in serum creatinine of TAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48

Change from baseline in eGFRCKD-EPI of TAF 25 mg QD versus TDF-containing regimens at 
Week 48
The secondary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
3.1.3.
Other Endpoints of Interest
The exploratory endpoints of this study are:
 
 
CCI


CCI
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3.2. 
Study Design 
Final 
Amendment 3 
This is a randomized, open label study to evaluate the antiviral activity ofTAF 25 mg QD versus 
TDF (dose per the local label) containing regimens. Approximately fifty (50) adult CHB subjects 
with Stage 2 or greater chronic kidney disease and have received a liver transplant will be eligible 
for emollment. They will be randomized in a 1:1 ratio (A: B) to the treatment anns for 48 weeks. 
Approximately 40 of 50 subjects will be emolled with eGFRcKD-EPI < 60 ml/min/1.73m2. 
Figure 3-1. 
CONFIDENTIAL 
Study Schema 
Screening 
Randomization 1:1 (A: B) 
Arm A: TAF 25mg QD 
Week48 
Page46 
Arm B: TDF (dose per the local 
label) alone or in combination 
Treatment Free Follow-Up Phase 
subjects followed for 24 weeks after 
the discontinuation ofTAF or until 
and alternative CHB treatment is 
started, whichever occurs first 
18 Jtme 2019 


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3.3.
Study Treatments
Approximately 50 subjects with CHB and Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be assigned to one of the two treatment arms (A: B) for 48 weeks. 
Randomization will be stratified by baseline renal function (eGFRCKD-EPI < 50 ml/ min/1.73m2
and ≥50 ml/ min/1.73m2).

Treatment Arm A: approximately 25 subjects administered TAF 25 mg oral daily

Treatment Arm B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals per local practice
3.4.
Duration of Treatment
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to Screening, subjects will be randomized to receive TAF or TDF alone or in 
combination with approved antivirals per local practice.
At Week 48, per Principal Investigator (PI) discretion, subjects will be eligible to receive TAF 
25 mg daily and
 they will be followed for 24 weeks after the discontinuation of 
TAF (i.e., Treatment Free Follow-Up, TFFU) or until an alternative CHB treatment is started, 
whichever occurs first.
3.5.
End of Study
The end of the study will be the last subjects’ last observation or visit.
3.6.
Biomarker Testing
3.6.1.
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 exploratory systemic and/or tissue specific biomarkers with study drug 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the bone and renal biomarkers –such as, C-type collagen sequence (CTX) and procollagen 
type 1 N-terminal propeptide (P1NP), retinol binding protein and beta-2-microglobulin. 
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. Samples 
may be stored by Gilead Sciences for a period of 15 years.
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects, who are 18 years or older, with chronic hepatitis B, currently virally 
suppressed with Stage 2 or greater chronic kidney disease and have received a liver transplant. 
They will be randomized 1:1 to receive TAF 25 mg or continue with TDF alone or in 
combination with other approved antivirals for 48 weeks. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
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, over 18 years of age based on the date of the 
screening visit
3) Documented evidence of chronic HBV infection prior to transplantation 
4) Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from 
deceased or living donor 
5) Liver Transplant ≥ 12 weeks prior to screening
6) Maintained on TDF alone or in combination with other approved antivirals for HBV 
prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 12 weeks post-transplant prior to 
screening, with HBV DNA < LLOQ at screening
8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) must have a negative serum 
pregnancy test at Screening and a negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Multi-organ transplant that includes heart or lung recipient (subjects who have their liver 
transplant as part of a liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant 
and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 28 days of the Baseline/Day 1 
visit
10) Malignancy within 5 years prior to screening, with the exception of specific cancers that are 
cured by surgical resection (e.g., basal cell skin cancer, etc) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not eligible
11) Significant cardiovascular, pulmonary, or neurological disease
12) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
13) Use of any prohibited concomitant medications as described in Table 5-1


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14) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
15) Known hypersensitivity to study drugs, metabolites or formulation excipients
16) Lactating females or those who may wish to become pregnant during the course of the study


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Treatment Codes
The randomization will be performed via an Interactive Voice Response System (IVRS) or 
Interactive Web Response System (IWRS), whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. Eligible subjects (n = 50) will be randomized in a 1:1 ratio to receive either TAF 
or continue on TDF alone or in combination with other approved antivirals for 48 weeks.
Randomization will be stratified by baseline renal function (eGFRCKD-EPI < 50 ml/min/1.73m2
and ≥50 ml/min/1.73m2).
5.2.
Description and Handling of Tenofovir Alafenamide (TAF)
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (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. 
5.2.2.
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 material. Each bottle is enclosed with 
a white, continuous-thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed, and aluminum-faced liner. 
Study drug(s) to be distributed to centers in NZ and other participating countries shall be labeled 
to meet applicable requirements of local regulations.
5.2.3.
Storage and Handling
Study drug TAF 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. 


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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.
5.3.
Dosage and Administration of TAF
Subjects will be randomly assigned (1:1) to receive one of the following treatments:

Treatment Arm A: approximately 25 subjects administered TAF 25 mg QD

Treatment Arm B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals alone or in combination with other approved 
antivirals per local practice
After 48 weeks, subjects in treatment arms A and B will be eligible to receive TAF 25 mg daily 
It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
TAF tablets are to be administered orally with food, taken at approximately the same time each 
day.
5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Investigational agents or devices for any indication

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)

Systemic chemotherapeutic agents 
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Treatment-experienced subjects (defined as subjects meeting all entry criteria [including 
HBV DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any 
nucleoside or nucleotide analogue) receiving oral antiviral treatment at Screening must continue 
their treatment regimen until the time of randomization/Baseline/Day 1, when it will be 
discontinued.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of TAF.
Examples of representative medications which are prohibited or to be used with caution
from 21 days prior to Day 1 through the end of treatment are listed below:
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution
Medication Class
Prohibited Medications
Medications to Be Used with Caution
Anticonvulsantsa
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungalsb
Itraconazole, Ketoconazole
Antimycobacterialsa
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplementsa
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
a
May result in a decrease in the concentration of TAF 
b
May result in an increase in the concentrations of TAF
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. 
5.5.
Accountability for Tenofovir Alafenamide (TAF)
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.


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Investigational product accountability records will be provided to the study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit and/or bottles number dispensed

Record the date, quantity of used and unused IMP kit and/or bottles returned, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the 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 kits and/or 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. 
The investigator must document any deviation from protocol procedures and notify the sponsor.
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 be randomized 
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 3.2. 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
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements. 
6.2.1.
Screening Visit (Day −45 to Day 1 of Treatment)
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 medical history, including Hepatitis B history and treatment history

Review of inclusion/exclusion criteria
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
Review of AEs and concomitant medications

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), body weight, and height

Perform DXA scan of spine and hip. DXA scan will be performed at any time during the 
Screening period and should be completed at least 14 days prior to the first dose of the study 
drug, in order to ensure an acceptable pre-dose DXA scan

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed 
as needed)
Other viral serology (HCV, HIV and HDV)
eGFRCKD-EPI
Serum β-hCG pregnancy test (for all female subjects of child-bearing potential)
Alpha-fetoprotein (AFP). Subjects with an AFP >50 ng/mL or other findings concerning 
HCC must have an appropriate evaluation (e.g., CT scan) to rule out HCC prior to being 
able to enter into the study

Obtain urine sample for urinalysis, and urine drug screen 

Record any serious adverse events (SAE) and all adverse events (AE) related to protocol 
mandated procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
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.


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6.2.2.
Baseline Assessments (Day 1)
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 medical history, HBV history and HBV treatment history on any changes since 
screening visit

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight

Review of inclusion/exclusion criteria

Review of AEs and concomitant medication

Complete the “Fracture Risk Assessment” (FRAX®) eCRF

Cr EDTA Renal Scan 

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed)
eGFRCKD-EPI
Blood sample for Vitamin D assessment 
Blood sample for Fibrotest®
Blood sample for PBMC 
Blood sample for PK
HBV resistance surveillance
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
Randomization

Fasting blood sample for bone, renal 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

Pregnancy test (for females of child-bearing potential; in case of a positive urine test, a serum 
pregnancy test will be done)
6.3.
Treatment Assessments
6.3.1.
Study Week Assessments (Weeks 4-48)
The following evaluations will be performed at Weeks 4-48 unless specified;

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit (Weeks 24, and 48 only)

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight (Weeks 12, 24, and 48 only) 

Perform symptom-driven physical examination including vital signs, and body weight 
(Weeks 4, 8, 20, and 36 only)

Review of AEs and concomitant medications

Cr EDTA Renal Scan (Week 48 only)

Perform DXA scan of spine and hip (Weeks 24 and 48 only)

Perform study drug accountability

Dispense study drugs 
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
Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) (Weeks 24 and 48 only)
eGFRCKD-EPI 
Blood sample for Fibrotest® (Weeks 24 and 48 only)
Blood sample for Vitamin D assessment (Weeks 24 and 48 only)
Blood sample for AFP (Weeks 24 and 48 only)
Blood sample for PK
Blood sample for PBMC (Weeks 24 and 48 only)
HBV resistance surveillance

Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose. Subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing, the plasma PK samples from these subjects can be collected anytime 
(not timed) (Weeks 8 and 24 only)

Urine pregnancy test (for all female subjects of child-bearing potential)

Urinalysis (Weeks 4, 12, 24, and 48 only)

Fasting blood sample for bone and renal biomarkers −no food or drinks, except water, at 
least 8 hours prior to blood collection (Weeks 4, 12, 24, and 48 only)

Fasting urine sample for renal biomarkers (Weeks 4, 12, 24, and 48 only)

Fasting blood sample for 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 (Weeks 24 and 48 only)
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6.3.3.
Early Discontinuation (ED) Visit
The ED visit should be performed within 14 days from notification of study discontinuation

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects 

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight 
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
Review of AEs and concomitant medications

Perform DXA scan of spine and hip

Perform study drug accountability

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
eGFRCKD-EPI
Blood sample for Fibrotest®
Blood sample for Vitamin D assessment
Blood sample for AFP 
HBV resistance surveillance

Urine pregnancy test (for all female subjects of child-bearing potential)

Urinalysis 

Fasting blood sample for bone and renal biomarkers −no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers 

Fasting blood sample for 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 
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6.4.
Post-Treatment Assessments
6.4.1.
All Other Subjects Who Discontinue TAF
Subjects who have received at least one dose of TAF and discontinue treatment prematurely
 
will be followed every 
4 weeks for 24 weeks off treatment in accordance with TFFU schedule of assessments or until 
initiation of alternative CHB therapy, whichever comes first. 
6.4.1.1.
Treatment Free Follow-Up (TFFU) Visit Assessments (± 7 Days)
The following evaluations will be performed at follow up visits for subjects when they 
discontinue TAF unless otherwise specified. For more details, refer to Appendix 2.

Review of AEs and concomitant medications

Symptom-directed physical examination

Collect vital signs and body weight

Urine pregnancy test (for all female subjects of child-bearing potential)

Urinalysis

Obtain blood samples for laboratory assessments as follows:
Serum chemistry, hematology and coagulation tests
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
eGFRCKD-EPI
HBV resistance surveillance
6.5.
Assessments for Premature Discontinuation from Study
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.
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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

Subjects with confirmed eGFRCKD-EPI of < 15 mL/min/1.73m2 at any time during the study 
will have their study drug permanently discontinued

Lack of efficacy (virologic failure) 

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 48 are not permitted to discontinue 
study drug prior to the Week 48 visit

Discontinuation of study drug for subjects 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

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
 
 
 
 
 
 
 
 
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6.9.
Resistance Surveillance
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for resistance 
mutations may be attempted for all viremic subjects (HBV DNA ≥69 IU/mL). 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 virology sample for potential resistance surveillance will be collected at each study visit. 
6.10.
End of Study
The end of this study will be the last subject’s last observation (or visit).
CCI
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

Persistent or significant disability/incapacity


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
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 are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator 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 sub investigator 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 (e.g., 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 (e.g., 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 5). 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. AEs 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 (i.e., 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 Pharmacovigilance and Epidemiology (PVE), previously known 
as Drug Safety and Public Health, 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 30 days
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 PVE.

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 PVE 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, 
i.e., the eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead PVE:
Fax:
Email:
Medical Monitor:
Name: 
Telephone:
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.
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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 4.

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 5)

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 
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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.
Management of Potential Nephrotoxicity
eGFRCKD-EPI will be followed post-baseline during the study. All subjects on treatment with 
baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to <50 mL/min/1.73m2 at any 
post-baseline visit and those with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73m2 regardless of 
baseline eGFRCKD-EPI should have serum creatinine measured again within 3 calendar days of 
receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be 
measured and the estimated glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be 
calculated and compared with the baseline measurement of this parameter. 
7.5.5.1.
For subjects on TDF:

For subjects with baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to 
< 50 mL/min/1.73m2 at any post-baseline visit:
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, the 
subject will be required to undergo dose modification to every other day dosing of TDF
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, and 
the subject has undergone dose modification to every other day dosing of TDF and 
subsequently develops a confirmed eGFRCKD-EPI ≥ 50 mL/min/1.73m2, the subject may 
revert to once daily dosing of TDF after discussion with the Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73 m2 and
≥15 mL/min/1.73 m2:
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73m2 and ≥15 mL/min/1.73 m2, the
subject will be required to undergo dose modification to every 96 hours dosing of TDF
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73 m2 and ≥15 mL/min/1.73 m2, 
and the subject has undergone dose modification to once every 96 hours dosing of TDF
and subsequently develops a confirmed CLCr ≥ 30 mL/min/1.73 m2, the subject may 
revert to every other day dosing of study drug after discussion with the 
Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 15 mL/min/1.73 m2: 
If the eGFRCKD-EPI is confirmed to be <15 mL/min/1.73 m2, the subject will be required to 
permanently discontinue treatment according to Section 7.5.5.3
7.5.5.2.
For subjects on TAF:

If the eGFRCKD-EPI is confirmed to be ≥15 mL/min/1.73 m2, no dose modifications are 
required


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7.5.5.3.
For subjects on TAF or TDF:

All subjects with a confirmed eGFRCKD-EPI < 15 mL/min/1.73 m2 will be required to 
permanently discontinue treatment 

All subjects 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 two weeks of 
receipt of results
7.5.6.
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
7.5.6.1.
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.


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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.
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.
7.5.6.2.
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, 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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7.5.7.
Management of Ocular Safety
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.
Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
develops signs or symptoms of posterior uveitis, investigators should contact the Gilead 
Medical Monitor to discuss the need for additional ophthalmologic evaluation including dilated 
fundoscopy and optical coherence tomography (OCT).
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, 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).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure 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 duration of the study, including the protocol –
required post treatment follow-up period, to the Gilead PVE 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.
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 PVE. The subject should receive appropriate monitoring and 
care until the conclusion of the pregnancy. The outcome should be reported to Gilead PVE 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 PVE. Gilead PVE 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 PVE using the 
pregnancy and pregnancy outcome forms within 24 hours throughout the duration of the study, 
including the protocol–required post treatment follow-up period. 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 PVE, fax 
number 
 or email 
 Refer to Appendix 6 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.
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7.6.2.2.
Reporting Other Special Situations
All special situations reports (SSRs) will be recorded in the eCRF database within the timelines 
outlined in the eCRF completion guideline. 
Electronic Special Situations Report (eSSR) Reporting Process

Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event
throughout the duration of the study, including the protocol–required post treatment 
follow-up period. Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SSR information electronically, i.e., the eCRF 
database is not functioning, record the SSR on the paper serious adverse event reporting form 
and submit within 24 hours to:
Gilead PVE:
Email:
Fax:
Gilead Medical Monitor:
Name: 
Phone:
Fax:
Email:

As soon as it is possible to do so, any SSR reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

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 7.3 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.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the safety and tolerability of TAF 25 mg QD versus TDF-containing regimens as 
determined by the change from baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus TDF-containing regimens in maintaining
viral suppression at Week 24
The secondary objectives of this study are: 

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus TDF-containing regimens as determined by 
the change from baseline in eGFRCKD-EPI at Week 48 

To evaluate the efficacy of TAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48
The exploratory objectives of this study are:
 
 
 
 
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8.1.2.
Primary Endpoint
The primary safety endpoint is:

Change from baseline in eGFRCKD-EPI of TAF 25 mg QD versus TDF-containing regimens at 
Week 24 
The primary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 24
8.1.3.
Secondary Endpoint
The secondary safety endpoints are:

Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48

Change from baseline in serum creatinine of TAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48

Change from baseline in serum eGFRCKD-EPI of TAF 25 mg QD versus TDF-containing 
regimens at Week 48
The secondary efficacy endpoint is:

Proportion of subjects with HBV DNA < 20 IU/mL at Week 48
8.1.4.
Other Endpoints of Interest
The exploratory endpoints are:
 
 
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8.2.
Analysis Conventions
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 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment.
8.2.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the treatment actually received. All data collected during treatment will be included 
in the safety summaries. Data collected during TFFU will be summarized or listed separately. 
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are randomized and have received at least 
one dose of study medication and for whom concentration data of any analytes of interest
(eg, TAF and TFV) 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.
8.3.
Data Handling Conventions
For the primary endpoint missing data will be handled using a missing = failure approach, unless 
otherwise specified.
For key secondary safety endpoints, an analysis will be performed using the Last Observation 
Carried Forward (LOCF) method to impute the missing data.
For other categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach. For the drug resistant mutations endpoint, a missing = excluded 
approach will be employed.
Sensitivity analyses will be performed as warranted.
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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when the study subjects complete 24 weeks of 
the treatment period or discontinue prematurely. The response rate of each treatment arm will be 
presented. A two-sided 95% confidence interval, adjusted for the randomization stratification 
factor (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) in the 
proportion of subjects who maintained viral suppression (HBV DNA < 20 IU/mL) at 
Weeks 24 and 48 will be constructed.
8.5.2.
Secondary Analyses
The approach used for primary efficacy analysis will be applied for secondary efficacy endpoint
as in Section 8.5.1.
8.6.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last 
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment and TFFU periods will be included in data listings.
8.6.1.
Primary Safety Analysis
The change from baseline in eGFRCKD-EPI at Week 24 will be summarized.
8.6.2.
Secondary Safety Analyses
The change from baseline in eGFRCKD-EPI at Week 48 will be performed. 
The percent change from baseline in hip and spine BMD at Weeks 24 and 48 will be 
summarized.
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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 by treatment group. 
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 
treatment up to the date of last dose of treatment. 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 by treatment group.
8.6.5.
Laboratory Evaluations
Selected laboratory data (using 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 5. 
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 and including the date of 
last dose of treatment will be summarized by treatment group. If baseline data are missing, then 
any graded abnormality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing.
8.7.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for TAF and TFV using descriptive 
statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation.
 
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8.8.
Biomarker Analysis
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1
N-terminal propeptide (P1NP), and selected renal biomarkers, including urine retinol binding
protein, and urine beta-2-microglobulin, will be summarized by treatment group and visit using
descriptive statistics. 
8.9.
Sample Size
This is an exploratory study. No formal sample size calculation was performed.
8.10.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data once after 30 subjects have completed 12 weeks of treatment, and provide 
recommendation to Gilead whether 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, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design.
Subsequent meetings will be held on an ad hoc basis. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
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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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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. 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) 
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. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
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conducting the consent discussion, and also by an impartial witness if required by IEC or 
local requirements.
 
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, the IRB/IEC 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 in the lab 
manual. 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, IEC
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);

Documentation of the reason(s) a consented subject is not enrolled
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
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 
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 


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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, 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.
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 IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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.
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 
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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.
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of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic 
hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an 
expert panel on behalf of the European Society of Pediatric Gastroenterology, 
Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, et al. Randomized 
trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B 
immunoglobulin withdrawal after liver transplantation. Liver Transpl 2013;19 
(6):594-601.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2015.
World Health Organization (WHO). Guidelines for the Prevention, Care and Treatment of 
Persons with Chronic Hepatitis B Infection. 2015a.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015b.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 94
18 June 2019
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
CCI


PPD
PPD
PPD
Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment3 
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of 
Tenofovir Alafenamide (TAF) versus Tenofovir Disoproxil Fumarate 
Regimens in Subjects with Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant 
GS-US-320-3912, Amendment 3, 18 June 2019 
This protocol has been approved by Gilead Sciences, Inc. The foJlowing signature documents 
this approval. 
Author 
Date 
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. I 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, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 95 
18 June 2019 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 96
18 June 2019
Appendix 2.
Study Procedures Table
Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
ED
TFFUq
Visit
Windowsa
± 3 Days
± 7
Days
Written Informed 
Consent
X
Review of 
Inclusion/Exclusion 
Criteria 
X
X
Medical History, 
including HBV 
history
X
X
Review 
Concomitant 
Medications
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 
including vital 
signs, and weight 
X
X
X
X
X
X
Height
X
Symptom-directed 
Physical Exam
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXAc (spine & hip) 
X
X
X
X
FRAX® Fracture 
Risk Assessment 
Tool
X
CCI


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 97
18 June 2019
Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
ED
TFFUq
Visit
Windowsa
± 3 Days
± 7
Days
Cr EDTA renal scan
X
X
Study Drug 
Accountability
X
X
X
X
X
X
X
X
Study Drug 
Dispensed/Retrieved 
X
X
X
X
X
X
X
X
X
Dosing in-clinicd
X
X
Serum Chemistry 
and Liver Function 
Testse
X
X
X
X
X
X
X
X
X
X
X
eGFRCKD-EPI 
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
Cystatin C 
(for estimated GFR)
X
X
X
X
X
X
X
X
Plasma HBV DNA 
Levels 
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg 
(qualitative)f
X
X
X
X
X
X
Serum HBeAg 
(qualitative)f
X
X
X
X
X
X
Sample collection 
for HBV Resistance 
Surveillanceg
X
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
X
X
X
Fibrotest®
X
X
X
X
Vitamin D
X
X
X
X
CCI


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 98
18 June 2019
Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
ED
TFFUq
Visit
Windowsa
± 3 Days
± 7
Days
Whole blood for 
PBMC
X
X
X
Plasma PKm
X
X
X
X
X
X
X
X
Fasting Blood for 
Bone Biomarkersh
X
X
X
X
X
X
Fasting Blood for 
Renal Biomarkersh
X
X
X
X
X
X
Fasting Urine for 
Renal Biomarkersi
X
X
X
X
X
X
Fasting Metabolic 
Panelo
X
X
X
X
Serum Pregnancy 
Testj
X
Urine Pregnancy 
Testj
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
Urine drug screen
X
Health Related 
Quality of Life 
Surveysl
X
X
X
X
CCI
CCI


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 99
18 June 2019
Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
TFFUq
Visit
Windowsa
± 3 Days
± 7
Days
Imaging Testn
X
a
The out of visit window is ± 3 days until Week 48,
, and ± 7 days for TFFU visits. 
b
Vital signs include blood pressure, pulse, respiration rate, and temperature.
c
The initial DXA will be performed during Screening and should be completed at least 14 days prior to the first dose of study drug. The Week 48 DXA window is – 3 days 
only. DXA is required for Early Discontinuation (ED) visit if not done within the last 24 weeks.
d
It is preferred that subjects take their study drug according to a morning dosing schedule; subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 8 visits.
e
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). At Baseline, Weeks 24, 48, 96, 144 and 192/ED, subject will be fasting for serum glucose and metabolic panel. Coagulation panel will be 
done at Screening and then as a reflex only test for ALT flares.
f
Qualitative HBsAg and HBeAg will be performed at Screening, Baseline (BL), Weeks 24, 48, 72, 96, 120, 144, 168, 192 and ED. HBeAb and HBsAb testing will be 
performed as reflex testing as needed.
g
Sequence analysis of the HBV pol/RT for possible resistance mutation(s) may be attempted for any subject that experiences viremia (HBV DNA > 69 IU/mL).
h
Blood for selected bone biomarkers and renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected > 24 weeks prior.
i
Urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected > 24 weeks prior.
j
For female subjects of childbearing potential, the serum beta-HCG test will be performed at Screening. Urine test will be performed at all other visits as indicated. 
Positive urine test will be confirmed with serum test. Pregnancy tests should include prevention counseling. 
l
Health Related Quality of Life surveys included in this study are: SF-36, CLDQ, and WPAI. The surveys will be administered at BL, Weeks 24, 48, 96, 144, 192 and 
Early Discontinuation Visits, if applicable.
m
At Weeks 8 and 24 the plasma PK samples should be collected between 15 minutes and 4 hours post-dose.
n
At Screening, α-fetoprotein (AFP) will be measured and subjects with an AFP >50 ng/mL or other findings concerning HCC must undergo imaging test (e.g., CT scan) to rule 
out HCC.
o
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides)
p
At Week 48, per Principal Investigator (PI) discretion, subjects will be eligible to receive TAF 25 mg daily 
 
q
Subjects who have received at least one dose of TAF and discontinue treatment prematurely
 will be 
followed every 4 weeks for 24 weeks off treatment in accordance with TFFU visits or until initiation of alternative CHB therapy, whichever comes first. 
CCI
CCI
CCI
CCI
CCI
CCI


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 100
18 June 2019
Appendix 3.
CCI
CCI


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 101
18 June 2019
Appendix 4.
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 recurrences that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 102
18 June 2019
Appendix 5.
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 103
18 June 2019
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 104
18 June 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatermia 
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 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 105
18 June 2019
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 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 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)
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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
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


Tenofovir Alafenamide (TAF)
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CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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/Lto <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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Amendment 3
CONFIDENTIAL
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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


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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


Tenofovir Alafenamide (TAF)
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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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Gilead Sciences, Inc.
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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 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 
weakness 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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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 6.
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 orchiectomy 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.

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


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
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.
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.


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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.

Prot_002.pdf: 
Study Title: 
Sponsor: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety ofTenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fmnarate (TDF)-containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Chronic Hepatitis B 
GS-US-320-3912 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Fax: 
Original: 
Amendment 1 : 
Amendment 2: 
PD 
PPD 
PPD 
PPD 
PPD 
PPD 
07 June 2016 
22 November 2016 
28 March 2017 
CONFIDENTIALITY STATEMENT 
The infmmation contained in this docmnent, particularly unpublished data, is the propeliy 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 infmmation 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 infmmation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessru.y to obtain infmmed consent from those 
persons to whom the dmg may be administered. 


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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....................................................................15
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................21
1.2.1.
General Information .............................................................................................................21
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................24
1.3.
Rationale and Risk/Benefit Assessment for this Study ..........................................................................42
1.4.
Rationale for Dose Selection..................................................................................................................43
1.5.
Compliance ............................................................................................................................................43
2.
OBJECTIVES.....................................................................................................................................................44
3.
STUDY DESIGN................................................................................................................................................45
3.1.
Endpoints ...............................................................................................................................................45
3.1.1.
Primary Endpoints................................................................................................................45
3.1.2.
Secondary Endpoints............................................................................................................45
3.1.3.
Other Endpoints of Interest ..................................................................................................45
3.2.
Study Design..........................................................................................................................................46
3.3.
Study Treatments ...................................................................................................................................47
3.4.
Duration of Treatment............................................................................................................................47
3.5.
End of Study...........................................................................................................................................47
3.6.
Biomarker Testing..................................................................................................................................47
3.6.1.
Biomarker Samples to Address the Study Objectives ..........................................................47
3.6.2.
Biomarker Samples for Optional Future Research...............................................................48
3.6.3.
Biomarker Samples for Optional Genomic Research...........................................................48
3.6.4.
Intensive PK Substudy .........................................................................................................48
4.
SUBJECT POPULATION..................................................................................................................................49
4.1.
Number of Subjects and Subject Selection ............................................................................................49
4.2.
Inclusion Criteria....................................................................................................................................49
4.3.
Exclusion Criteria...................................................................................................................................50
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................52
5.1.
Randomization, and Treatment Codes ...................................................................................................52
5.2.
Description and Handling of Tenofovir Alafenamide (TAF).................................................................52
5.2.1.
Formulation..........................................................................................................................52
5.2.2.
Packaging and Labeling .......................................................................................................52
5.2.3.
Storage and Handling...........................................................................................................52
5.3.
Dosage and Administration of TAF.......................................................................................................53
5.4.
Prior and Concomitant Medications.......................................................................................................53
5.5.
Accountability for Tenofovir Alafenamide (TAF).................................................................................54
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................55
6.
STUDY PROCEDURES ....................................................................................................................................56


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................56
6.2.
Pretreatment Assessments......................................................................................................................56
6.2.1.
Screening Visit (Day −45 to Day 1 of Treatment) ...............................................................56
6.2.2.
Baseline Assessments (Day 1)..............................................................................................58
6.3.
Treatment Assessments..........................................................................................................................59
6.3.1.
Study Week Assessments (Weeks 4-48) ..............................................................................59
6.3.2.
Study Week Assessments for Optional Treatment Extension Phase 
(Weeks 48-144)....................................................................................................................61
6.3.3.
Early Discontinuation (ED) Visit .........................................................................................62
6.4.
Post-Treatment Assessments..................................................................................................................63
6.4.1.
All Other Subjects Who Discontinue TAF...........................................................................63
6.5.
Assessments for Premature Discontinuation from Study.......................................................................64
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................64
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................65
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................66
6.9.
Resistance Surveillance..........................................................................................................................66
6.10.
End of Study...........................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69
7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Toxicity Management ............................................................................................................................71
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................72
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................72
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................72
7.5.4.
Management of Bone Evaluation.........................................................................................72
7.5.5.
Management of Potential Nephrotoxicity.............................................................................73
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................74
7.5.7.
Management of Ocular Safety..............................................................................................76
7.6.
Special Situations Reports......................................................................................................................76
7.6.1.
Definitions of Special Situations..........................................................................................76
7.6.2.
Instructions for Reporting Special Situations.......................................................................77
8.
STATISTICAL CONSIDERATIONS................................................................................................................79
8.1.
Analysis Objectives and Endpoints........................................................................................................79
8.1.1.
Analysis Objectives..............................................................................................................79
8.1.2.
Primary Endpoint .................................................................................................................80
8.1.3.
Secondary Endpoint .............................................................................................................80
8.1.4.
Other Endpoints of Interest ..................................................................................................80
8.2.
Analysis Conventions.............................................................................................................................81
8.2.1.
Analysis Sets ........................................................................................................................81
8.3.
Data Handling Conventions ...................................................................................................................81
8.4.
Demographic Data and Baseline Characteristics ...................................................................................82
8.5.
Efficacy Analysis ...................................................................................................................................82


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8.5.1.
Primary Analysis..................................................................................................................82
8.5.2.
Secondary Analyses .............................................................................................................82
8.6.
Safety Analysis.......................................................................................................................................82
8.6.1.
Primary Safety Analysis.......................................................................................................82
8.6.2.
Secondary Safety Analyses ..................................................................................................82
8.6.3.
Extent of Exposure...............................................................................................................83
8.6.4.
Adverse Events.....................................................................................................................83
8.6.5.
Laboratory Evaluations ........................................................................................................83
8.7.
Pharmacokinetic Analysis......................................................................................................................83
8.8.
Biomarker Analysis................................................................................................................................84
8.9.
Sample Size............................................................................................................................................84
8.10.
Data Monitoring Committee ..................................................................................................................84
9.
RESPONSIBILITIES..........................................................................................................................................85
9.1.
Investigator Responsibilities ..................................................................................................................85
9.1.1.
Good Clinical Practice..........................................................................................................85
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................85
9.1.3.
Informed Consent.................................................................................................................85
9.1.4.
Confidentiality......................................................................................................................86
9.1.5.
Study Files and Retention of Records ..................................................................................86
9.1.6.
Case Report Forms...............................................................................................................87
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................88
9.1.8.
Inspections............................................................................................................................88
9.1.9.
Protocol Compliance............................................................................................................88
9.2.
Sponsor Responsibilities ........................................................................................................................88
9.2.1.
Protocol Modifications.........................................................................................................88
9.2.2.
Study Report and Publications .............................................................................................89
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................89
9.3.1.
Payment Reporting...............................................................................................................89
9.3.2.
Access to Information for Monitoring..................................................................................89
9.3.3.
Access to Information for Auditing or Inspections ..............................................................90
9.3.4.
Study Discontinuation..........................................................................................................90
10.
REFERENCES ...................................................................................................................................................91
11.
APPENDICES ....................................................................................................................................................94
Appendix 1.
Investigator Signature Page....................................................................................................95
Appendix 2.
Study Procedures Table..........................................................................................................96
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule.................................................100
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................101
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............102
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................124


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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................27
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) ........................................28
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) ...................................................................................................................................29
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) .............................30
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set)...........................................................32
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................33
Table 1-7.
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)...........................................................................................................................34
Table 1-8.
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)...........35
Table 1-9.
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) ..........................................37
Table 1-10.
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)...................38
Table 1-11.
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) .........................40
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution.....................................54
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................46


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy 
and Safety of Tenofovir Alafenamide (TAF) versus Tenofovir 
Disoproxil Fumarate (TDF)–containing Regimens in Subjects with 
Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant
Clinical Trials.gov 
Identifier:
TBD
Study Centers Planned:
Approximately 1 center in New Zealand
Objectives:
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at 
Week 24
The secondary objectives of this study are as follows: 

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the percent change 
from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 48

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at
Week 48


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Study Design: 
Tllis is a randomized, open-label, single center Phase 2 study to 
evaluate the safety and efficacy ofTAF 25 mg QD versus TDF in 
adult chronic hepatitis B infection (CHB) subjects with Stage 2 or 
greater chronic kidney disease and have received a liver transplant. 
CONFIDENTIAL 
Approximately 50 subjects will be randomized in a 1: 1 ratio to 
either continue clment treatment regimen with TDF alone or in 
combination with other approved antivirals or to receive T AF 
25 mg PO daily. Approximately 40 of 50 subjects will be em olled 
with eGFRam-EPI < 60 ml/min/1. 73m2. 
Randomization will be stratified by baseline renal ftmction 
(eGFRcKD-EPI < 50 ml/min/1.73m2 and ~ 50 ml/min/1.73m2) 
• 
Treatment Arm A : approximately 25 subjects admirustered 
TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 25 subjects to continue 
admirustration ofTDF alone or in combination with other 
approved antivirals as per local practice 
PPD 
The primaty analysis will occur at Week 24 with the primary 
efficacy endpoint being the maintenance of viral suppression 
(HBV DNA < 20 IU/mL). 
Page 7 
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Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
Approximately 50 
Final 
Amendment2 
Adult subjects with CHB who are cunently virally suppressed, 
receiving TDF alone or in combination with other approved 
antivirals as per local practice, with Stage 2 or greater chronic 
kidney disease and have received a liver transplant. 
T AF will be administered orally once daily for 48 weeks for 
subjects in Treatment Aim A. Subjects in Treatment Aim B will 
continue on TDF alone or in combination with other a roved 
antivirals. PPD 
Inclusion Criteria 
Subjects must meet!!! of the following inclusion criteria to be 
eligible to participate in the study: 
1) Must have the ability to understand and sign a written infonned 
consent f01m; consent must be obtained prior to initiation of 
study procedures 
2) Adult male or non-pregnant female subjects, over 18 years of 
age based on the date of the screening visit 
3) Documented evidence of chronic HBV infection prior to 
transplantation 
4) Primaty or secondaty (re-transplant), liver alone or liver and 
kidney transplant recipient from deceased or living donor 
5) Liver Transplant~ 12 weeks prior to screening 
6) Maintained on TDF alone or in combination with other 
approved autivirals for HBV prophylaxis or treatment 
7) Have been on approved HBV OAV treatment for at least 
12 weeks post-transplant prior to screening, with 
HBV DNA < LLOQ at screening 
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28 March 2017 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 9
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8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) 
must have a negative serum pregnancy test at Screening and a 
negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible to participate in the study:
1) Multi-organ transplant that includes heart or lung recipient 
(subjects who have their liver transplant as part of a 
liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular 
carcinoma (HCC) post-transplant and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic 
encephalopathy, hepatorenal syndrome, hepatopulmonary 
syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at 
screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on 
anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection 
requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 
28 days of the Baseline/Day 1 visit


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment2 
1 0) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g., basal cell skin cancer, etc.) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not 
eligible 
11) Significant cm·diovascular, puhnonary, or neurological disease 
12) Use of investigational agents within 3 months of screening, 
unless allowed by the Sponsor 
13) Use of any prohibited medications as described in Table 5-1 
14) Clment alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance 
15) Known hypersensitivity to study diugs, metabolites or 
f01mulation excipients 
16) Lactating females or those who may wish to become pregnant 
during the course of the study 
• 
Screening Visit 
• 
Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 20, 
24, 36, and 48 
• PPD 
Screening assessments include: 
• 
Safety laborat01y tests ( chemistiy, hematology, and 
coagulation) 
• 
HBV DNA levels 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be perfonned as needed) 
• 
HCV, HDV and HIV testing 
• 
Alpha-fetoprotein (AFP) 
• 
eGFRcKD-EPI 
• 
Hip and Spine DXA Scan 
• 
Urinalysis, urine diug screen 
• 
Serum beta human chorionic gonadotropin (P-hCG, for all 
female subjects of child-bem·ing potential) 
• 
Physical examination (with height and body weight), 
medical hist01y, vital signs, concomitant medications, and 
adverse events 
Page 10 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
On-treatment assessments include: 
Final 
Amendment2 
• 
Safety laboratmy tests ( chemistly, hematology, and 
coagulation),urine pregnancy tests (for all female subjects of 
child-bearing potential), urinalysis, physical examination 
(with weight), vital signs, concomitant medications, and 
adverse events 
• 
• 
Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobul_!n, uric acid and phosphate 
at Baseline, Weeks 4, 12, 24, 48, PD 
CrEDTA 
• 
Serum Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-tenninal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathyroid hmmone at 
Baseline, Weeks 4, 12, 24, 48, ED, PD 
• 
Fracture Risk Assessment will be evaluated at Baseline 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be erfmmed as needed) 
at Baseline and Weeks 24, 48, ED PP 
• 
HBV DNA levels at Baseline and at each study visit thereafter, 
PPD 
• 
PBMC specimens are collected at Baseline, Weeks 24, and 48 
• 
Fibrotest® and vitamin D assessments at Baseline, 
Weeks 24, 48, ED.PPD 
• 
Serum storage for potential resistance testing (sequencing and 
phenotypic analyses 2 at Baseline and at each study visit 
thereafter, PPD 
~~~~~~----------------~ 
Page 11 
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Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Test Product, Dose, and 
Mode of Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
CONFIDENTIAL 
• 
Health Related Quality of Life (HRQoL) Surveys (SF-36, 
CLDQ, and WPAI) at Baseline, Weeks 24, 48, ED, PD 
• 
Single plasma PK samples at Baseline and at treatment visits 
through Week 48 
The following samples will also be collected during the study: 
• 
Plasma, semm, and urine for future biomarker analysis will be 
collected at Baseline PPD 
• PPD 
See Section 6 for fmther infmm ation. 
Open label TAF will be supplied as 25 mg tablets for daily oral 
administration with food 
Open-label TDF alone or in combination with or without other 
antivirals administered per local practice 
Adverse events (AEs) and clinicallaboratmy tests will be collected 
at eve!:Y visit throughout the study lP~""P_D __ 
..--~--.---.--' 
he propmtion of subjects in 
each treatment rum with an AE leading to eru·ly discontinuation of 
study drug(s) and propmiion of subjects with serious adverse events 
will be summru·ized throu h Weeks 24, 48.PPD 
.,__ _____ .... 
The primary safety endpoint is: 
• 
Change from baseline in eGFRcKD-EPI of T AF 25 mg QD versus 
TDF-containing regimens at Week 24 
The secondary safety endpoints are: 
• 
Percent change from baseline in hip and spine bone mineral 
density (BMD) ofTAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in semm creatinine ofTAF 25 mg QD 
versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI of T AF 25 mg QD versus 
TDF-containing regimens at Week 48 
Page 12 
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Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Efficacy: 
Pharmacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
The primary efficacy endpoint is: 
Final 
Amendment 2 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
All subjects will have single plasma PK samples drawn at each 
treatment visit through Week 48. At Weeks 8 and 24 the PK sample 
should be collected between 15 minutes and 4 hours post-dose. 
PPD 
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. The 
response rate for each treatment arm will be summarized. 
A two-sided 95% confidence interval adjusted for the 
randomization stratification factor (the adjusted Mantel-Haenszel 
proportions), for the difference (TAF ~ TDF) in the proportion of 
subjects who maintained viral suppression (HBV DNA< 20 IU/mL) 
at Weeks 24, and 48 will be constructed. 
Page 13 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Sample Size: 
Final 
Amendment 2 
The change from baseline in eGFRcKD-EPI at Weeks 24, 48, PPD 
II will be summarized. 
The percent change from baseline in hip and spine BMD at 
Weeks 24, 48, PPD 
will be summarized. The change from 
baseline in serum creatinine at Weeks 24, 48, PPD 
will be 
summarized. All secondary continuous endpoints will be 
summarized using an 8-number summary (n, mean, standard 
deviation, median, Ql, Q3, minimum, and maximum). All 
categorical secondary endpoints will be summarized by number and 
percentage of subjects who meet the endpoint. 
This is an exploratory study. No formal sample size calculation was 
performed. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
Page 14 
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Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 2
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
Degrees Celsius
°F
Degrees Fahrenheit
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
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)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI/C
Cobicistat
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
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry
E2
Estradiol


Tenofovir Alafenamide (TAF)
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Amendment 2
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EC
Ethics Committee
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)
IRB
Institutional review board
IV
Intravenous


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction


Tenofovir Alafenamide (TAF)
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TAF
tenofovir alafenamide
TAF Fumarate
tenofovir alafenamide fumarate, GS-7340-03
TDF
tenofovir disoproxil fumarate
TFFU
Treatment Free Follow-Up
TFV
tenofovir
TFV-DP
tenofovir diphosphate
TLOVR
Time to loss of virologic response
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
TSH
Thyroid stimulating hormone
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


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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}. Importantly, not all subjects will experience all phases of 
infection {Terrault 2015}. 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 


Tenofovir Alafenamide (TAF)
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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 
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 develop in the precore or core promoter region 
of the virus {Sarin 2015}. HBeAg-negative CHB affects about 10% of pediatric subjects 
{Sokal 2013}. The goal of anti-HBV therapy, in children as in adults, is to improve long-term 
survival and quality of life by reducing disease progression to cirrhosis, decompensated liver 
disease, and HCC {Sarin 2015, Sokal 2013}. As seroclearance of HBsAg is a rare spontaneous 
occurrence in children with CHB, durable anti-HBe seroconversion in HBeAg-positive subjects 
is considered a good 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}. As in adults, reduction 
of viremia to levels below assay detection can lead to reduced inflammation and slowing or 
reversal of fibrosis {Marcellin 2013, Sokal 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) 2012, Liaw 2012}. Additionally, while 
development of resistance to entecavir (ETV) is low in treatment-naive 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 6 years of use {Kitrinos 2014}.
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) 2012, Liaw 2012, 
Lok 2009}. Although highly effective, use of TDF is associated with nephrotoxicity and 
bone-related toxicity in some subjects.


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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 {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 the 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}. 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. A New Drug 
Application (NDA) for TAF 25 mg tablets was filed on 11-January, 2016 for the treatment of 
CHB in adults.
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 next generation 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 (GS-7340), in blood and biological 
fluids.
For further information on TAF (GS-7340), refer to the current investigator’s brochure for TAF.
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. 


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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 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, (GS-7340), 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.
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.


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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 tenofovir in the cells of the lymphoreticular system. The 
primary route of elimination of tenofovir 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. Tenofovir was the major 
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of 
tenofovir in dogs and fecal elimination of tenofovir in rats and dogs are negligible.
Tenofovir 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. 
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 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. 


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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, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program
for CHB includes 2 ongoing Phase 3 studies in hepatitis B e antigen (HBeAg)-negative and
HBeAg-positive subjects with CHB, a Phase 1b antiviral activity and safety/tolerability study in
subjects with CHB, as well as several Phase 1 safety, PK/pharmacodynamics (PD), and drug
interaction studies in healthy subjects (including Chinese and Japanese subjects) and in subjects
with impaired renal or hepatic function. 
In some studies, TAF was administered as a single agent or as part of the F/TAF,
FTC/RPV/TAF, or E/C/F/TAF FDC tablets. 
TAF clinical studies are listed below: 

GS-US-320-0101, a Phase 1b study to evaluate the pharmacokinetics, safety, viral kinetics,
and anti-HBV activity of TAF in treatment-naive adults with CHB (completed)
{Agarwal 2015}

GS-US-320-1228, a Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability
of TAF in healthy Japanese and non-Japanese subjects (completed)


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
GS-US-320-1229, a Phase 1 study to evaluate the pharmacokinetics of a single dose and
repeat doses of TAF 25 mg in healthy Chinese subjects (completed; data analysis is ongoing)

GS-US-320-1382, a Phase 1 study to evaluate the effect of food on a single dose of 
TAF 25 mg in healthy subjects (completed)

GS-US-320-1615, a Phase 1 study to evaluate the pharmacokinetics of a single dose of 
TAF 25 mg in subjects with severe hepatic impairment and subjects with normal liver 
function (completed)

GS-US-320-0108, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg 
once daily versus TDF 300 mg once daily for the treatment of HBeAg-negative subjects with 
CHB (ongoing)

GS-US-320-0110, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg
once daily versus TDF 300 mg once daily for the treatment of HBeAg-positive subjects with
CHB (ongoing)

GS-US-120-0108, a Phase 1, open-label, parallel-design study to evaluate the
pharmacokinetics of TAF in subjects with severe renal impairment (completed)

GS-US-120-0109, a Phase 1 mass balance study to evaluate the pharmacokinetics,
metabolism and excretion of TAF in healthy subjects (completed)

GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with
normal, mild, and moderately impaired hepatic function (completed)

GS-US-120-1538, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and MDZ (oral and intravenous) in healthy subjects (completed)

GS-US-120-1554, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and RPV in healthy subjects (completed)

GS-US-311-1386, a Phase 1 study that evaluated the effect of food on the PK of TAF and
FTC when administered as an F/TAF fixed-dose combination tablet in healthy subjects
(completed)

GS-US-311-1387, a Phase 1 study that evaluated the drug-drug interaction (DDI) potential
between CBZ and TAF administered as F/TAF in healthy subjects (completed)

GS-US-311-1790, a Phase 1 study that evaluated the DDI potential between F/TAF or
GS-9883 and norgestimate/ethinyl estradiol in healthy female subjects (completed)


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
GS-US-320-4018, a Phase 3, randomized (1:1), double-blind, multicenter, active-controlled 
study to evaluate the safety and efficacy of TAF 25 mg every day (QD) in virologically 
suppressed subjects who switch from TDF to TAF compared to continued TDF treatment 
(ongoing)

GS-US-320-4035, a Phase 2, open label, multi-center, single-arm study to evaluate the 
safety, tolerability, and efficacy of switching to TAF 25 mg QD in virologically suppressed 
subjects with CHB and renal impairment (moderate or severe renal impairment, or those with 
end-stage renal disease (ESRD) maintained on hemodialysis), and/or hepatic impairment 
(Child-Pugh-Turcotte Class B and C) (submitted/ planned)
Please refer to the latest version of the investigator’s brochure for additional information.
An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below 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, subjects 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 are 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) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase 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 Subjectsa)
Data Presented
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 and GS-US-320-0110 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%
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. 


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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
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 (upper limit of normal 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 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 all time points from Week 8 onward using the 
M = F method.
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 at 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.


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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. 
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.


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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 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 polymorphic site substitutions, and 
2 had a conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated 
with resistance to TFV were detected 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.
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; 


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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).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures 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.


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Table 1-5. 
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set) 
GS-US-320-0108 and GS-US-320-0110 
TAF25 mg 
TDF300 mg 
Duration of Exposure to Study Regimen (Weeks) 
(N = 866) 
(N = 432) 
N 
866 
432 
Mean (SD) 
58.9 (14.71) 
59.0 (15.58) 
Median 
56.1 
56.1 
Q1, Q3 
48.1, 64.4 
48.1,64.7 
Min, Max 
0.1,96.3 
0.1, 96.3 
Total Exposure to Study Drug n(%) 
2': 4 Weeks [28 days] 
860 (99.3%) 
426 (98.6%) 
2': 8 weeks [56 days] 
858 (99.1 %) 
426 (98.6%) 
2': 12weeks [84 days] 
854 (98.6%) 
423 (97.9%) 
2': 16 Weeks [112 days] 
851 (98.3%) 
422 (97.7%) 
2': 20 Weeks [140 days) 
851 (98.3%) 
422 (97.7%) 
2': 24 Weeks [168 days] 
851 (98.3%) 
419 (97.0%) 
2': 28 Weeks [196 days) 
849 (98.0%) 
418 (96.8%) 
2': 32 Weeks [224 days) 
843 (97.3%) 
418 (96.8%) 
2': 36 Weeks [252 days] 
838 (96.8%) 
418 (96.8%) 
2': 40 Weeks [280 days] 
835 (96.4%) 
418 (96.8%) 
2': 44 Weeks [308 days] 
832 (96.1%) 
418 (96.8%) 
2': 48 Weeks [336 days] 
669 (77.3%) 
346 (80.1 %) 
p p D 
Duration of exposure to blinded study drug was the munber of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date ofblinded study drug. 
Source: TAF Week 48 ISS, Table 4 
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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-6 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).
Table 1-6.
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


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Common Adverse Events
Table 1-7 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)
Table 1-7.
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.


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Serious Adverse Events
Table 1-8 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.
Table 1-8.
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.


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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 %)
Table 1-9 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.


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Table 1-9.
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
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 


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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 1-10 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).
Table 1-10.
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


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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 1-11 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 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 1-11.
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 (TAF 22.8%, 


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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.
1.3.
Rationale and Risk/Benefit Assessment for this Study
While the number of liver transplants for CHB consequences is low in the United States 
(~350/year), in countries with high prevalence of CHB, HBV remains the most important cause 
of liver transplantation {Lee 2015}. Without prophylaxis, patients with CHB receiving a liver 
transplant have near universal re-infection of the graft {Samuel 1993}. Current practice is to treat
prior and post-transplant patients with oral nucleos(t)ide polymerase inhibitors and Hepatitis B 
Immunoglobulin (HBIG) to prevent infection of the new liver. Study 203-0107 demonstrated in a 
small group of post-liver transplant patients that treatment with TDF/FTC alone was equivalent 
to TDF/FTC + HBIG after 72 weeks of follow-up {Teperman 2013}.With these interventions, 
infection of the graft has been reduced to < 10% {Katz 2010}. While practice patterns for 
continuation of HBIG can vary by center, all patients must remain on lifelong nucleos(t)ide 
analog treatment.
After receiving a liver transplant, the majority of patients develop some degree of chronic kidney 
disease, with over 18% having a GFR< 30 ml/min within 5 years of transplant mainly as a result 
of the use of calcineurin inhibitors (CNI) {Lucey 2013, Ojo 2003}. CNIs are a mainstay of 
immunosuppression immediately after transplantation and can lead to acute or chronic kidney 
injury through hemodynamic changes or direct nephrotoxic effects. While some centers reduce 
or eliminate CNIs from immunosuppressive regimens over time, many continue patients lifelong 
on CNIs. Even in those patients who stop CNIs, the renal effects are often not reversible. This 
persistent renal dysfunction, therefore, can complicate antiviral treatment with medications such 
as TDF. 
For these patients who have received a liver transplant and have renal insufficiency, TAF may 
provide an alternative to currently used treatments by achieving viral suppression while resulting 
in improved safety of bone and renal parameters compared to TDF-based regimens.


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1.4.
Rationale for Dose Selection
A 25-mg dose of TAF was selected for use in the Phase 3 non-inferiority studies based upon the 
magnitude of HBV DNA decline, systemic TFV exposure, and the safety profile. In
Study GS-US-320-0101, the magnitude of HBV DNA decreases observed over 28 days in
subjects with CHB given TAF at doses of 8, 25, 40, and 120 mg were similar indicating a lack of 
dose effect; these decreases were also comparable with the TDF 300-mg dose, which is the dose 
of TDF approved for treatment of CHB. In subjects who received TAF 25 mg, reduced systemic 
TFV exposures (approximately 92%) were observed relative to those who received the TDF 
300-mg dose, which is consistent with data in HIV-infected subjects who received TAF 25 mg as 
a single agent in Study GS-US-120-0104.
The selection of 25 mg TAF dose in this study is further supported by the results from the 
dedicated severe renal impairment study (GS-US-120-0108). In that study, plasma TAF exposure 
in subjects with severe renal impairment was less than 2-fold higher than TAF exposure in 
matched controls with normal renal function. For TFV, mean AUC was ~6-fold higher in renally 
impaired subjects as compared to matched controls. Importantly, TFV exposure was within the 
range of TFV exposures achieved following administration of a TDF-containing regimen in 
subjects with normal renal function. As such, dose adjustment of TAF in severe renal impairment 
was not warranted.
The PK/PD relationship between TAF plasma exposure and efficacy was also explored using 
data from the Phase 3 Studies GS-US-320-0108 and GS-US-320-0110. Importantly, in both 
studies virologic suppression (HBV DNA < 29 IU/mL) was uniform across the categories of 
TAF exposures, with no trends in exposure-response relationship observed.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


Tenofovir Alafenamide (TAF) 
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2. 
OBJECTIVES 
The primary objectives ofthis study are: 
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• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
3.1.1. 
Primary Endpoints 
The primary safety endpoint is: 
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• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
3.1.2. 
Secondary Endpoints 
The secondary safety endpoints are: 
• 
Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week48 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
3.1.3. 
Other End points of Interest 
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3.2. 
Study Design 
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This is a randomized, open label study to evaluate the antiviral activity ofT AF 25 mg QD versus 
TDF (dose per the local label) containing regimens. Approximately fifty (50) adult CHB subjects 
with Stage 2 or greater chronic kidney disease and have received a liver transplant will be eligible 
for emollment. They will be randomized in a 1: 1 ratio (A: B) to the treatment rums for 48 weeks. 
Approximately 40 of 50 subjects will be emolled with eGFRcKD-EPI < 60 ml/min/1. 73m2. 
Figure 3-1. 
Study Schema 
Screening 
Randomization 1:1 (A: B) 
Arm A: TAF 25mg QD 
Arm B: TDF (dose per the local 
label) alone or in combination 
I 
I 
Week48 
l 
~ 
Treatment Free Follow-Up Phase 
PPD 
subjects followed for 24 weeks after 
the discontinuation ofTAF or until 
and alternative CHB treatment is 
started, whichever occurs first 
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3.3. 
Study Treatments 
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Approximately 50 subjects with CHB and Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be assigned to one of the two treatment atms (A: B) for 48 weeks. 
Randomization will be stratified by baseline renal function ( eGFRam-EPI < 50 ml/ min/1. 73m2 
and~ 50 ml/ min/1.73m2). 
• 
Treatment Arm A: approximately 25 subjects administered TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals per local practice 
3.4. 
Duration of Treatment 
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to Screening, subjects will be randomized to receive T AF or TDF alone or in 
combination with approved antivirals per local practice. 
PPD 
If subjects choose PPD 
~·~~,--~~ 
---~~··--~-"---~~~--~--~~~.--~~--~~--~~--
discontinue T AF prematurely, they will be followed for 24 weeks after the discontinuation of 
TAF (i.e., Treatment Free Follow-Up, TFFU) or lmtil an altemative CHB treatment is started, 
whichever occurs first. 
3.5. 
End of Study 
The end of the study will be the last subjects' last observation or visit. 
3.6. 
Biomarker Testing 
3.6.1. 
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 exploratoty systemic and/or tissue specific biomarkers with study dmg 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the bone and renal biomarkers -such as, C-type collagen sequence (CTX) and procollagen 
type 1 N-te1minal propeptide (PINP), retinol binding protein and beta-2-Inicroglobulin. 
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 cunent 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 att knowledge. Samples 
may be stored by Gilead Sciences for a period of 15 years. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 50 subjects, who are 18 years or older, with chronic hepatitis B, currently virally 
suppressed with Stage 2 or greater chronic kidney disease and have received a liver transplant. 
They will be randomized 1:1 to receive TAF 25 mg or continue with TDF alone or in 
combination with other approved antivirals for 48 weeks. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
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, over 18 years of age based on the date of the 
screening visit
3) Documented evidence of chronic HBV infection prior to transplantation 
4) Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from 
deceased or living donor 
5) Liver Transplant ≥ 12 weeks prior to screening
6) Maintained on TDF alone or in combination with other approved antivirals for HBV 
prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 12 weeks post-transplant prior to 
screening, with HBV DNA < LLOQ at screening
8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) must have a negative serum 
pregnancy test at Screening and a negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Multi-organ transplant that includes heart or lung recipient (subjects who have their liver 
transplant as part of a liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant 
and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 28 days of the Baseline/Day 1 
visit
10) Malignancy within 5 years prior to screening, with the exception of specific cancers that are 
cured by surgical resection (e.g., basal cell skin cancer, etc) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not eligible
11) Significant cardiovascular, pulmonary, or neurological disease
12) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
13) Use of any prohibited concomitant medications as described in Table 5-1


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14) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
15) Known hypersensitivity to study drugs, metabolites or formulation excipients
16) Lactating females or those who may wish to become pregnant during the course of the study


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Treatment Codes
The randomization will be performed via an Interactive Voice Response System (IVRS) or 
Interactive Web Response System (IWRS), whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. Eligible subjects (n = 50) will be randomized in a 1:1 ratio to receive either TAF 
or continue on TDF alone or in combination with other approved antivirals for 48 weeks.
Randomization will be stratified by baseline renal function (eGFRCKD-EPI < 50 ml/min/1.73m2
and ≥50 ml/min/1.73m2).
5.2.
Description and Handling of Tenofovir Alafenamide (TAF)
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (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. 
5.2.2.
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 material. Each bottle is enclosed with 
a white, continuous-thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed, and aluminum-faced liner. 
Study drug(s) to be distributed to centers in NZ and other participating countries shall be labeled 
to meet applicable requirements of local regulations.
5.2.3.
Storage and Handling
Study drug TAF 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. 


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Consideration should be given to handling, preparation, and disposal through measures that 
minimize dmg contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling. 
5.3. 
Dosage and Administration of TAF 
Subjects will be randomly assigned (1:1) to receive one of the following treatments: 
• 
Treatment Arm A: approximately 25 subjects administered T AF 25 mg QD 
• 
Treatment Arm B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals alone or in combination with other approved 
antivirals per local practice 
PO 
It is prefened that subjects take their study dmg according to a moming dosing schedule; 
however, evening dosing is allowable. 
T AF tablets are to be administered orally with food, taken at approximately the same time each 
day. 
5.4. 
Prior and Concomitant Medications 
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. 
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment: 
• 
fu.vestigational agents or devices for any indication 
• 
Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscamet, cisplatin, pentamidine) 
• 
Probenecid 
• 
Agents that reduce renal fimction or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir) 
• 
Systemic chemotherapeutic agents 
• 
Bisphosphonates 
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Treatment-experienced subjects (defined as subjects meeting all entry criteria [including 
HBV DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any 
nucleoside or nucleotide analogue) receiving oral antiviral treatment at Screening must continue 
their treatment regimen until the time of randomization/Baseline/Day 1, when it will be 
discontinued.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of TAF.
Examples of representative medications which are prohibited or to be used with caution
from 21 days prior to Day 1 through the end of treatment are listed below:
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution
Medication Class
Prohibited Medications
Medications to Be Used with Caution
Anticonvulsantsa
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungalsb
Itraconazole, Ketoconazole
Antimycobacterialsa
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplementsa
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
a
May result in a decrease in the concentration of TAF 
b
May result in an increase in the concentrations of TAF
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. 
5.5.
Accountability for Tenofovir Alafenamide (TAF)
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
Investigational product accountability records will be provided to the study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit and/or bottles number dispensed

Record the date, quantity of used and unused IMP kit and/or bottles returned, along with the 
initials of the person recording the information.


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5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the 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 kits and/or 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 
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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. 
The investigator must document any deviation from protocol procedures and notify the sponsor. 
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 be randomized 
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 3.2. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen ifthere 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 
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements. 
6.2.1. 
Screening Visit (Day -45 to Day 1 of Treatment) 
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: 
PPD 
• 
Obtain medical history, including Hepatitis B history and treatment history 
• 
Review of inclusion/exclusion criteria 
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
Review of AEs and concomitant medications

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), body weight, and height

Perform DXA scan of spine and hip. DXA scan will be performed at any time during the 
Screening period and should be completed at least 14 days prior to the first dose of the study 
drug, in order to ensure an acceptable pre-dose DXA scan

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed 
as needed)
Other viral serology (HCV, HIV and HDV)
eGFRCKD-EPI
Serum β-hCG pregnancy test (for all female subjects of child-bearing potential)
Alpha-fetoprotein (AFP). Subjects with an AFP >50 ng/mL or other findings concerning 
HCC must have an appropriate evaluation (e.g., CT scan) to rule out HCC prior to being 
able to enter into the study

Obtain urine sample for urinalysis, and urine drug screen 

Record any serious adverse events (SAE) and all adverse events (AE) related to protocol 
mandated procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
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.


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6.2.2.
Baseline Assessments (Day 1)
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 medical history, HBV history and HBV treatment history on any changes since 
screening visit

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight

Review of inclusion/exclusion criteria

Review of AEs and concomitant medication

Complete the “Fracture Risk Assessment” (FRAX®) eCRF

Cr EDTA Renal Scan 

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed)
eGFRCKD-EPI
Blood sample for Vitamin D assessment 
Blood sample for Fibrotest®
Blood sample for PBMC 
Blood sample for PK
Plasma, serum, and urine for storage
HBV resistance surveillance


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• 
Fasting blood sample for bone, renal 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 
• 
Urine sample for urinalysis, and for storage 
• 
Pregnancy test (for females of child-bearing potential; in case of a positive urine test, a semm 
pregnancy test will be done) 
• PPD 
6.3. 
Treatment Assessments 
6.3.1. 
Study Week Assessments (Weeks 4-48) 
The following evaluations will be pe1f01med at Weeks 4-48 unless specified; 
• 
Provide Health Related Quality ofLife surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit (Weeks 24, and 48 only) 
• 
Perf01m complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight (Weeks 12, 24, and 48 only) 
• 
Perf01m symptom-driven physical examination including vital signs, and body weight 
(Weeks 4, 8, 20, and 36 only) 
• 
Review of AEs and concomitant medications 
• 
Cr EDTA Renal Scan (Week 48 only) 
• 
Perf01m DXA scan of spine and hip (Weeks 24 and 48 only) 
• 
Perf01m study dmg accountability 
• 
Dispense study dmgs 
• 
Obtain blood samples for laborat01y assessments as follows: 
-
Safety laborat01y tests (semm chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
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Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) (Weeks 24 and 48 only) 
-
eGFRcKD-EPI 
-
Blood sample for Fibrotest® (Weeks 24 and 48 only) 
-
Blood sample for Vitamin D assessment (Weeks 24 and 48 only) 
-
Blood sample for AFP (Weeks 24 and 48 only) 
-
Blood sample for PK 
PO 
-
Blood sample for PBMC (Weeks 24 and 48 only) 
-
Plasma, serum, and urine for storage 
-
HBV resistance surveillance 
• 
Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose. Subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing, the plasma PK samples from these subjects can be collected anytime 
(not timed) (Weeks 8 and 24 only) 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for bone and renal biomarkers- no food or drinks, except water, at 
least 8 hours prior to blood collection (Weeks 4, 12, 24, and 48 only) 
• 
Fasting urine sample for renal biomarkers (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for 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 (Weeks 24 and 48 only) 
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6.3.3. 
Early Discontinuation (ED) Visit 
Final 
Amendment 2 
The ED visit should be performed within 14 days from notification of study discontinuation 
• 
Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects 
• 
Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight 
• 
Review of AEs and concomitant medications 
• 
Perform DXA scan of spine and hip 
• 
Perform study drug accountability 
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Obtain blood samples for laboratory assessments as follows: 
-
Safety laboratory tests (serum chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
Final 
Amendment 2 
-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
-
eGFRcKD-EPI 
-
Blood sample for Fibrotest® 
-
Blood sample for Vitamin D assessment 
-
Blood sample for AFP 
PD 
-
HBV resistance surveillance 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis 
• 
Fasting blood sample for bone and renal biomarkers- no food or drinks, except water, at 
least 8 hours prior to blood collection 
• 
Fasting urine sample for renal biomarkers 
• 
Fasting blood sample for 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 
6.4. 
Post-Treatment Assessments 
6.4.1. 
All Other Subjects Who Discontinue TAF 
Subjects who have received at least one dose of TAF and discontinue treatment prematurely or 
choose not to continue in the Optional Treatment Extension Phase will be followed every 
4 weeks for 24 weeks off treatment in accordance with TFFU schedule of assessments or until 
initiation of alternative CHB therapy, whichever comes first. 
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6.4.1.1. 
Treatment Free Follow-Up (TFFU) Visit Assessments(± 7 Days) 
Final 
Amendment 2 
The following evaluations will be performed at follow up visits for subjects when they 
discontinue T AF unless otherwise specified. For more details, refer to Appendix 2. 
• 
Review of AEs and concomitant medications 
• 
Symptom-directed physical examination 
• 
Collect vital signs and body weight 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis 
• 
Obtain blood samples for laboratory assessments as follows: 
-
Serum chemistry, hematology and coagulation tests 
-
Quantification of plasma HBV DNA levels 
-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
-
eGFRcKD-EPI 
PD 
-
HBV resistance surveillance 
6.5. 
Assessments for Premature Discontinuation from Study 
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. 
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 
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• 
Subjects with confirmed eGFRcKD-EPI of < 15 mL/min/ L 73m2 at any time during the study 
will have their study drug permanently discontinued 
• 
Lack of efficacy (virologic failure) 
• 
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 48 are not permitted to discontinue 
study drug prior to the Week 48 visit 
• 
Discontinuation of study drug for subjects 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 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 6 
• 
Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC) 
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6.8. 
Urine, Serum and Plasma for Storage 
Final 
Amendment2 
A portion of the blood samples collected at each visit starting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its reseru·ch partners for HBV 
genotyping/phenotyping assays or their development, for 
· 
the amount of HBV in the 
for measurement of antiviral 
levels in the 
A portion of the urine samples collected at each visit strutina at Baseline will be frozen and 
stored. These stored urine samples may be used by Sponsor PPD 
~----------------------~ 
.__11(in addition to the tests planned for the study). 
At the conclusion of this study, these samples may be retained in storage by 
Gilead Sciences, Inc. for a period up to 15 years. 
6.9. 
Resistance Surveillance 
Sequence analysis of the HBV polymerase/reverse transcriptase (poVRT) for resistance 
mutations may be attempted for all viremic subjects (HBV DNA ~ 69 IU/mL). 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 
sepru·ate virology sample for potential resistance surveillance will be collected at each study visit. 
6.10. 
End of Study 
The end of this study will be the last subject's last observation (or visit). 
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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

Persistent or significant disability/incapacity


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
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 are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator 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 sub investigator 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 (e.g., 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 (e.g., 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 5). 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. AEs 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 (i.e., 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 
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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 rep01ted. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30 days 
period; however, if the investigator leams of any SAEs that occur after study paliicipation 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 
infonnation to Gilead DSPH within 24 hours of the investigator's knowledge of the event. 
Detailed instmctions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE inf01mation electronically, 
i.e., the eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting f01m and submit within 24 hours to: 
Gilead DSPH: 
Fax: 
Email: 
Medical Monitor: 
Name: 
Telephone: 
Fax: 
Email: 
+1 (650) 522-5477 
Safety _FC@gilead.com 
Anuj Gaggar, MD PhD 
PPD 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instmctions in the eCRF completion guidelines. 
• If an SAE has been rep01ted via a paper fonn because the eCRF database has been locked, no 
fmther action is necessruy. 
• 
For fatal or life-threatening events, copies of hospital case rep01ts, autopsy reports, and other 
documents are also to be subtnitted 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 infonnation may be requested to ensure the timely completion of accurate safety 
rep01ts. 
• 
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 
f01m. 
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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 4.

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 5)

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.
Management of Potential Nephrotoxicity
eGFRCKD-EPI will be followed post-baseline during the study. All subjects on treatment with 
baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to <50 mL/min/1.73m2 at any 
post-baseline visit and those with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73m2 regardless of 
baseline eGFRCKD-EPI must have serum creatinine measured again within 3 calendar days of 
receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be 
measured and the estimated glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be 
calculated and compared with the baseline measurement of this parameter. 
7.5.5.1.
For subjects on TDF:

For subjects with baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to 
< 50 mL/min/1.73m2 at any post-baseline visit:
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, the 
subject will be required to undergo dose modification to every other day dosing of TDF
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, and 
the subject has undergone dose modification to every other day dosing of TDF and 
subsequently develops a confirmed eGFRCKD-EPI ≥ 50 mL/min/1.73m2, the subject may 
revert to once daily dosing of TDF after discussion with the Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73 m2 and
≥15 mL/min/1.73 m2:
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73m2 and ≥15 mL/min/1.73 m2, the 
subject will be required to undergo dose modification to every 96 hours dosing of TDF
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73 m2 and ≥15 mL/min/1.73 m2, 
and the subject has undergone dose modification to once every 96 hours dosing of TDF
and subsequently develops a confirmed CLCr ≥30 mL/min/1.73 m2, the subject may 
revert to every other day dosing of study drug after discussion with the 
Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 15 mL/min/1.73 m2: 
If the eGFRCKD-EPI is confirmed to be <15 mL/min/1.73 m2, the subject will be required to 
permanently discontinue treatment according to Section 7.5.5.3
7.5.5.2.
For subjects on TAF:

If the eGFRCKD-EPI is confirmed to be ≥15 mL/min/1.73 m2, no dose modifications are 
required


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7.5.5.3.
For subjects on TAF or TDF:

All subjects with a confirmed eGFRCKD-EPI < 15 mL/min/1.73 m2 will be required to 
permanently discontinue treatment 

All subjects 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 two weeks of 
receipt of results
7.5.6.
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
7.5.6.1.
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.


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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.
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.
7.5.6.2.
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, 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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7.5.7.
Management of Ocular Safety
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.
Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
develops signs or symptoms of posterior uveitis, investigators should contact the Gilead 
Medical Monitor to discuss the need for additional ophthalmologic evaluation including dilated 
fundoscopy and optical coherence tomography (OCT).
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, 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).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure 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 duration of the study, including the protocol –
required post treatment 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.
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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
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 throughout the duration of the study, 
including the protocol–required post treatment follow-up period. 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 +1 (650) 522-5477 or email Safety_FC@gilead.com. Refer to Appendix 6 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.


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7.6.2.2. 
Reporiing Other Special Situations 
Final 
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All special situations repot1s (SSRs) will be recorded in the eCRF database within the time lines 
outlined in the eCRF completion guideline. 
Electronic Special Situations Report ( eSSR) Reporting Process 
• 
Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
infotmation to Gilead DSPH within 24 hours of the investigator's knowledge of the event 
throughout the duration of the study, including the protocol-required post treatment 
follow-up period. Detailed instmctions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SSR infotmation electronically, i.e., the eCRF 
database is not ftmctioning, record the SSR on the paper serious adverse event repotiing fmm 
and submit within 24 hours to: 
Gilead DSPH: 
Email: 
Fax: 
Gilead Medical Monitor: 
Name: 
Phone: 
Fax: 
Email: 
Safety _FC@gilead.com 
+I (650) 522-5477 
Anuj Gaggar, MD PhD 
PPD 
PPD 
1-'1-'U 
• 
As soon as it is possible to do so, any SSR repm1ed via paper must be transcribed into the 
eCRF Database according to insttuctions in the eCRF completion guidelines. 
• If an SSR has been reported via a paper form because the eCRF database has been locked, no 
fut1her action is necessruy. 
• 
These repm1s 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 
repmted on the special situations repmi fmm; however, for special situations that result in 
AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
fotm. 
• 
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 7.3 and the CRF/eCRF completion guidelines for full insttuctions on the 
mechanism of special situations repotiing. 
All clinical sequelae in relation to these special situation repmis will be repotted as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE repoti form. Details of the symptoms 
and signs, clinical management, and outcome will be repotted, when available. 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives ofthis study are: 
Final 
Amendment 2 
• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
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8.1.2. 
Primary Endpoint 
The primary safety endpoint is: 
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• 
Change from baseline in eGFRcKD-EPI of TAF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
8.1.3. 
Secondary Endpoint 
The secondary safety end points are: 
• 
Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in serum eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing 
regimens at Week 48 
The secondary efficacy endpoint is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
8.1.4. 
Other Endpoints of Interest 
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PPD 
8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
Final 
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The primary analysis set for efficacy analysis is the Full Analysis Set (F AS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment. 
8.2.1.2. 
Safety 
The primaty analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study dmg. Subjects will be analyzed 
according to the treatment actually received. All data collected during treatment will be included 
in the safety summaries. Data collected during TFFU will be summarized or listed separately. 
8.2.1.3. 
Phatmacokinetics 
The PK analysis set will include all subjects who m·e randomized and have received at least 
one dose of study medication atld for whom concentration data of any analytes of interest 
(eg, TAF and TFV) are available. The PK analysis set will be used for analyses of concentration 
data. 
PD 
8.2.1.4. 
Biomarkers 
The Biomarker analysis set will include all subjects who have evaluable biomarkers data. 
8.3. 
Data Handling Conventions 
For the primaty endpoint missing data will be handled using a missing = failure approach, unless 
otherwise specified. 
For key secondaty safety endpoints, an analysis will be perfmmed using the Last Observation 
Canied Fotward (LOCF) method to impute the missing data. 
For other categorical secondaty efficacy endpoints, missing data will be handled using a 
missing= failure approach. For the dmg resistant mutations endpoint, a missing= excluded 
approach will be employed. 
Sensitivity analyses will be perfmmed as wananted. 
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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when the study subjects complete 24 weeks of 
the treatment period or discontinue prematurely. The response rate of each treatment arm will be 
presented. A two-sided 95% confidence interval, adjusted for the randomization stratification 
factor (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) in the 
proportion of subjects who maintained viral suppression (HBV DNA < 20 IU/mL) at 
Weeks 24 and 48 will be constructed.
8.5.2.
Secondary Analyses
The approach used for primary efficacy analysis will be applied for secondary efficacy endpoint
as in Section 8.5.1.
8.6.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last 
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment and TFFU periods will be included in data listings.
8.6.1.
Primary Safety Analysis
The change from baseline in eGFRCKD-EPI at Week 24 will be summarized.
8.6.2.
Secondary Safety Analyses
The change from baseline in eGFRCKD-EPI at Week 48 will be performed. 
The percent change from baseline in hip and spine BMD at Weeks 24 and 48 will be 
summarized.
The change from baseline in serum creatinine at Weeks 24 and 48 will be summarized.


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8.6.3. 
Extent of Exposure 
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A subject's extent of exposure to IMP data will be generated from the IMP administration data. 
Exposure data will be summarized by treatment group. 
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 
treatment up to the date of last dose oftreatment. 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 by treatment group. 
8.6.5. 
Laboratory Evaluations 
Selected laboratory data (using 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 5. 
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 and including the date of 
last dose of treatment will be summarized by treatment group. If baseline data are missing, then 
any graded abnormality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing. 
8.7. 
Phannacokinetic Analysis 
Pharmacokinetic parameters will be listed and summarized forT AF and TFV using descriptive 
statistics ( eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation. 
PPD 
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8.8.
Biomarker Analysis
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1
N-terminal propeptide (P1NP), and selected renal biomarkers, including urine retinol binding
protein, and urine beta-2-microglobulin, will be summarized by treatment group and visit using
descriptive statistics. 
8.9.
Sample Size
This is an exploratory study. No formal sample size calculation was performed.
8.10.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data once after 30 subjects have completed 12 weeks of treatment, and provide 
recommendation to Gilead whether 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, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design.
Subsequent meetings will be held on an ad hoc basis. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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. 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) 
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. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 approved consent form for documenting 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 


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conducting the consent discussion, and also by an impartial witness if required by IEC or 
local requirements. For genomic testing, the consent form will inform subjects about genomic 
testing and sample retention, and their right to receive clinically relevant genomic analysis 
results.
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, the IRB/IEC 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 in the lab 
manual. 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, IEC
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);

Documentation of the reason(s) a consented subject is not enrolled


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
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 
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 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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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, 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.
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 IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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.
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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 91
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10.
REFERENCES
Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et al. Twenty-eight day safety, 
antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of 
chronic hepatitis B infection. J Hepatol 2015;62 (3):533-40.
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective Lymphoid Cell 
and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-
7340. Mol Pharm 2013;10 (2):459-66.
Centers for Disease Control (CDC), Division of Viral Hepatitis. Viral Hepatitis Surveillance 
United States, 2013.  2013.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection [published version]. J 
Hepatology 2012;57:167-85.
Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on 
disease progression and prognostic factors. J Hepatol 2008;48 (2):335-52.
Foran JA. Principles for the Selection of Doses in Chronic Rodent Bioassays. Environ Health 
Perspect 1997;105 (1):18-20.
G. B. D. Mortality Causes of Death Collaborators. Global, regional, and national age-sex specific 
all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a 
systematic analysis for the Global Burden of Disease Study 2013. Lancet 
2015;385 (9963):117-71.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
2015;1 (4):505-27.
Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis B virus infection after 
liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? 
Systematic review and meta-analysis. Transpl Infect Dis 2010;12 (4):292-308.
Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al. No detectable 
resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with 
chronic hepatitis B. Hepatology 2014;59 (2):434-42.
Lee SG, Moon DB, Hwang S, Ahn CS, Kim KH, Song GW, et al. Liver transplantation in Korea: 
past, present, and future. Transplant Proc 2015;47 (3):705-8.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 92
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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. 
Hepatol International 2012;6:531-61.
Lok AS, McMahon BJ. AASLD Practice Guideline Update: Chronic hepatitis B: update 2009. 
Hepatology 2009;50 (3):661-2.
Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, Blumberg E, et al. Long-term management 
of the successful adult liver transplant: 2012 practice guideline by the American 
Association for the Study of Liver Diseases and the American Society of 
Transplantation. Liver Transpl 2013;19 (1):3-26.
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-
year open-label follow-up study. Lancet 2013;381 (9865):468-75.
Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of Efficient 
Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus 
Therapy [Accepted Manuscript]. Antimicrob Agents Chemother 2015;59 
(6):3563-9.
Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, et al. Chronic renal failure 
after transplantation of a nonrenal organ. N Engl J Med 2003;349 (10):931-40.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: 
new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 
2012;30 (12):2212-9.
Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency 
virus activity and cellular metabolism of a potential prodrug of the acyclic 
nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), 
Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother 1998;42 
(3):612-7.
Ruane PJ, Dejesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral 
Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir 
Alafenamide as 10-Day Monotherapy in HIV-1-Positive Adults. J Acquir Immune 
Defic Syndr 2013;63 (4):449-55.
Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou J-P, et al. Liver 
transplantation in European patients with the hepatitis B surface antigen. N Engl J 
Med 1993;329 (25):1842-7.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
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.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic 
hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an 
expert panel on behalf of the European Society of Pediatric Gastroenterology, 
Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, et al. Randomized 
trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B 
immunoglobulin withdrawal after liver transplantation. Liver Transpl 2013;19 
(6):594-601.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2015.
World Health Organization (WHO). Guidelines for the Prevention, Care and Treatment of 
Persons with Chronic Hepatitis B Infection. 2015a.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015b.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment2 
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of 
Tenofovir Alafenamide (T AF) versus Tenofovir Disoproxil Fumarate (TO F)-containing 
Regimens in Subjects with Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant 
GS-US-320-3912, Amendment 2, 28 March 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Anuj 
aggar, MD 
D 
Author 
Date 
PPD 
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. I 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, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 95 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Appendix 2. 
Study Procedures Table 
Screening 
(-45 Days) 
BL 
4 
4 +24 Hrs 
Visit 
Windows• 
Written Informed 
X 
Consent 
Review of 
Inclusion/Exclusion 
X 
X 
Criteria 
Medical History, 
including HBV 
X 
X 
history 
Review 
Concomitant 
X 
X 
X 
Medications 
Adverse Events 
X 
X 
X 
X 
Complete Physical 
Examination 
X 
X 
including vital 
signs, and weight 
Height 
X 
Symptom-directed 
X 
Physical Exam 
Body weight 
X 
X 
X 
Vital Signsb 
X 
X 
X 
Randomization 
X 
DXAc (spine & hip) 
X 
FRAX
00 Fracture 
Risk Assessment 
X 
Tool 
CONFIDENTIAL 
8 
8 +24 Hrs 
12 
20 
24 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 96 
36 
48 PPD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ED 
X 
X 
X 
X 
X 
X 
Final 
Amendment 2 
TFFUq 
± 7 Days 
X 
X 
X 
X 
X 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Screening 
(-45 Days) 
Visit 
Windows• 
Cr EDT A renal scan 
Study Drug 
Accormtability 
Study Drug 
Dispensed/Retrieved 
Dosing in-clinicd 
Serum Chemistry 
and Liver Frmction 
X 
Testse 
eG FRcKD-EPI 
X 
Hematology 
X 
Cystatin C 
X 
(for estimated G FR) 
Plasma HBV DNA 
X 
Levels 
Serum HBsAg 
(qualitative/ 
X 
Serum HBeAg 
(qualitative )f 
X 
Sample collection 
for HBV Resistance 
Surveillanceg 
HIV-1, HDV, HCV 
X 
u-fetoprotein 
X 
Fibrotest
00 
Vitamin D 
CONFIDENTIAL 
BL 
4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 +24 Hrs 
8 
8 +24 Hrs 
12 
20 
24 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 97 
36 
48 PPD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ED 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 2 
TFFUq 
± 7 Days 
X 
X 
X 
X 
X 
X 
X 
X 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Screening 
(-45 Days) 
Visit 
\:Vindows• 
Whole blood for 
PBMC 
PlasmaPKm 
Fasting Blood for 
Bone Biomarkersh 
Fasting Blood for 
Renal Biomarkersh 
Fasting Urine for . 
Renal Biomarkers' 
Fasting Metabolic 
Panel
0 
Senun Pregnancy 
X 
Test' 
Urin.e Pregnancy 
Test' 
Urinalysis 
X 
Urine dmg screen 
X 
PPD 
Semm, and plasma 
for storage 
U1ine for Storage 
Health Related 
Quality of Life 
Stuveys1 
CONFIDENTIAL 
BL 
4 
4 +24 Hrs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 
8 +24 Hrs 
12 
20 
24 
± 3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 98 
36 
48 PPD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ED 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 2 
TFFU'I 
± 7 Days 
X 
X 
X 
28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Final 
Amendment 2 
Screening 
PPD 
(-45 Days) 
BL 
4 
4 +24 H rs 
8 
8 +24 H rs 
12 
20 
24 
36 
48 
ED 
TFFU'I 
Visit 
\:Vindows• 
± 3 Days 
± 7 Days 
Imaging Testn 
X 
PPD 
a 
b 
c 
d 
e 
f 
g 
h 
lll 
n 
0 
IT 
q 
The out of visit window is ± 3 days until Week 48, ±PPD 
I and ± 7 days for 1FFU visits. 
Vttal stgns mclude blood pressm·e, pulse, resptrahon rate, and temperature. 
The initial DXA will be petfonned during Screening and should be completed at least 14 days prior to the fu-st dose of study drug. The Week 48 DXA window is- 3 days 
only. DXA is required for Early Discontinuation (ED) visit if not done within the last 24 weeks. 
It is prefen·ed that subje.cts take theit· study drug according to a momu1g dosing schedule; subjects who elect to dose in the evenu1g the previous day are not requit·ed to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 8 visits. 
Senun chemistry and Liver Fm1ction Tests: alkaline phosphatase, AST, ALT, GGT, total bilirubu1, direct and u1direct bilimbin, total protein, albmnin, LDH, CPK, 
bicarbonate, BUN, calcimn, chloride, creatu1ine, gluc.ose, phosphoms, magnesium, potassimn, sodium, m·ic acid, and an1ylase (reflex lipase testin2: is pe1f01med in subjects 
with total amylase > 1.5 x ULN). At Baseline, Weeks 24, 48,1:j and PPO' lED, subject will be fasting for senun glucose and metabolic panel. Coagulation panel will be done 
at Screenu1g and then as a reflex only test for AL T flares. 
Qualitative HBsAg and HBeAg will be perfonned at Screening, Baseline (BL), Weeks 24, 48, PPD 
, and ED. HBeAb and HBsAb testing will be performed as 
reflex testing as needed. 
Sequence analysis of the HBV pol/RT for possible resistance mutation(s) may be attempted for any subject that experiences vit·emia (HBV DNA > 69 IU/mL). 
Blood for selected bone biomarkers and renal biomarkers will be collected u1 a fasted state. Required for ED visit if the last sample was collected> 24 weeks prior. 
Urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected > 24 weeks prior. 
For female subjects of childbearing potential, the senun beta-HCG test will be perfonned at Screening. Urine test will be performed at all other visits as indicated. 
Positive m-ine test will be confinned with senun test. Pregnane)' tests should include prevention cotmseling,;.. -----------------
eafiliRelated Quahty ofLile sm-veys include"cr'Ui'iilts study are: SF-36, CLDQ, and-w!>AI"The sm-veys will be'ii"dlnintstered at'BL,WeekS'24, 48, PPD 
and 
Early Discontinuation Visits, if applicable. 
At Weeks 8 and 24 the plasma PK samples should be collected between 15 minutes and 4 hom-s post-dose. 
At Screening, a-fetoprotein (AFP) will be measm·ed and subjects with an AFP >50 ng/mL or other findings conceming HCC must m1dergo inuging test (e.g., CT scan) to mle 
out HCC. 
Fastit1g_glucose and lip~anel total cholesterol, HDL, direct LDL, trig,_
l)',,_c_e_n_
·d_e~
s'-------------------------------. 
Suojects wnohave received at least one dose ofTAF and discontinue treahnent prematurely or choose not to continue in the Optional Treatment Extension Phase will be 
followed every 4 weeks for 24 weeks off n·eahnent in accordance with TFFU visits or m1tilu1itiation of altemative CHB therapy, whichever comes first. 
CONFIDENTIAL 
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28 March 2017 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page 100 
Final 
Amendment 2 
28 March 2017 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 101
28 March 2017
Appendix 4.
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 recurrences that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 102
28 March 2017
Appendix 5.
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 103
28 March 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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 104
28 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatermia 
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 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 105
28 March 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 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 106
28 March 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
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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 107
28 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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/Lto <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.  


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 108
28 March 2017
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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 109
28 March 2017
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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 110
28 March 2017
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


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 
weakness 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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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.


Tenofovir Alafenamide (TAF)
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Amendment 2
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Appendix 6.
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 orchiectomy 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.


Tenofovir Alafenamide (TAF)
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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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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Amendment 2
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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.

Prot_001.pdf: 
Study Title: 
Sponsor: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety ofTenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fumarate (TDF)-containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
TBD 
Chronic Hepatitis B 
GS-US-320-3912 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Fax: 
Original: 
07 Jtme 2016 
Amendment I: 
22 November 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly unpublished data, is the property or 
tmder 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 inf01mation 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 inf01mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessruy to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


Tenofovir Alafenamide (TAF)
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Amendment 1
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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....................................................................14
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................20
1.2.1.
General Information .............................................................................................................20
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................20
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................23
1.3.
Rationale and Risk/Benefit Assessment for this Study ..........................................................................41
1.4.
Rationale for Dose Selection..................................................................................................................42
1.5.
Compliance ............................................................................................................................................42
2.
OBJECTIVES.....................................................................................................................................................43
3.
STUDY DESIGN................................................................................................................................................44
3.1.
Endpoints ...............................................................................................................................................44
3.1.1.
Primary Endpoints................................................................................................................44
3.1.2.
Secondary Endpoints............................................................................................................44
3.1.3.
Other Endpoints of Interest ..................................................................................................44
3.2.
Study Design..........................................................................................................................................44
3.3.
Study Treatments ...................................................................................................................................45
3.4.
Duration of Treatment............................................................................................................................46
3.5.
End of Study...........................................................................................................................................46
3.6.
Biomarker Testing..................................................................................................................................46
3.6.1.
Biomarker Samples to Address the Study Objectives ..........................................................46
3.6.2.
Biomarker Samples for Optional Future Research...............................................................46
3.6.3.
Biomarker Samples for Optional Genomic Research...........................................................47
3.6.4.
Intensive PK Substudy .........................................................................................................47
4.
SUBJECT POPULATION..................................................................................................................................48
4.1.
Number of Subjects and Subject Selection ............................................................................................48
4.2.
Inclusion Criteria....................................................................................................................................48
4.3.
Exclusion Criteria...................................................................................................................................49
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................50
5.1.
Randomization, and Treatment Codes ...................................................................................................50
5.2.
Description and Handling of Tenofovir Alafenamide (TAF).................................................................50
5.2.1.
Formulation..........................................................................................................................50
5.2.2.
Packaging and Labeling .......................................................................................................50
5.2.3.
Storage and Handling...........................................................................................................51
5.3.
Dosage and Administration of TAF.......................................................................................................51
5.4.
Prior and Concomitant Medications.......................................................................................................51
5.5.
Accountability for Tenofovir Alafenamide (TAF).................................................................................52
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................53
6.
STUDY PROCEDURES ....................................................................................................................................54


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................54
6.2.
Pretreatment Assessments......................................................................................................................54
6.2.1.
Screening Visit (Day −45 to Day 1 of Treatment) ...............................................................54
6.2.2.
Baseline Assessments (Day 1)..............................................................................................56
6.3.
Treatment Assessments..........................................................................................................................57
6.3.1.
Study Week Assessments (Weeks 4-48) ..............................................................................57
6.3.2.
Study Week Assessments Weeks for Optional Treatment Extension Phase 
(Weeks 60-144)....................................................................................................................59
6.3.3.
Early Discontinuation (ED) Visit .........................................................................................60
6.4.
Post-Treatment Assessments..................................................................................................................61
6.4.1.
All Other Subjects Who Discontinue Study Drug................................................................61
6.5.
Assessments for Premature Discontinuation from Study.......................................................................61
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................62
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................62
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................63
6.9.
Resistance Surveillance..........................................................................................................................63
6.10.
End of Study...........................................................................................................................................63
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................64
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
7.1.1.
Adverse Events.....................................................................................................................64
7.1.2.
Serious Adverse Events........................................................................................................64
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................65
7.2.2.
Assessment of Severity ........................................................................................................66
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................66
7.4.
Gilead Reporting Requirements.............................................................................................................68
7.5.
Toxicity Management ............................................................................................................................68
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................69
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................69
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................69
7.5.4.
Management of Bone Evaluation.........................................................................................69
7.5.5.
Management of Potential Nephrotoxicity.............................................................................70
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................71
7.5.7.
Management of Ocular Safety..............................................................................................73
7.6.
Special Situations Reports......................................................................................................................73
7.6.1.
Definitions of Special Situations..........................................................................................73
7.6.2.
Instructions for Reporting Special Situations.......................................................................74
8.
STATISTICAL CONSIDERATIONS................................................................................................................76
8.1.
Analysis Objectives and Endpoints........................................................................................................76
8.1.1.
Analysis Objectives..............................................................................................................76
8.1.2.
Primary Endpoint .................................................................................................................76
8.1.3.
Secondary Endpoint .............................................................................................................77
8.1.4.
Other Endpoints of Interest ..................................................................................................77
8.2.
Analysis Conventions.............................................................................................................................77
8.2.1.
Analysis Sets ........................................................................................................................77
8.3.
Data Handling Conventions ...................................................................................................................78
8.4.
Demographic Data and Baseline Characteristics ...................................................................................78
8.5.
Efficacy Analysis ...................................................................................................................................79


Tenofovir Alafenamide (TAF)
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8.5.1.
Primary Analysis..................................................................................................................79
8.5.2.
Secondary Analyses .............................................................................................................79
8.6.
Safety Analysis.......................................................................................................................................79
8.6.1.
Primary Safety Analysis.......................................................................................................79
8.6.2.
Secondary Safety Analyses ..................................................................................................79
8.6.3.
Extent of Exposure...............................................................................................................79
8.6.4.
Adverse Events.....................................................................................................................79
8.6.5.
Laboratory Evaluations ........................................................................................................80
8.7.
Pharmacokinetic Analysis......................................................................................................................80
8.8.
Biomarker Analysis................................................................................................................................80
8.9.
Sample Size............................................................................................................................................80
8.10.
Data Monitoring Committee ..................................................................................................................81
9.
RESPONSIBILITIES..........................................................................................................................................82
9.1.
Investigator Responsibilities ..................................................................................................................82
9.1.1.
Good Clinical Practice..........................................................................................................82
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................82
9.1.3.
Informed Consent.................................................................................................................82
9.1.4.
Confidentiality......................................................................................................................83
9.1.5.
Study Files and Retention of Records ..................................................................................83
9.1.6.
Case Report Forms...............................................................................................................84
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................85
9.1.8.
Inspections............................................................................................................................85
9.1.9.
Protocol Compliance............................................................................................................85
9.2.
Sponsor Responsibilities ........................................................................................................................85
9.2.1.
Protocol Modifications.........................................................................................................85
9.2.2.
Study Report and Publications .............................................................................................86
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................86
9.3.1.
Payment Reporting...............................................................................................................86
9.3.2.
Access to Information for Monitoring..................................................................................86
9.3.3.
Access to Information for Auditing or Inspections ..............................................................87
9.3.4.
Study Discontinuation..........................................................................................................87
10.
REFERENCES ...................................................................................................................................................88
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule...................................................96
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................97
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............98
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120


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Amendment 1
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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................25
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) ........................................26
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) ...................................................................................................................................28
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) .............................29
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set)...........................................................31
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................32
Table 1-7.
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)...........................................................................................................................33
Table 1-8.
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)..........34
Table 1-9.
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) ..........................................36
Table 1-10.
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)...................37
Table 1-11.
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) .........................39
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution.....................................52
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................45


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 6
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy 
and Safety of Tenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant
Clinical Trials.gov 
Identifier:
TBD
Study Centers Planned:
Approximately 1 center in New Zealand
Objectives:
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at 
Week 24
The secondary objectives of this study are as follows: 

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the percent change 
from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 48

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at
Week 48


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Study Design: 
Tllis is a randomized, open-label, single center Phase 2 study to 
evaluate the safety and efficacy ofTAF 25 mg QD versus TDF in 
adult chronic hepatitis B infection (CHB) subjects with Stage 2 or 
greater cln·onic kidney disease and have received a liver transplant. 
CONFIDENTIAL 
Approximately 60 subjects will be randomized in a 1:1 ratio to 
either continue current treatment regimen with TDF alone or in 
combination with other approved antivirals or to receive T AF 
25 mg PO daily. At least 50 subjects will be emolled with 
eGFRcKD-EPI < 50 mVmin/1.73m2. 
Randomization will be stratified by baseline renal ftmction 
( eGFRcKD-EPI < 50 mVmin/1. 73m2 and~ 50 mVmin/1. 73m2) 
• 
Treatment Arm A: approximately 30 subjects admillistered 
TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 30 subjects to continue 
admillistration of TDF alone or in combination with other 
approved antivirals as per local practice 
PPD 
The primaty analysis will occur at Week 24 with the primruy 
efficacy endpoint being the maintenance of viral suppression 
(HBV DNA < 20 IU/mL). 
Page 7 
22 November 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
Approximately 60 
Final 
Amendment 1 
Adult subjects with CHB who are cunently virally suppressed, 
receiving TDF alone or in combination with other approved 
antivirals as per local practice, with Stage 2 or greater chronic 
kidney disease and have received a liver transplant. 
TAP will be administered orally once daily for 48 weeks for 
subjects in Treatment Arm A. PPD 
Inclusion Criteria 
Subjects must meet .!!! of the following inclusion criteria to be 
eligible to pa1ticipate in the study: 
1) Must have the ability to understand and sign a written infmmed 
consent fmm; consent must be obtained prior to initiation of 
study procedures 
2) Adult male or non-pregnant female subjects, over 18 years of 
age based on the date of the screening visit 
3) Documented evidence of chronic HBV infection prior to 
transplantation 
4) Prima1y or secondary (re-transplant), liver alone or liver and 
kidney transplant recipient from deceased or living donor 
5) Liver Transplant~ 12 weeks prior to screening 
6) Maintained on TDF alone or in combination with other 
approved antivirals for HBV prophylaxis or treatment 
7) Have been on approved HBV OA V treatment for at least 
12 weeks post-transplant prior to screening, with 
HBV DNA < LLOQ at screening 
8) Screening eGFRcKD-EPI < 90 ml/mi..n/1. 73m2 
9) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in 
Appendix 6 
10) Women considered of child bearing potential (see Appendix 6) 
must have a negative sennn pregnancy test at Screening and a 
negative urine test at Baseline before dosing 
11) Must be willing and able to comply with all study requirements 
Page8 
22 November 2016 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 9
22 November 2016
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible to participate in the study:
1) Multi-organ transplant that includes heart or lung recipient 
(subjects who have their liver transplant as part of a 
liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular 
carcinoma (HCC) post-transplant and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic 
encephalopathy, hepatorenal syndrome, hepatopulmonary 
syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at 
screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on 
anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection 
requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 
28 days of the Baseline/Day 1 visit
10) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g., basal cell skin cancer, etc.) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not 
eligible
11) Significant cardiovascular, pulmonary, or neurological disease
12) Use of investigational agents within 3 months of screening, 
unless allowed by the Sponsor
13) Use of any prohibited medications as described in Table 5-1
14) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment 1 
15) Known hypersensitivity to study drugs, metabolites or 
formulation excipients 
16) Lactating females or those who may wish to become pregnant 
during the course of the study 
• 
Screening Visit 
• 
Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 20, 
24, 36 and 4 PPD 
~----------------------------------~ 
Screening assessments include: 
• 
Safety laboratory tests (chemistry, hematology, and 
coagulation) 
• 
HBV DNA levels 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed) 
• 
HCV, HDV and HIV testing 
• 
Alpha-fetoprotein (AFP) 
• 
eGFRcKD-EPI 
• 
Serum Renal Biomarkers including phosphate, Cystatin C, 
• 
Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobulin, uric acid and phosphate 
• 
Serum Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-terminal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathyroid hormone. 
• 
Hip and Spine DXA Scan 
• 
Urinalysis, urine drug screen 
• 
Serum beta human chorionic gonadotropin (~-hCG, for all 
female subjects of child-bearing potential) 
• 
Physical examination (with height and body weight), 
medical history, vital signs, concomitant medications, and 
adverse events 
On-treatment assessments include: 
• 
Safety laboratory tests (chemistry, hematology, and 
coagulation),urine pregnancy tests (for all female subjects of 
child-bearing potential), urinalysis, physical examination, vital 
signs, concomitant medications, and adverse events 
• 
Serum Renal Biomarkers including phos2hate, Cystatin C at 
Baseline, Weeks 4, 12, 24, 48, PPD 
and Early 
Discontinuation (ED) 
Page 10 
22 November 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
• 
Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobulin, uric acid and phosphate 
at Baseline, Weeks 4, 12, 24, 48, PPD 
and ED 
• 
• 
Senun Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-terminal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathY!·oid hoxmone at 
Baseline, Weeks 4, 12, 24, 48, PPD 
and ED 
and ED 
• 
Fracture Risk Assessment will be evaluated at Baseline 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testtng wiJ be petfotmed as needed) 
at Baseline and Weeks 24, 48, PPD and ED 
• 
HBV DNA levels at Baseline and at each study visit thereafter, 
PPD 
• 
PBMC specimens are collected at Baseline, Weeks 24, and 48 
• 
Health Related Quality of Life (HRQoL) Surveys 
(SF-36, CLDQ, and WPAI) at Baseline, Weeks 24, 48, PPD 
and ED 
• 
Single plasma PK samples at each treatment visits through 
Week48 
The following samples will also be collected during the study: 
• PPD 
• PPD 
See Section 6 for further infotmation. 
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Test Product, Dose, and 
Mode of Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
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Open label TAF will be supplied as 25 mg tablets for daily oral 
administration 
Open-label TDF alone or in combination with or without other 
antivirals administered per local practice 
Adverse events (AEs) and clinical laboratory tests will be collected 
at every visit and summarized through treatment extension Phase at 
Week 144. The proportion of subjects in each treatment arm with 
an AE leading to early discontinuation of study drug(s) and 
proportion of subjects with serious adverse events will be 
summarized through Weeks 24, 48, PPD 
~----------------~ 
The primary safety endpoint is: 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus 
TDF-containing regimens at Week 24 
The secondary safety end points are: 
• 
Percent change from baseline in hip and spine bone mineral 
density (BMD) ofTAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD 
versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus 
TDF-containing regimens at Week 48 
The primary efficacy endpoint is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
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Pharmacokinetics: 
All subjects will have single plasma PK samples drawn at each 
treatment visit through Week 48. At Weeks 8 and 24 the PK sample 
should be collected between 15 minutes and 4 hours post-dose. 
Statistical Methods: 
Sample Size: 
PPD 
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. The 
response rate for each treatment arm will be summarized. 
A two-sided 95% confidence interval adjusted for the 
randomization stratification factor (the adjusted Mantel-Haenszel 
proportions), for the difference (TAF ~ TDF) in the proportion of 
subjects who maintained viral suppression (HBV DNA< 20 IU/mL) 
at Week 24 will be constructed. 
The change from baseline in eGFRcKD-EPI at Weeks 24 and 48 will 
be summarized. 
The percent change from baseline in hip and spine BMD at 
Weeks 24 and 48 will be summarized. The change from baseline in 
serum creatinine at Weeks 24 and 48 will be summarized. All 
secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Ql, Q3, 
minimum, and maximum). All categorical secondary endpoints will 
be summarized by number and percentage of subjects who meet the 
endpoint. 
This is an exploratory study. No formal sample size calculation was 
performed. 
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
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
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)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI/C
Cobicistat
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
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry
E2
Estradiol


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EC
Ethics Commitee
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)
IRB
Institutional review board
IV
Intravenous


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IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction


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TAF
tenofovir alafenamide
TAF Fumarate
tenofovir alafenamide fumarate, GS-7340-03
TDF
tenofovir disoproxil fumarate
TFV
tenofovir
TFV-DP
tenofovir diphosphate
TLOVR
Time to loss of virologic response
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
TSH
Thyroid stimulating hormone
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


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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 et al 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 et al 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 et al 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 et al 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) et al 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 et al 2008, Sarin et al 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 et al 2008, Sokal et al 2013}. Importantly, not all 
subjects will experience all phases of infection {Terrault et al 2015}. 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 


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followed by loss of HBeAg with seroconversion to anti-HBe. In the inactive CHB phase, 
subjects have undetectable or low levels 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 develop in the 
precore or core promoter region of the virus {Sarin et al 2015}. HBeAg-negative CHB affects 
about 10% of pediatric subjects {Sokal et al 2013}. The goal of anti-HBV therapy, in children as 
in adults, is to improve long-term survival and quality of life by reducing disease progression to 
cirrhosis, decompensated liver disease, and HCC {Sarin et al 2015, Sokal et al 2013}. As 
seroclearance of HBsAg is a rare spontaneous occurrence in children with CHB, durable 
anti-HBe seroconversion in HBeAg-positive subjects is considered a good 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 et al 2015}. As in adults, reduction of viremia to levels below assay 
detection can lead to reduced inflammation and slowing or reversal of fibrosis 
{Marcellin et al 2013, Sokal et al 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 et al 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) 2012, Liaw et al 2012}. Additionally, 
while development of resistance to entecavir (ETV) is low in treatment-naive 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 et al 2009}. In contrast, resistance to tenofovir 
disoproxil fumarate (TDF; Viread®) has not been documented through 6 years of use 
{Kitrinos et al 2014}.
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) 2012, 
Liaw et al 2012, Lok et al 2009}. Although highly effective, use of TDF is associated with 
nephrotoxicity and bone-related toxicity in some subjects.


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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 {Agarwal et al 2015, Babusis et al 2013, Murakami et al 2015, Ruane et al 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 the 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 et al 2015}. 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. A New 
Drug Application (NDA) for TAF 25 mg tablets was filed on 11-January, 2016 for the treatment 
of CHB in adults.
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 next generation 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 (GS-7340), in blood and biological 
fluids.
For further information on TAF (GS-7340), refer to the current investigator’s brochure for TAF.
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. 


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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 et al 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 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 et al 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, (GS-7340), 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.
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.


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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 tenofovir in the cells of the lymphoreticular system. The 
primary route of elimination of tenofovir 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. Tenofovir was the major
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of 
tenofovir in dogs and fecal elimination of tenofovir in rats and dogs are negligible.
Tenofovir 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. 
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 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. 


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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, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program
for CHB includes 2 ongoing Phase 3 studies in hepatitis B e antigen (HBeAg)-negative and
HBeAg-positive subjects with CHB, a Phase 1b antiviral activity and safety/tolerability study in
subjects with CHB, as well as several Phase 1 safety, PK/pharmacodynamics (PD), and drug
interaction studies in healthy subjects (including Chinese and Japanese subjects) and in subjects
with impaired renal or hepatic function. 
In some studies, TAF was administered as a single agent or as part of the F/TAF,
FTC/RPV/TAF, or E/C/F/TAF FDC tablets. 
TAF clinical studies are listed below: 

GS-US-320-0101, a Phase 1b study to evaluate the pharmacokinetics, safety, viral kinetics,
and anti-HBV activity of TAF in treatment-naive adults with CHB (completed)
{Agarwal et al 2015}

GS-US-320-1228, a Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability
of TAF in healthy Japanese and non-Japanese subjects (completed)


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
GS-US-320-1229, a Phase 1 study to evaluate the pharmacokinetics of a single dose and
repeat doses of TAF 25 mg in healthy Chinese subjects (completed; data analysis is ongoing)

GS-US-320-1382, a Phase 1 study to evaluate the effect of food on a single dose of 
TAF 25 mg in healthy subjects (completed)

GS-US-320-1615, a Phase 1 study to evaluate the pharmacokinetics of a single dose of 
TAF 25 mg in subjects with severe hepatic impairment and subjects with normal liver 
function (completed)

GS-US-320-0108, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg 
once daily versus TDF 300 mg once daily for the treatment of HBeAg-negative subjects with 
CHB (ongoing)

GS-US-320-0110, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg
once daily versus TDF 300 mg once daily for the treatment of HBeAg-positive subjects with
CHB (ongoing)

GS-US-120-0108, a Phase 1, open-label, parallel-design study to evaluate the
pharmacokinetics of TAF in subjects with severe renal impairment (completed)

GS-US-120-0109, a Phase 1 mass balance study to evaluate the pharmacokinetics,
metabolism and excretion of TAF in healthy subjects (completed)

GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with
normal, mild, and moderately impaired hepatic function (completed)

GS-US-120-1538, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and MDZ (oral and intravenous) in healthy subjects (completed)

GS-US-120-1554, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and RPV in healthy subjects (completed)

GS-US-311-1386, a Phase 1 study that evaluated the effect of food on the PK of TAF and
FTC when administered as an F/TAF fixed-dose combination tablet in healthy subjects
(completed)

GS-US-311-1387, a Phase 1 study that evaluated the drug-drug interaction (DDI) potential
between CBZ and TAF administered as F/TAF in healthy subjects (completed)

GS-US-311-1790, a Phase 1 study that evaluated the DDI potential between F/TAF or
GS-9883 and norgestimate/ethinyl estradiol in healthy female subjects (completed)
Please refer to the latest version of the investigator’s brochure for additional information.


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An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below 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, subjects 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 are 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) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase from 
Week 144 to Week 384 (8 year total study period).
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen
(Number of Subjectsa)
Data Presented
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 


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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 and GS-US-320-0110 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%
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


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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 (upper limit of normal range: ≤ 30 U/L for males and ≤19 U/L 
for females {Lok et al 2009, Terrault et al 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 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 all time points from Week 8 onward using the 
M = F method.
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 at 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.


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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. 
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.


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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 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 polymorphic site substitutions, and 
2 had a conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated 
with resistance to TFV were detected 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.
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; 


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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).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures 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.


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Table 1-5. 
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set) 
GS-US-320-0108 and GS-US-320-0110 
TAF25 mg 
TDF300 mg 
Duration of Exposure to Study Regimen (Weeks) 
(N = 866) 
(N = 432) 
N 
866 
432 
Mean (SD) 
58.9 (14.71) 
59.0 (15.58) 
Median 
56.1 
56.1 
Q1, Q3 
48.1, 64.4 
48.1,64.7 
Min, Max 
0.1,96.3 
0.1, 96.3 
Total Exposure to Study Drug n(%) 
2': 4 Weeks [28 days] 
860 (99.3%) 
426 (98.6%) 
2': 8 weeks [56 days] 
858 (99.1 %) 
426 (98.6%) 
2': 12weeks [84 days] 
854 (98.6%) 
423 (97.9%) 
2': 16 Weeks [112 days] 
851 (98.3%) 
422 (97.7%) 
2': 20 Weeks [140 days) 
851 (98.3%) 
422 (97.7%) 
2': 24 Weeks [168 days] 
851 (98.3%) 
419 (97.0%) 
2': 28 Weeks [196 days) 
849 (98.0%) 
418 (96.8%) 
2': 32 Weeks [224 days) 
843 (97.3%) 
418 (96.8%) 
2': 36 Weeks [252 days] 
838 (96.8%) 
418 (96.8%) 
2': 40 Weeks [280 days] 
835 (96.4%) 
418 (96.8%) 
2': 44 Weeks [308 days] 
832 (96.1%) 
418 (96.8%) 
2': 48 Weeks [336 days] 
669 (77.3%) 
346 (80.1 %) 
p p D 
Duration of exposure to blinded study drug was the munber of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date ofblinded study drug. 
Source: TAF Week 48 ISS, Table 4 
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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-6 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).
Table 1-6.
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


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Common Adverse Events
Table 1-7 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)
Table 1-7.
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.


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Serious Adverse Events
Table 1-8 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.
Table 1-8.
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.


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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 %)
Table 1-9 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.


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Table 1-9.
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
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 


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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 1-10 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).
Table 1-10.
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


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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 1-11 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 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 1-11.
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 (TAF 22.8%, 


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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.
1.3.
Rationale and Risk/Benefit Assessment for this Study
While the number of liver transplants for CHB consequences is low in the United States 
(~350/year), in countries with high prevalence of CHB, HBV remains the most important cause of 
liver transplantation {Lee et al 2015}. Without prophylaxis, patients with CHB receiving a liver 
transplant have near universal re-infection of the graft {Samuel et al 1993}. Current practice is to 
treat prior and post-transplant patients with oral nucleos(t)ide polymerase inhibitors and 
Hepatitis B Immunoglobulin (HBIG) to prevent infection of the new liver. Study 203-0107 
demonstrated in a small group of post-liver transplant patients that treatment with TDF/FTC alone
was equivalent to TDF/FTC + HBIG after 72 weeks of follow-up {Teperman et al 2013}.With 
these interventions, infection of the graft has been reduced to < 10% {Katz et al 2010}. While 
practice patterns for continuation of HBIG can vary by center, all patients must remain on lifelong 
nucleos(t)ide analog treatment. 
After receiving a liver transplant, the majority of patients develop some degree of chronic kidney 
disease, with over 18% having a GFR< 30 ml/min within 5 years of transplant mainly as a result 
of the use of calcineurin inhibitors (CNI) {Lucey et al 2013, Ojo et al 2003}. CNIs are a 
mainstay of immunosuppression immediately after transplantation and can lead to acute or 
chronic kidney injury through hemodynamic changes or direct nephrotoxic effects. While some 
centers reduce or eliminate CNIs from immunosuppressive regimens over time, many continue 
patients lifelong on CNIs. Even in those patients who stop CNIs, the renal effects are often not 
reversible. This persistent renal dysfunction, therefore, can complicate antiviral treatment with 
medications such as TDF. 
For these patients who have received a liver transplant and have renal insufficiency, TAF may 
provide an alternative to currently used treatments by achieving viral suppression while resulting 
in improved safety of bone and renal parameters compared to TDF-based regimens.


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1.4.
Rationale for Dose Selection
A 25-mg dose of TAF was selected for use in the Phase 3 non-inferiority studies based upon the 
magnitude of HBV DNA decline, systemic TFV exposure, and the safety profile. In
Study GS-US-320-0101, the magnitude of HBV DNA decreases observed over 28 days in
subjects with CHB given TAF at doses of 8, 25, 40, and 120 mg were similar indicating a lack of 
dose effect; these decreases were also comparable with the TDF 300-mg dose, which is the dose 
of TDF approved for treatment of CHB. In subjects who received TAF 25 mg, reduced systemic 
TFV exposures (approximately 92%) were observed relative to those who received the TDF 
300-mg dose, which is consistent with data in HIV-infected subjects who received TAF 25 mg as
a single agent in Study GS-US-120-0104.
The selection of 25 mg TAF dose in this study is further supported by the results from the 
dedicated severe renal impairment study (GS-US-120-0108). In that study, plasma TAF exposure 
in subjects with severe renal impairment was less than 2-fold higher than TAF exposure in 
matched controls with normal renal function. For TFV, mean AUC was ~6-fold higher in renally 
impaired subjects as compared to matched controls. Importantly, TFV exposure was within the 
range of TFV exposures achieved following administration of a TDF-containing regimen in 
subjects with normal renal function. As such, dose adjustment of TAF in severe renal impairment 
was not warranted.
The PK/PD relationship between TAF plasma exposure and efficacy was also explored using 
data from the Phase 3 Studies GS-US-320-0108 and GS-US-320-0110. Importantly, in both 
studies virologic suppression (HBV DNA < 29 IU/mL) was uniform across the categories of 
TAF exposures, with no trends in exposure-response relationship observed.
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 ofthis study are: 
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• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
3.1.1. 
Primary Endpoints 
The primary safety endpoint is: 
Final 
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• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy endpoint is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
3.1.2. 
Secondary Endpoints 
The secondary safety end points are: 
• 
Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week48 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
3.1.3. 
Other Endpoints of Interest 
3.2. 
Study Design 
This is a randomized, open label study to evaluate the antiviral activity ofT AF 25 mg QD versus 
TDF (dose per the local label) containing regimens. Approximately sixty (60) subjects will be 
randomized in a 1:1 ratio (A: B) to the treatment arms for 48 weeks. At least 50 subjects will be 
enrolled with eGFRcrm-EPI < 50 mllmin/1.73m
2
. 
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Approximately 60 adult CHB subjects with Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be eligible for emollment. 
The primaty analysis will occur at Week 24 with the primmy efficacy endpoint being the 
maintenance of viral suppression (HBV DNA < 20 IU/mL). 
Figure 3-1. 
Study Schema 
Screening 
~ 
Randomization 1:1 (A:B) 
t 
t 
Arm A: TAF 25 mg QD 
Arm B: TDF (dose per the local label) alone 
or in combination with other approved 
I 
antivirals 
I 
I 
Week 48 Open Label TAF 25 mg QD 
lPPD 
!/Early Discontinuation Visit 
3.3. 
Study Treatments 
Approximately 60 subjects with CHB and Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be assigned to one of the two treatment mms (A:B) for 48 weeks. 
Randomization will be stratified by baseline renal ftmction ( eGFR.cKn.EPI < 50 mil min/1. 73m2 
and~ 50 mil min/1. 73m2). 
• 
Treatment Arm A: approximately 30 subjects administered TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 30 subjects to continue administration of TDF alone or in 
combination with other approved antivirals per local practice 
PPD 
CONFIDENTIAL 
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Tenofovir Alafenamide (TAF) 
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3.4. 
Duration of Treatment 
Final 
Amendment 1 
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to screening, subjects will be randomized to receive T AF or TDF alone or in 
combination with ap_£roved antivirals per local practice. PD 
3.5. 
End of Study 
The end of the study will be the last subjects' last observation or visit. 
3.6. 
Biomarker Testing 
3.6.1. 
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 exploratory systemic and/or tissue specific biomarkers with study dmg 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the bone and renal biomarkers - such as, C-type collagen sequence (CTX) and procollagen 
type 1 N-tenninal propeptide (PINP), retinol binding protein and beta-2-microglobulin. 
Because biomarker science is a rapidly evolving area of investigation, and adverse events in 
pmiicular 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 cunent 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 mi knowledge. Samples 
may be stored by Gilead Sciences for a period of 15 yem·s. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 60 subjects, who are 18 years or older, with chronic hepatitis B, currently virally 
suppressed with Stage 2 or greater chronic kidney disease and have received a liver transplant. 
They will be randomized 1:1 to receive TAF 25 mg or continue with TDF alone or in 
combination with other approved antivirals for 48 weeks. All subjects will be treated with TAF 
25 mg oral daily for 96 weeks after the first 48 weeks. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
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, over 18 years of age based on the date of the 
screening visit
3) Documented evidence of chronic HBV infection prior to transplantation 
4) Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from 
deceased or living donor 
5) Liver Transplant ≥ 12 weeks prior to screening
6) Maintained on TDF alone or in combination with other approved antivirals for HBV 
prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 12 weeks post-transplant prior to 
screening, with HBV DNA < LLOQ at screening
8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) must have a negative serum 
pregnancy test at Screening and a negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Multi-organ transplant that includes heart or lung recipient (subjects who have their liver 
transplant as part of a liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant 
and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
f)
eGFRCKD-EPI < 15 ml/min/1.73m2
6) Subjects on hemodialysis
7) Co-infection with HIV or HCV
8) Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics
9) Use of any prohibited medications listed in Section 5.4 within 28 days of the Baseline/Day 1 
visit
10) Malignancy within 5 years prior to screening, with the exception of specific cancers that are 
cured by surgical resection (e.g., basal cell skin cancer, etc) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not eligible
11) Significant cardiovascular, pulmonary, or neurological disease
12) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
13) Use of any prohibited concomitant medications as described in Table 5-1
14) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
15) Known hypersensitivity to study drugs, metabolites or formulation excipients
16) Lactating females or those who may wish to become pregnant during the course of the study


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Treatment Codes
The randomization will be performed via an Interactive Voice Response System (IVRS) or 
Interactive Web Response System (IWRS), whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. Eligible subjects (n = 60) will be randomized in a 1:1 ratio to receive either TAF 
or continue on TDF alone or in combination with other approved antivirals for 48 weeks.
Randomization will be stratified by baseline renal function (eGFRCKD-EPI < 50 ml/min/1.73m2
and ≥50 ml/min/1.73m2).
5.2.
Description and Handling of Tenofovir Alafenamide (TAF)
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (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. 
5.2.2.
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 material. Each bottle is enclosed with 
a white, continuous-thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed, and aluminum-faced liner. 
Study drug(s) to be distributed to centers in NZ 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.
All labels for TAF 25 mg bottles to be distributed in centers in the US and other participating 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and EU Guidelines to Good Manufacturing Practice, Annex 13 
Investigational Medicinal Products and/or other local regulations as applicable.


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5.2.3.
Storage and Handling
Study drug TAF 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.
5.3.
Dosage and Administration of TAF
Subjects will be randomly assigned (1:1) to receive one of the following treatments:

Treatment Arm A: approximately 30 subjects administered TAF 25 mg QD

Treatment Arm B: approximately 30 subjects to continue administration of TDF alone or in 
combination with other approved antivirals alone or in combination with other approved 
antivirals per local practice
After 48 weeks, subjects in treatment arms A and B will switch to open-label TAF 25 mg QD for 
up to an additional 96 weeks (Week 48 through Week 144/ED). 
It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
TAF tablets are to be administered orally with or without food, taken at approximately the same 
time each day.
5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Investigational agents or devices for any indication

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine)


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
Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)

Systemic chemotherapeutic agents 

Bisphosphonates
Treatment-experienced subjects (defined as subjects meeting all entry criteria [including HBV 
DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any nucleoside or 
nucleotide analogue) receiving oral antiviral treatment at Screening must continue their treatment 
regimen until the time of randomization/Baseline/Day 1, when it will be discontinued.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of TAF.
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. 
Examples of representative medications which are prohibited or to be used with caution
from 21 days prior to Day 1 through the end of treatment are listed below:
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution
Medication Class
Prohibited Medications
Medications to Be Used with Caution
Anticonvulsantsa
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungalsb
Itraconazole, Ketoconazole
Antimycobacterialsa
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplementsa
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
a
May result in a decrease in the concentration of TAF 
b
May result in an increase in the concentrations of TAF
5.5.
Accountability for Tenofovir Alafenamide (TAF)
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.


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Investigational product accountability records will be provided to the study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit and/or bottles number dispensed

Record the date, quantity of used and unused IMP kit and/or bottles returned, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the 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 kits and/or 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. 


Tenofovir Alafenamide (TAF) 
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6. 
STUDY PROCEDURES 
Final 
Amendment 1 
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. 
The investigator must document any deviation from protocol procedures and notify the sponsor. 
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 be randomized 
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 3.2. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen ifthere 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 
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements. 
6.2.1. 
Screening Visit (Day -45 to Day 1 of Treatment) 
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: 
PPD 
• 
Obtain medical history, including Hepatitis B history and treatment history 
• 
Review of inclusion/exclusion criteria 
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
Review of AEs and concomitant medications

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), body weight, and height

Perform DXA scan of spine and hip. DXA scan will be performed at any time during the 
Screening period and should be completed at least 14 days prior to the first dose of the study 
drug, in order to ensure an acceptable pre-dose DXA scan

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed 
as needed)
Other viral serology (HCV, HIV and HDV)
eGFRCKD-EPI
Serum β-hCG pregnancy test (for all female subjects of child-bearing potential)
Alpha-fetoprotein (AFP). Subjects with an AFP >50 ng/mL or other findings concerning 
HCC must have an appropriate evaluation (e.g., CT scan) to rule out HCC prior to being 
able to enter into the study

Obtain urine sample for urinalysis, and urine drug screen 

Record any serious adverse events (SAE) and all adverse events (AE) related to protocol 
mandated procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
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.


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6.2.2.
Baseline Assessments (Day 1)
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 medical history, HBV history and HBV treatment history on any changes since 
screening visit

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight

Review of inclusion/exclusion criteria

Review of AEs and concomitant medication

Complete the “Fracture Risk Assessment” (FRAX®) eCRF

Cr EDTA Renal Scan 

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed)
eGFRCKD-EPI
Blood sample for Vitamin D assessment 
Blood sample for Fibrotest®
Blood sample for PBMC 
Blood sample for PK
Plasma, serum, and urine for storage
HBV resistance surveillance

Randomization


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• 
Fasting blood sample for bone, renal biomarkers and metabolic assessment (glucose and lipid 
panel [total cholesterol, HDL, direct LDL, and triglycerides])- no food or drinks, except 
water, at least 8 homs prior to blood collection 
• 
Fasting mine sample for renal biomarkers 
• 
Urine sample for minalysis, and for storage 
• 
Pregnancy test (for females of child-bearing potential; in case of a positive mine test, a sennn 
pregnancy test will be done) 
• PPD 
6.3. 
Treatment Assessments 
6.3.1. 
Study Week Assessments (Weeks 4-48) 
The following evaluations will be performed at Weeks 4-48 lmless specified; 
• 
Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit (Weeks 24, and 48 only) 
• 
Perf01m complete physical examination including, vital signs (blood pressme, pulse, 
respiration rate and temperatme), and body weight (Weeks 12, 24, and 48 only) 
• 
Perf01m symptom-driven physical examination including vital signs, and body weight 
(Weeks 4, 8, 20, and 36 only) 
• 
Review of AEs and concomitant medications 
• 
Cr EDTA Renal Scan (Week 48 only) 
• 
Perf01m DXA scan of spine and hip (Weeks 24 and 48 only) 
• 
Perf01m study dmg accountability 
• 
Dispense study <hugs 
• 
Obtain blood samples for laborat01y assessments as follows: 
-
Safety laborat01y tests (semm chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be perf01med as 
needed) (Weeks 24 and 48 only) 
-
eGFRcKD-EPI 
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-
Blood sample for Fibrotest® (Weeks 24 and 48 only) 
-
Blood sample for Vitamin D assessment (Weeks 24 and 48 only) 
-
Blood sample for AFP (Weeks 24 and 48 only) 
-
Blood sample for PK 
~PD 
-
Blood sample for PBMC (Weeks 24 and 48 only) 
-
Plasma, serum, and urine for storage 
-
HBV resistance surveillance 
Final 
Amendment 1 
• 
Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose. Subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing, the plasma PK samples from these subjects can be collected anytime 
(not timed) (Weeks 8 and 24 only) 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for bone and renal biomarkers- no food or drinks, except water, at 
least 8 hours prior to blood collection (Weeks 4, 12, 24, and 48 only) 
• 
Fasting urine sample for renal biomarkers (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for 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 (Weeks 24 and 48 only) 
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6.3.3. 
Early Discontinuation (ED) Visit 
Final 
Amendment 1 
The ED visit should be performed within 14 days from notification of study discontinuation 
• 
Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects 
• 
Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight 
• 
Review of AEs and concomitant medications 
• 
Perform DXA scan of spine and hip 
• 
Perform study drug accountability 
• 
Obtain blood samples for laboratory assessments as follows: 
-
Safety laboratory tests (serum chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
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-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
-
eGFRcKD-EPI 
-
Blood sample for Fibrotest® 
-
Blood sample for Vitamin D assessment 
-
Blood sample for AFP 
-
HBV resistance surveillance 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis 
• 
Fasting blood sample for bone and renal biomarkers -no food or drinks, except water, at 
least 8 hours prior to blood collection 
• 
Fasting urine sample for renal biomarkers 
• 
Fasting blood sample for 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 
6.4. 
Post-Treatment Assessments 
6.4.1. 
All Other Subjects Who Discontinue Study Drug 
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug will be followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.5. 
Assessments for Premature Discontinuation from Study 
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. 
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6.6. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
Final 
Amendment 1 
• 
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 
• 
Subjects with confirmed eGFRcKD-EPI of < 15 mL/min/ 1. 73m2 at any time during the study 
will have their study drug permanently discontinued 
• 
Lack of efficacy (virologic failure) 
• 
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 48 are not permitted to discontinue 
study drug prior to the Week 48 visit 
• 
Discontinuation of study drug for subjects 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 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 6 
• 
Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC) 
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6.8. 
Urine, Serum and Plasma for Storage 
Final 
Amendment 1 
A portion of the blood samples collected at each visit stru.ting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its reseru.·ch pattners for HBV 
genotyping/phenotyping assays or their development, for 
· 
the amount of HBV in the 
for measurement of antiviral 
levels in the blood 
A p01iion of the mine samples collected at each visit statiing at Baseline will be frozen and 
stored. These stored mine samples may be used by Sponsor PPD 
._ _ _.(in addition to the tests planned for the study). 
....._ __________ ____. 
At the conclusion of this study, these samples may be retained in storage by 
Gilead Sciences, Inc. for a period up to 15 years. 
6.9. 
Resistance Surveillance 
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for resistance 
mutations may be attempted for all viremic subjects (HBV DNA ~ 69 IU/mL). 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 virology sample for potential resistance smveillance will be collected at each study visit. 
6.10. 
End of Study 
The end of this study will be the last subject's last observation (or visit). 
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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

Persistent or significant disability/incapacity


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
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 are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator 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 sub investigator 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 (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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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 (e.g., 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 5). 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 
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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 rep01ted. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30 days 
period; however, if the investigator leams of any SAEs that occur after study paliicipation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and rep01t 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 
infonnation to Gilead DSPH within24 hours of the investigator's knowledge of the event. 
Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE inf01mation electronically, ie, the eCRF 
database is not fimctioning, record the SAE on the paper serious adverse event rep01ting 
f01m and submit within 24 hours to: 
Gilead DSPH: 
Fax: 
Email: 
Medical Monitor: 
Name: 
Telephone: 
Fax: 
Email: 
+1 (650) 522-5477 
Safety _FC@gilead.com 
Anuj Gagaar, MD PhD 
PPD 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE rep01ted via paper must be transcribed into the 
eCRF Database according to instJ.uctions in the eCRF completion guidelines. 
• If an SAE has been rep01ted via a paper fonn because the eCRF database has been locked, no 
further action is necessruy. 
• 
For fatal or life-tln·eatening events, copies of hospital case reports, autopsy repolis, 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 tJ.·aceability of a document to the subject identifiers. 
• 
Additional inf01mation may be requested to ensure the timely completion of accurate safety 
rep01is. 
• 
Any medications necessmy for tJ.·eatment 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 
f01m. 
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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 4.

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 5)

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.
Management of Potential Nephrotoxicity
eGFRCKD-EPI will be followed post-baseline during the study. All subjects on treatment with 
baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to <50 mL/min/1.73m2 at any 
post-baseline visit and those with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73m2 regardless 
of baseline eGFRCKD-EPI must have serum creatinine measured again within 3 calendar days of 
receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be 
measured and the estimated glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be 
calculated and compared with the baseline measurement of this parameter. 
7.5.5.1.
For subjects on TDF: 

For subjects with baseline eGFRCKD-EPI ≥50 mL/min/1.73m2 that decline to 
< 50 mL/min/1.73m2 at any post-baseline visit:
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, the 
subject will be required to undergo dose modification to every other day dosing of TDF
If the eGFRCKD-EPI is confirmed to be ≥ 30 mL/min/1.73m2 and < 50 mL/min/1.73m2, and 
the subject has undergone dose modification to every other day dosing of TDF and 
subsequently develops a confirmed eGFRCKD-EPI ≥ 50 mL/min/1.73m2, the subject may 
revert to once daily dosing of TDF after discussion with the Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 30 mL/min/1.73 m2 and
≥15 mL/min/1.73 m2:
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73m2 and ≥15 mL/min/1.73 m2, the 
subject will be required to undergo dose modification to every 96 hours dosing of TDF
If the eGFRCKD-EPI is confirmed to be < 30 mL/min/1.73 m2 and ≥15 mL/min/1.73 m2, 
and the subject has undergone dose modification to once every 96 hours dosing of TDF
and subsequently develops a confirmed CLCr ≥ 30 mL/min/1.73 m2, the subject may 
revert to every other day dosing of study drug after discussion with the 
Gilead Medical Monitor

For all subjects with a post-baseline eGFRCKD-EPI < 15 mL/min/1.73 m2: 
If the eGFRCKD-EPI is confirmed to be <15 mL/min/1.73 m2 , the subject will be required 
to permanently discontinue treatment according to Section 7.5.5.3
7.5.5.2.
For subjects on TAF: 

If the eGFRCKD-EPI is confirmed to be ≥15 mL/min/1.73 m2, no dose modifications are 
required


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7.5.5.3.
For subjects on TAF or TDF: 

All subjects with a confirmed eGFRCKD-EPI < 15 mL/min/1.73 m2 will be required to 
permanently discontinue treatment 

All subjects 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 two weeks of 
receipt of results
7.5.6.
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
7.5.6.1.
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.


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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.
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.
7.5.6.2.
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, 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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7.5.7.
Management of Ocular Safety
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.
Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
develops signs or symptoms of posterior uveitis, investigators should contact the Gilead 
Medical Monitor to discuss the need for additional ophthalmologic evaluation including dilated 
fundoscopy and optical coherence tomography (OCT).
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, 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).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure 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 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.
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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
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 
+1 (650) 522-5477 or email Safety_FC@gilead.com. Refer to Appendix 6 for Pregnancy 
Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirements.


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7.6.2.2. 
Reporiing Other Special Situations 
Final 
Amendment 1 
All special situations rep01ts (SSRs) will be recorded in the eCRF database within the timelines 
outlined in the eCRF completion guideline. 
Electronic Special Situations Report ( eSSR) Reporting Process 
• 
Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
information to Gilead DSPH within 24 homs 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 SSR inf01mation electronically, i.e., the eCRF 
database is not fimctioning, record the SSR on the paper serious adverse event reporting fotm 
and submit within 24 homs to: 
Gilead DSPH: 
Gilead Medical Monitor: 
Email: 
Fax: 
Name: 
Phone: 
Fax: 
Email: 
Safety _FC@gilead.com 
+ 1 (650) 522-5477 
• 
As soon as it is possible to do so, any SSR rep01ied via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SSR has been reported via a paper form because the eCRF database has been locked, no 
finther action is necessary. 
• 
These repotts 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 
rep01ied on the special situations repott fotm; however, for special situations that result in 
AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
f01m. 
• 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reporied as "misuse," but may be more appropriately documented as a protocol deviation. 
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations repotiing. 
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 ru1dlor the SAE repoti fotm. Details of the symptoms 
and signs, clinical management, and outcome will be rep01ted, when available. 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives ofthis study are: 
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• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
8.1.2. 
Primary Endpoint 
The primary safety endpoint is: 
• 
Change from baseline in eGFRcKD-EPI of TAF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
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8.1.3. 
Secondary Endpoint 
The secondary safety end points are: 
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• 
Percent change from baseline in hip and spine bone mineral density (BMD) ofT AF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in serum eGFRcKD-EPI of TAF 25 mg QD versus TDF -containing 
regimens at Week 48 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
8.1.4. 
Other End points of Interest 
8.2. 
Analysis Conventions 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The primary analysis set for efficacy analysis is the Full Analysis Set (F AS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the treatment actually received. All data collected during treatment will be included 
in the safety summaries. 
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8.2.1.3. 
Phrumacokinetics 
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The PK analysis set will include all subjects who ru·e randomized and have received at least 
one dose of study medication and for whom concentration data of any analytes of interest 
( eg, TAF and TFV) ru·e available. The PK analysis set will be used for analyses of concentration 
data. 
PD 
8.2.1.4. 
Biomru·kers 
The Biomru·ker analysis set will include all subjects who have evaluable biomarkers data. 
8.3. 
Data Handling Conventions 
For the primruy endpoint missing data will be handled using a missing = failure approach, unless 
othe1wise specified. 
For key seconda1y safety endpoints, an analysis will be perf01med using the Last Observation 
Canied F01wru·d (LOCF) method to impute the missing data. 
For other categorical secondmy efficacy endpoints, missing data will be handled using a 
missing = failure approach. For the dmg resistant mutations endpoint, a missing = excluded 
approach will be employed. 
Sensitivity analyses will be perfonned as wananted. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall. 
Demographic smnmaries will include sex, race/ethnicity, randomization stratification group, and 
age. 
Baseline data will include a smrunruy of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (:S ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
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8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when the study subjects complete 24 weeks of 
the treatment period or discontinue prematurely. The response rate of each treatment arm will be 
presented. A two-sided 95% confidence interval, adjusted for the randomization stratification 
factor (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) in the 
proportion of subjects who maintained viral suppression (HBV DNA < 20 IU/mL) at Week 24 
will be constructed.
8.5.2.
Secondary Analyses
The approach used for primary efficacy analysis will be applied for secondary efficacy analysis 
as in Section 8.5.1.
8.6.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment will be included in data listings.
8.6.1.
Primary Safety Analysis
The change from baseline in eGFRCKD-EPI at Week 24 will be summarized.
8.6.2.
Secondary Safety Analyses
The change from baseline in eGFRCKD-EPI at Week 48 will be performed. 
The percent change from baseline in hip and spine BMD at Weeks 24 and 48 will be summarized.
The change from baseline in serum creatinine at Weeks 24 and 48 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 by treatment group. 
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 
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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 
treatment up to the date of last dose of treatment. Continuing adverse events diagnosed prior to 
the sta1t 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 strut 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 by treatment group. 
8.6.5. 
Laboratory Evaluations 
Selected laboratoty data (using units) will be summarized using only observed data. Data and 
change from baseline at all scheduled time points will be summarized. 
Graded laboratoty abnotmalities will be defmed using the grading scheme in Appendix 5. 
Incidence of treatment-emergent laboratoty abnotmalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of 
last dose of treatment will be summarized by treatment group. If baseline data are missing, then 
any graded abnotmality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratoty abnotmalities that occm before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing. 
8.7. 
Pharmacokinetic Analysis 
Phatmacokinetic parameters will be listed and summarized for T AF and TFV using descriptive 
statistics ( eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations ofT AF and TFV over time 
will be plotted in semi logarithmic and linear fotmats as mean± standard deviation. 
PD 
8.8. 
Biomarker Analysis 
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1 
N-te1minal propeptide (P1NP), and selected renal biomarkers, including mine retinol binding 
protein, and mine beta-2-microglobulin, will be summarized by treatment group and visit using 
descriptive statistics. 
8.9. 
Sample Size 
This is an exploratoty study. No formal sample size calculation was perfotmed. 
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8.10.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data once after 30 subjects have completed 12 weeks of treatment, and provide 
recommendation to Gilead whether 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, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design.
Subsequent meetings will be held on an ad hoc basis. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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. 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) 
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. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 approved consent form for documenting 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 


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conducting the consent discussion, and also by an impartial witness if required by IEC or 
local requirements. For genomic testing, the consent form will inform subjects about genomic 
testing and sample retention, and their right to receive clinically relevant genomic analysis 
results.
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, the IRB/IEC 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 in the lab 
manual. 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, IEC
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);

Documentation of the reason(s) a consented subject is not enrolled


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
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 
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 


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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 QA, 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, 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.
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 IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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.
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 
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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.
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transplantation in European patients with the hepatitis B surface antigen. N Engl J 
Med 1993;329 (25):1842-7.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 90
22 November 2016
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
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.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic 
hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an 
expert panel on behalf of the European Society of Pediatric Gastroenterology, 
Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, et al. Randomized 
trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B 
immunoglobulin withdrawal after liver transplantation. Liver Transpl 2013;19 
(6):594-601.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2015.
World Health Organization (WHO). Guidelines for the Prevention, Care and Treatment of 
Persons with Chronic Hepatitis B Infection. 2015a.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015b.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 91
22 November 2016
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


Tenofovir Alafenarnide (T AF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
Gll.EAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment l 
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of 
Tenofovir Alafenamide {T AF) versus Tenofovir Disoproxil Fumarate (TDF)-containing 
Regimens in Subjects with Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant 
Gs-Us-320-3912, Amendment 1, 22 November 2016 
This protocol bas been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Anuj daggar,
hD 
Author 
Date 
~
p =--=
po
=------
:SJ&namre 
INVESTIGATOR STATEMENT 
I have read the protocol, including aU appendices, and l agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated 
Twill provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. 1 will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
PrincipaJ Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page92 
22 November 20 16 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Appendix 2. 
Study Procedures Table 
Screening 
(-45 Days) 
Visit Windows 
Written Informed Consent 
X 
Review of Inclusion/Exclusion Criteria 
X 
Medical History, including HBV history 
X 
Review Concomitant Medications 
X 
Adverse Events 
X 
Complete Physical Examination including 
X 
vi tal signs, and weight 
Height 
X 
Symptom-directed Physical Exam 
Body weight 
X 
Vital Signs b 
X 
Randomization 
DXAc (spine & hip) 
X 
FRAX
00 Fracture Risk Assessment Tool 
Cr EDT A renal scan 
Study Drug Accountability 
Study Drug Dispensed/Retrieved 
Dosing in-clinicd 
Serum Chemistry and Liver Function Tests• 
X 
eGFRcKD-EPI 
X 
Hematology 
X 
CONFIDENTIAL 
BL 
4 
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 
8 
+24 Hrs 
8 
+24 Hrs 
12 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 93 
20 
24 
36 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
48 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 1 
PPD[; 
r---
f---
r---
f---
X 
f---
X 
f---
X 
f---
f---
f---
X 
f---
X 
f---
r---
X 
f---
f---
f---
X 
f---
X 
f---
f---
X 
r---
X 
f---
X 
22 November 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Cystatin C (for estimated GFR) 
Plasma HBV DNA Levels 
Senun HBsAg (qualitativel 
Serum HBeAg (qualitative i 
Sample collection for HBV Resistance 
Surveillanceg 
HIV-1, HDV, HCV 
a-fetoprotein 
Fibrotest® 
Vitamin D 
Whole blood for PBMC 
Plasma PKm 
Fasting Blood for Bone Biomarkersh 
Fasting Blood for Renal Biomarkersh 
Fasting Urine for Renal Biomarkers; 
Fasting Metabolic Panel
0 
Serum Pregnancy Tes~ 
Urine Pregnancy Testi 
Ulinalysis 
Uline dmg screen 
~PPD 
Senun, and plasma for storage 
CONFIDENTIAL 
Scl'eening 
4 
(-45 Days) 
BL 
4 
+24 H1·s 
Visit Windows• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 94 
8 
8 
+24 Hl'S 
12 
20 
24 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
36 
48 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 1 
PPD 
ED 
-
-
X -
X 
-
X -X -
X 
-
-
X -
X 
-
X --
-
X -X -
X 
-
X 
-
-
X 
-
X -
~ 
22 November 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Final 
Amendment 1 
Scl'eening 
4 
8 
PPD~ 
(-45 Days) 
BL 
4 
+24 H1·s 
8 
+24 Hl'S 
12 
20 
24 
36 
48 
Visit Windows• 
±3 Days 
--
Urine for Storage 
X 
X 
X 
X 
X 
X 
X 
X 
X --
Health Related Quality of Life Smveys1 
X 
X 
X 
X 
f---
Imaging Test" 
X 
PPD 
a 
b 
c 
d 
e 
f 
g 
h 
m 
n 
0 
The out of visit window is ± 3 days nntil Week 48 and ± 14 days thereafter. 
Vital signs include blood pressm·e, pulse, respu·ation rate, and temperatme. 
The initial DXA will be pe1fonned dm·ing Screening and should be completed at least 14 days prior to the first dose of study dmg. The Week 48 DXA window is- 3 days 
only. DXA is required for Early Discontinuation (ED) visit if not done within the last 24 weeks. 
It is prefen·ed that subjects take theu· study drug according to a moming dosing schedule; subjects who elect to dose in the evening the previous day are not requu·ed to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 8 visits. 
Senun chemistry and Liver Flmction Tests: alkaill1e phosphatase, AST, ALT, GGT, total bilirubin, direct and u1direct bilirubin, total protein, albmnil1, LDH, CPK, 
bicarbonate, BUN, calcimn. chloride, creatu1ine, gluc.ose, phosphorus, magnesimn, potassimn, sodimn, m·ic acid, and amylase (reflex lipase testu1g is perfonned in subjects 
with total amylase> 1.5 x ULN). At Baseline, Weeks 24, 48, PPD 
lED, subject will be fasting for senm1 glucose and metabolic paneL Coagulation panel will be done 
at Screening and then as a reflex only test for ALT flares. 
Qualitative HBsAg and HBeAg will be pe1fonned at Sct·eening, Baseline (BL), Weeks 24, 48, PPD 
, and ED. HBeAb and HBsAb testu1g will be performed as 
reflex testing as needed. 
Sequence analysis of the HBV pol!R T for possible resistance mutation(s) may be attempted for any subject that experiences viretnia (HBV DNA > 69 IU/mL). 
Blood for selected bone biomarkers and renal biomarkers will be collected in a fasted state. Requu·ed for ED visit if the last sample was collected> 24 weeks prior. 
Urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected > 24 weeks prior. 
For female subjects of childbearu1g potential, the senun beta-HCG test will be perfonned at Screening. Urine test will be performed at all other visits as indicated. 
Positive m-ine test will be confumed with senun test. Pregnancy tests should include prevention cotulSelingc.;.. -----------------
Heaftli Related"Quahty of LiFe smveys incluaed'm th1s study are: SF-36, CLDQ, and"WPAI. The smveys win be adlninistered at BL, WeeKs 24, 48, 
and 
Early Discontumation Visits, if applicable. 
At Weeks 8 and 24 the plasma PK samples should be collected between 15 mumtes and 4 hom-s post-dose. 
At Screening, a-fetoprotein (AFP) will be measm·ed and subjects with an AFP >50 ng/mL or other findings conceming HCC must lmdergo inlagu1g test (e.g., CT scan) to mle 
out HCC. 
Fastu1g glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides) 
CONFIDENTIAL 
Page 95 
22 November 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page 96 
Final 
Amendment 1 
22 November 2016 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 97
22 November 2016
Appendix 4.
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 recurrences that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 98
22 November 2016
Appendix 5.
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 99
22 November 2016
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 100
22 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatermia 
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 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 101
22 November 2016
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 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 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


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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
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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/Lto <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


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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


Tenofovir Alafenamide (TAF)
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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 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 
weakness 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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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 6.
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 orchiectomy 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.

SAP_007.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety of Tenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver 
Transplant
Name of Test Drug:
Tenofovir Alafenamide (TAF)
Study Number:
GS-US-320-3912
Protocol Version (Date):
Amendment 3.0 (18 June 2019)
Analysis Type:
Final Analysis 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
11 June 2021
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


TAF 
GS-US-320-3912 Statistical Analysis Plan - Final Analysis 
Version 1.0 
Final 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ............................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................................................................ 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ .4 
LIST OF ABBREVIATIONS ......................................................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................................................................. 7 
1. 1. 
Study Objectives ........................................................................................................................................ 7 
1.2. 
Study Design ............................................................................................................................................. 8 
1.3. 
Sample Size and Power ............................................................................................................................. 9 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 10 
2.1. 
Interi1n Analyses ...................................................................................................................................... 10 
2.1. 1. 
DMC Analysis ....................................................................................................................... 10 
2. 1.2. 
Week 24 Analysis (Prima1y Analysis) .................................................................................. 10 
2.1.3. 
Week 48 Analysis .................................................................................................................. 10 
2.1.4. 
Final Analysis ........................................................................................................................ 10 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................. 11 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
Analysis Sets ........................................................................................................................................... 11 
3.1. 1. 
Rando1nized Analysis Set ...................................................................................................... 11 
3 .1. 2. 
Full Analysis Set (FAS) ......................................................................................................... 11 
3.1.3. 
Safe 
Anal sis Set ................................................................................................................ 11 
-
3.1.5. 
Sero og1ca y Ev ua e Fu Ana ys1s Set or HBsAg 
Loss/Seroconversion ............................................................................................................. 12 
3.1.6. 
Serologically Evaluable Full Analysis Set for HBeAg 
Loss/Seroconversion ............................................................................................................. 12 
3.1.7. 
DXA Analysis Set ................................................................................................................. 12 
3.1.7.1. 
Hip DXA Analysis Set. .................................................................................... 12 
3.1.7.2. 
Spine DXA Analysis Set ................................................................................. 12 
Subject Grouping ..................................................................................................................................... 12 
Strata and Covariates ............................................................................................................................... 13 
Examination of Subject Subgroups ......................................................................................................... 13 
Missing Data and Outliers ....................................................................................................................... 13 
3 .5. 1. 
Missing Data .......................................................................................................................... 13 
3.5.2. 
Outliers .................................................................................................................................. 13 
Data Handling Conventions and Transfo1mations .................................................................................. 14 
Analysis Visit Windows .......................................................................................................................... 14 
3. 7.1. 
Definition of Study Day ........................................................................................................ 14 
3. 7.2. 
Analysis Visit Windows ........................................................................................................ 16 
3.7.3. 
Selection of Data in the Event of Multiple Records for an Analysis Visit 
Day ........................................................................................................................................ 19 
4. 
SUBJECT DISPOSITION ................................................................................................................................... 21 
4.1. 
4.2. 
4.3. 
Subject Enrollment and Disposition ........................................................................................................ 21 
Extent of Study Thug Exposure and Adherence ...................................................................................... 22 
4.2.1. 
Duration of Exposure to Randoinized Study Thug ................................................................ 22 
4.2.2. 
Adherence to Randomized Stud Drno ................................................................................. 22 
CONFIDENTIAL 
Page2 
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4.4.
Assessment of COVID-19 Impact...........................................................................................................25
4.4.1.
Protocol Deviations Due to COVID-19 ................................................................................25
4.4.2.
Missed and Virtual Visits due to COVID-19 ........................................................................25
5.
BASELINE CHARACTERISTICS .....................................................................................................................26
5.1.
Demographics and Baseline Characteristics ...........................................................................................26
5.2.
Other Baseline Characteristics ................................................................................................................26
5.3.
Medical History.......................................................................................................................................27
6.
EFFICACY ANALYSES.....................................................................................................................................28
6.1.
Primary Efficacy Endpoint......................................................................................................................28
6.1.1.
Definition of the Primary Efficacy Endpoint ........................................................................28
6.1.2.
Analysis of the Primary Efficacy Endpoint...........................................................................28
6.1.3.
Secondary Analysis of the Primary Efficacy Endpoint.........................................................28
6.2.
Other Efficacy Endpoints ........................................................................................................................28
6.2.1.
Definition of Secondary and Other Efficacy Endpoints........................................................28
6.2.2.
Analysis Methods for Secondary and Other Efficacy Endpoints..........................................29
6.3.
Changes from Protocol-Specified Efficacy Analyses .............................................................................29
7.
SAFETY ANALYSES.........................................................................................................................................30
7.1.
Adverse Events and Deaths.....................................................................................................................30
7.1.1.
Adverse Event Dictionary .....................................................................................................30
7.1.2.
Adverse Event Severity .........................................................................................................30
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................30
7.1.4.
Relationship of AEs to Study Procedure...............................................................................30
7.1.5.
Serious Adverse Events.........................................................................................................31
7.1.6.
Treatment-Emergent Adverse Events....................................................................................31
7.1.6.1.
Definition of Treatment-Emergent Adverse Events........................................31
7.1.6.2.
Incomplete Dates .............................................................................................31
7.1.7.
Summaries of Adverse Events and Deaths............................................................................33
7.2.
Laboratory Evaluations ...........................................................................................................................34
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................34
7.2.1.1.
Metabolic Assessments....................................................................................35
7.2.1.2.
Calcium Correlated for Albumin.....................................................................35
7.2.2.
Graded Laboratory Values ....................................................................................................35
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................36
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities................................36
7.2.2.3.
Summaries of Laboratory Abnormalities ........................................................37
7.2.3.
ALT Elevation.......................................................................................................................37
7.2.4.
Liver-related Laboratory Evaluations....................................................................................37
7.3.
Bone Safety Analysis ..............................................................................................................................38
7.3.1.
Bone Mineral Density (BMD)...............................................................................................38
7.3.2.
Bone Biomarkers...................................................................................................................39
7.3.3.
Fracture Events......................................................................................................................39
7.3.4.
Assessment of Fracture Probability.......................................................................................39
7.3.5.
Bone Events...........................................................................................................................40
7.4.
Renal Safety Analysis..............................................................................................................................40
7.4.1.
Confirmed Renal Abnormalities............................................................................................40
7.4.2.
Serum Creatinine and Serum Cystatin C...............................................................................40
7.4.3.
Estimated Glomerular Filtration Rate ...................................................................................41
7.4.4.
Treatment-emergent Proteinuria (Dipstick) ..........................................................................42
7.4.5.
Urine RBP to Creatinine Ratio and Beta 2 Microglobulin to Creatinine 
Ratio ......................................................................................................................................42
7.4.6.
Proteinuria by Quantitative Assessment................................................................................43
7.4.7.
Other Renal Biomarkers........................................................................................................43


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7.4.8.
Cr EDTA ...............................................................................................................................44
7.5.
Body Weight............................................................................................................................................44
7.6.
Prior Hepatitis B Medications .................................................................................................................44
7.7.
Concomitant Medications........................................................................................................................44
7.8.
Other Safety Measures ............................................................................................................................45
7.9.
Changes From Protocol-Specified Safety Analyses................................................................................45
8.
REFERENCES.....................................................................................................................................................46
9.
SOFTWARE.........................................................................................................................................................47
10.
SAP REVISION...................................................................................................................................................48
11.
APPENDICES......................................................................................................................................................49
Appendix 1.
Study Procedures Table...........................................................................................................50
Appendix 2.
Data Collection of COVID-19 Data ........................................................................................54
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HBV DNA, Hematology, Serum Chemistry and Liver 
Function Tests, eGFR (by CG and CKD-EPI), UACR, UPCR, TmP/GFR, FEPO4, 
FEUA, Non-fasting Glucose, Weight, and Vital Sign Assessments .......................................17
Table 3-2.
Analysis Visit Windows for Fasting Glucose, Serum Cystatin C and eGFR by CKD-
EPI Cystatin C .........................................................................................................................18
Table 3-3.
Analysis Visit Windows for BMD Results from DXA, Fibrotest, Lipid Panel and 
HBV Serology .........................................................................................................................18
Table 3-4.
Analysis Visit Windows for Cr EDTA Renal Scan .................................................................18
Table 3-5.
Analysis Visit Windows for Renal and Bone Biomarkers ......................................................19
Table 3-6.
Analysis Visit Windows for Post Treatment Assessments......................................................19
Table 7-1.
Normal, Osteopenia, and Osteoporosis as Defined by T-score...............................................38
Table 7-2.
Method of Serum Creatinine Correction .................................................................................41


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CONFIDENTIAL
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LIST OF ABBREVIATIONS
AASLD
American Association for the Study of Liver Diseases
AE
adverse event
ALT
alanine aminotransferase (SGPT)
Anti-HBe
antibody to HBeAg
Anti-HBs
antibody to HBsAg
AST
aspartate aminotransferase (SGOT)
BLQ
below the limit of quantitation
BMD
bone mineral density
BMI
body mass index
bsAP
bone specific alkaline phosphatase
CDER
Center for Drug Evaluation and Research
CG
Cockcroft-Gault
CHB
chronic hepatitis B
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration formula for calculating 
glomerular filtration rate
CLCr
creatinine clearance
CMH
Cochran-Mantel-Haenszel
Cr EDTA
Chronium ethylenediamine tetraacetic acid
CRF
case report form
CTX
c-type collagen sequence
CV
coefficient of variation
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ESDD
early study drug discontinuation
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEPO4
fractional excretion of filtered phosphate
FEUA
fractional excretion of uric acid
GFR
glomerular filtration rate
Gilead
Gilead Sciences, Inc.
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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HDL
high density lipoprotein
HDV
hepatitis D virus
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IVRS
interactive voice response system  
IWRS
interactive web response system
LDL
low density lipoprotein
LLN
LLOQ
lower limit of the normal range
lower limit of quantitation
LLT
lower-level term
LOCF
last observation carried forward
M = E
Missing = Excluded
M = F
Missing = Failure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mantel-Haenszel 
OAV
Oral antiviral
OC
osteocalcin
P1NP
procollagen type 1 N-terminal propeptide
PP
per protocol
PT
preferred term
Q
quartile
Q1
first quartile
Q3
third quartile
RBP
retinol binding protein
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TAF
tenofovir alafenamide 
TDF
TFFU
tenofovir disoproxil fumarate (Viread®)
Treatment Free Follow-Up
TFLs
tables, figures, and listings
TFV
tenofovir
TFV-DP
tenofovir-diphosphate
TmP
tubular maximum reabsorption rate of phosphate
UACR
urine albumin to creatinine ratio
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio
WHO
World Health Organization


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INTRODUCTION 
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This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for the final analysis of Study 
GS-US-320-3912. This SAP is based on the study protocol Amendment 3.0 dated 18 June 2019 
and the electronic case repo1i fonn (eCRF). The SAP will be finalized prior to data finalization. 
Any changes made after the finalization of the SAP will be documented in the clinical study 
repo1i (CSR). 
1.1. 
Study Objectives 
The prima1y objectives of this study are as follows: 
• 
To evaluate the safety and tolerability ofTAF 25 mg once daily (QD) versus TDF-containing 
regimens as determined by the change from baseline in estimated glomernlar filtration rate 
by Chronic Kidney Disease Epideiniology Collaboration fo1mula (eGFRcKD-EPV at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondaiy objectives of this study ai·e as follows: 
• 
To evaluate the safety ofTAF 25 mg QD versus TDF-containing regimens as dete1mined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety ofTAF 25 mg QD versus TDF-containing regimens as dete1mined by 
the change from baseline in sennn creatinine at Weeks 24 and 48 
• 
To evaluate the safety ofTAF 25 mg QD versus TDF-containing regimens as dete1mined by 
the change from baseline in eGFRc!<D-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
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1.2.
Study Design
This is a randomized, open-label, single center Phase 2 study to evaluate the safety and efficacy 
of TAF 25 mg QD versus TDF in adult chronic hepatitis B (CHB) infection subjects with Stage 2 
or greater chronic kidney disease and have previously received a liver transplant.
Treatment Groups
Approximately 50 subjects will to be randomized 1:1 to either continue current treatment 
regimen with TDF (alone or in combination with other approved antivirals) or to receive TAF 
25 mg orally daily. Approximately 40 of 50 subjects were to be enrolled with eGFRCKD-EPI 
< 60 ml/min/1.73m2. Randomization was stratified by screening renal function (eGFRCKD-EPI 
< 50 ml/min/1.73m2 and ≥ 50 ml/min/1.73m2)

Treatment Arm A: approximately 25 subjects administered TAF 25 mg oral daily

Treatment Arm B: approximately 25 subjects to continue administration of TDF alone or in 
combination with other approved antivirals as per local practice
Key Eligibility Criteria
Subjects were to have met the following key eligibility criteria:

Documented evidence of chronic HBV infection prior to transplantation

Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from 
deceased or living donor

Liver Transplant ≥ 12 weeks prior to screening

Maintained on TDF alone or in combination with other approved antivirals for HBV 
prophylaxis or treatment

Have been on approved HBV oral antiviral (OAV) treatment for at least 12 weeks post-
transplant prior to screening, with HBV DNA < lower limit of quantitation (LLOQ) at 
screening

Screening eGFRCKD-EPI < 90 ml/min/1.73m2
Study Periods/Phases
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to Screening, subjects will be randomized to receive TAF or TDF alone or in 
combination with approved antivirals per local practice.


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choose to not continue or discontinue TAF prematurely, they will be followed for 24 weeks after 
the discontinuation of study tr·eatment (ie, Treatment Free Follow-Up, TFFU) or until an 
alternative CHB u-eatment is started, whichever occurs first. In this SAP, the first 48 weeks of 
stud tr·eatment is refened to as randomized hase 
Schedule of Assessments 
Laborato1y analyses (sernm chemistry, liver tests, hematology, plasma HBV DNA levels, 
pregnancy testing [for females of childbearing potential]), body weight, vital signs, adverse 
events (AEs and concomitant medications will be erfonned at screenin baseline Week 4 
12 20 24 
HBV serology 
ualitative HBsAg and HBeAg) will be perfonned at screening, baseline, 
Weeks 24, 48, 
and ED. HBeAb and HBsAb testing will be perfo1med as reflex 
testing as needed. Bone and renal biomarker testing will be perfonned at baseline and then at 
defined intervals throughout the study. Vitamin D assessments, FibroTest® and fasting metabolic 
assessments fasting glucose and lipid panel) will be perfo1med at baseline, Weeks 24, 
ED visit. Chronium eth lenediamine tetr·aacetic acid (Cr EDTA) renal scan will be 
at baseline, Week 48 
visit. 
h sical examinations will be perfo1med at screening, baseline, and Weeks 12, 24, 48, 
/ED visit. Symptom directed physical examinations including body weight 
assessment will be conducted at all other visits. Dual energy x-ray absorptiometry (DXA) scans 
of the hip and spine should be perfo1med during Screening and should be completed at least 
14 days prior to the first dose of study drng, and will be conducted at Weeks 24, 48, _ 
-
and the ED visit if not done within the last 24 weeks of this visit. Plasma, sernm, and urine 
will be collected at baseline and at eve1y visit thereafter for storage. 
Treatment Free Follow-Up (TFFU) assessments will occur eve1y 4 weeks for 24 weeks and 
include the followin : vital si ns hematolo 
sennn chemistry, liver function tests, and plasma 
HBV DNA. 
Randomization 
Subjects who meet eligibility criteria will be randomized 1: 1 to receive T AF or either 
continue on TDF alone or in combination with other approved antivirals for 48 weeks. 
Randomization was str·atified by screening renal function ( eGFRcKD-EPI < 50 ml/min/1. 73m2 
and 
50 ml/min/1. 73m2) 
1.3. 
Sample Size and Power 
This is an explorato1y study. No fonnal sample size calculation was perfo1med. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
DMC Analysis 
The data monitoring committee (DMC) reviewed the progress of the study and performed review 
of safety data after 30 subjects had completed 12 weeks of treatment. The DMC noted no safety 
concerns that would merit altering the course of the study and recommended that the study 
should proceed as planned.
The DMC’s specific activities were defined by a mutually agreed charter, which defined the 
DMC’s membership, conduct and meeting schedule. More details are documented in the 
independent DMC charter.
2.1.2.
Week 24 Analysis (Primary Analysis)
The Week 24 analysis was conducted after the last subject completed the Week 24 visit or 
prematurely discontinued study drug. This analysis was described in the Week 24 Analysis SAP 
dated 19 March 2018. This is considered the primary analysis of the study. All analyses except 
PK analyses will be reproduced in the Final Analysis.
2.1.3.
Week 48 Analysis
The Week 48 analysis was conducted after the last subject completed the randomized phase at 
Week 48 visit or prematurely discontinued study drug. This was an interim analysis performed 
based on a data snapshot. 
2.1.4.
Final Analysis
The final statistical analysis for the study will be conducted after all subjects have completed the 
study, outstanding data queries have been resolved or adjudicated as unresolvable, and the data 
have been cleaned and finalized. This SAP describes the analysis plan for the Final Analysis.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set unless 
otherwise specified, and sorted by subject ID number, visit date, and time (if applicable). Data 
collected on log forms, such as AEs, will be presented in chronological order within a subject. 
The treatment group to which subjects were randomized will be used in the listings. 
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
Randomized Analysis Set
The Randomized Analysis Set will include all subjects who are randomized into the study. This 
is the primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set (FAS)
The FAS will include all randomized subjects who have received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment to which they were randomized. This is the 
primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all subjects who have received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment they actually received during the 
randomized phase. The actual treatment received will differ from the randomized treatment only 
when their actual treatment differs from randomized treatment for the entire treatment duration. 
This is the primary analysis set for safety analyses.


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3.1.5. 
Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion 
The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drng, and with serology 
data showing the subject to be HBsAg positive and HBsAb negative or missing at baseline. 
Subjects will be analyzed according to the ti·eatment to which they were randomized. 
3.1.6. 
Serologically Evaluable Full Analysis Set for HBeAg Loss/Seroconversion 
The Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drng, and with serology 
data showing the subject to be HBeAg positive and HBeAb negative or missing at baseline. 
Subjects will be analyzed according to the ti·eatment to which they were randomized. 
3.1.7. 
3.1.7.1. 
DXA Analysis Set 
Hip DXA Analysis Set 
The Hip DXA Analysis Set will include all subjects who were randomized and had received at 
least 1 dose of study diug, and had nonmissing baseline hip BMD values. Subjects will be 
analyzed according to the ti·eatment they actually received during the randomized phase. 
3.1.7.2. 
Spine DXA Analysis Set 
The Spine DXA Analysis Set will include all subjects who were randomized and had received at 
least 1 dose of study diug, and had nonmissing baseline spine BMD values. Subjects will be 
analyzed according to the ti·eatment they actually received during the randomized phase. 
3.2. 
Subject Grouping 
For efficacy analysis, subjects will be analyzed by randomized ti·eatment. For safety analysis 
using the Safety Analysis Set, subjects will be analyzed by actual ti·eatment received during the 
randomized phase. 
Subjects will be grouped into the following ti·eatment groups: 
Randomized phase summaries: 
• 
TAF25mg 
• 
TDF-containing regimens 
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3.3. 
Strata and Covariates 
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Subjects were to be randomly assigned to treatment groups via the interactive voice or web 
response system (IXRS) in a 1: 1 ratio using a strntified randomization schedule. Strntification 
was based on the following variables: 
• 
Screening renal function ( eGFRcKD-EPI < 50 mL/min/1. 73m2 and ~ 50 mL/min/1. 73m2) 
3.4. 
Examination of Subject Subgroups 
There are no prespecified subject subgroupings for efficacy and safety analysis. 
3.5. 
3.5.1. 
Missing Data and Outliers 
Missing Data 
In general, missing data will not be imputed, unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
A missing baseline laborato1y result will be treated as n01mal (ie, no toxicity grade) for the 
laborato1y abnonnality summaiy. 
Both baseline and postbaseline borderline results for HBeAg, hepatitis B e antibody (HBeAb ), 
HBsAg, and hepatitis B surface antibody (HBsAb) will be imputed as follows: 
• 
HBsAb/HBeAb borderline 
HBsAb/HBeAb negative 
• 
HBsAg/HBeAg borderline 
HBsAg/HBeAg positive 
For missing last dosing date of study dmg, imputation mies ai·e described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for 
prior and concomitant medications in Section 7. 7. 
3.5.2. 
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the analyses. 
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3.6.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows except for direct bilirubin, urine 
creatinine, and serum cystatin C:

A value that is 1 unit less than the lower LOQ will be used for calculation of descriptive 
statistics if the datum is reported in the form of “< x” (x is considered as the lower LOQ). For 
example, if the values are reported as < 50 and < 5.0, then values of 49 and 4.9 will be used 
for calculation of summary statistics, respectively. 

A value that is 1 unit above the upper LOQ will be used for calculation of descriptive 
statistics if the datum is reported in the form of “> x” (x is considered as the upper LOQ). 
Values with decimal points will follow the same logic as stated above. 

The lower or upper LOQ will be used for calculation of descriptive statistics if the data is 
reported in the form of “≤ x” or “≥ x” (x is considered as the lower or upper LOQ, 
respectively).
For direct bilirubin, a value of “< 0.1” is imputed as 0.09. For urine creatinine, a value of “< 1” is 
handled as a missing value in its summary and the calculation of related ratios. For serum 
cystatin C, a value of “< 0.10” is handled as a missing value in the calculation of estimated 
glomerular filtration rate (eGFR).
For HBV DNA, if the value in IU/mL (AMPLIPREP TAQM) is above the upper limit of 
quantification, the corresponding diluted value (AMPLIPREP TAQ), if available, will be used.
3.7.
Analysis Visit Windows
3.7.1.
Definition of Study Day
Study Day 1 is defined as the day when the first dose of study drug was taken, as recorded on 
the Study Drug Administration eCRF form.
Since the TDF group subjects are to continue administration of TDF alone or in combination 
with other approved antivirals as per local practice, for the TDF group the Study Day 1 is defined 
as: the first actual dose date on or after the latest lab or PK visit date with Baseline/Day 1 visit.


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Study days are calculated relative to Study Day 1. For events that occuned on or after 
Study Day 1 date, study days are calculated as (visit date - Study Day 1 + 1). For events that 
occuned prior to Study Day 1, study days are calculated as (visit date - Study Day 1). 
Follow-up days are for visits occuning during the 24-week ti·eatment-free follow-up period and 
calculated as (visit date - last dose date). 
Last Dose Date of Randomized Drug is the latest non-missing end date of randomized diug, 
recorded on the Study Drng Administi·ation eCRF f01m with "Study Drng Pennanently 
Discontinued" box checked for subjects who prematurely discontinued randomized diu g or who 
completed randomized drng according to the Randomized Study Drng Completion eCRF. If the 
last dose date ofrandomized diu g is missing (eg, due to lost to follow up) for subjects who 
prematurely discontinued randomized diug, or for subjects who are still on randomized diug, the 
latest of non-missing randomized study diu g start dates and end dates the clinical visit dates and 
the laborato1y visit dates excluding the dates of 
24-week 
ti·eatment-free follow-up visits will be used to impute the last dose date of randomized drng. 
For subjects who premature! discontinued randomized stud 
or who completed 
randomized study drng 
the Last Dose Date 
is the same as Last Dose Date of Randomized Study Drng. 
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Last Study Date is the latest of non-missing study dmg (randomized- phase) staii 
dates and end dates, the clinic visit, the laborato1y visit and DXA visit dates including the 
24-week treatment-free follow-up visit date for subjects who prematurely discontinued study or 
who completed study according to Study Completion eCRF. 
Baseline value for the randomized phase ( except DXA BMD) is defined as the last 
non-missing value obtained on or prior to Study Day 1. For DXA BMD, the baseline value is 
defined as the last non-missing value on or prior to Study Day 14. 
3.7.2. 
Analysis Visit Windows 
Subject visits might not occur on protocol-specified days. Therefore, for the pmpose of analysis, 
observations will be assigned to analysis windows. 
The following windows (Table 3-1 to Table 3-5) apply to baseline and on-treatment assessments 
only. For summaries and analysis, assessments will first~ed into baseline and on-
treatment assessments occuning during the randomized-
phase, before applying 
analysis windows. 
· 
· 
· 
mized study dmg 
, laborato1y assessments up to and including 
ays, and DXA assessments up to and 
including the last dose date of the randomized study dmg + 14 days, will be considered as 
baseline or on-treatment during the randomized phase. 
For subjects who have not discontinued the randomized study dmg pe1manently, data collected 
up to database finalization date will be considered as baseline or on-treatment of the randomized 
phase. 
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For subjects who discontinue study drng early due to HBsAg loss with confmned 
seroconversion, all efficacy data including data collected after the last dose date of the study chu g 
will be reassigned analysis visits using the on-treatment assessment windows (Table 3-1 and 
Table 3-3). 
The analysis windows for HBV DNA, hematology, sennn chemistry and liver function tests, 
eGFR (by CG and CKD-EPI), renal biomarkers urine albumin to creatinine ratio (UACR), urine 
protein to creatinine ratio (UPCR), renal tubular maximum reabsorption rate of phosphate to the 
glomernlar filtration rate (TmP/GFR), urine fractional excretion of filtered phosphate (FEP04), 
fractional excretion of uric acid (FEUA), non-fasting glucose, weight, and vital sign assessments 
are provided in Table 3-1. 
Table 3-1. 
Nominal Visit 
Baseline 
Week4 
Week8 
Week 12 
Week 20 
Week 24 
Week 36 
Week48 
Analysis Visit Windows for HBV DNA, Hematology, Serum 
Chemistry and Liver Function Tests, eGFR (by CG and CKD-EPI), 
UACR, UPCR, TmP/GFR, FEP04, FEUA, Non-fasting Glucose, 
Weight, and Vital Sign Assessments 
Nominal Study Day 
Lower Limit 
Upper Limit 
1 
28 
2 
41 
56 
42 
69 
84 
70 
111 
140 
112 
153 
168 
154 
209 
252 
210 
293 
336 
294 
377 (4J9b) 
b 
Applies to UACR, UPCR, TmP/GFR, FEP04 and FEUA only. 
The analysis window for Fasting Glucose, Sennn Cystatin C and eGFR by CKD-EPI Cystatin C 
is in Table 3-2. 
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Table 3-2.
Analysis Visit Windows for Fasting Glucose, Serum Cystatin C and 
eGFR by CKD-EPI Cystatin C
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
55
Week 12
84
56
125
Week 24
168
126
251
Week 48
336
252
419
The analysis windows for BMD results from DXA, fasting and non-fasting lipid panel including 
direct low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol to 
HDL ratio, Fibrotest and HBV serology are presented in Table 3-3.
Table 3-3.
Analysis Visit Windows for BMD Results from DXA, Fibrotest, Lipid 
Panel and HBV Serology
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1(14a)
Week 24
168
2(15a)
251
Week 48
336
252
503
a
Applies to DXA only. Upper limit for baseline DXA BMD is Day 14 and lower limit for Week 24 DXA BMD is Day 15.
The analysis windows for Cr EDTA renal scan are presented in Table 3-4. 
Table 3-4.
Analysis Visit Windows for Cr EDTA Renal Scan
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
Week 48
336
2
503
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The analysis windows for renal biomarkers including urine retinol binding protein (RBP) to 
creatinine ratio, urine beta-2-microglobulin to creatinine ratio, and bone biomarkers including 
serum parathyroid hormone (PTH), C-type collagen sequence (CTX), procollagen type 1 N-
terminal propeptide (P1NP), osteocalcin (OC), and bone specific alkaline phosphatase (bsAP) 
are presented in Table 3-5.
Table 3-5.
Analysis Visit Windows for Renal and Bone Biomarkers
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
55
Week 12
84
56
125
Week 24
168
126
251
Week 48
336
252
419
Data collected after the last dose date will be considered as post-treatment visits. The analysis 
windows for post-treatment assessments are presented in Table 3-6.
Table 3-6.
Analysis Visit Windows for Post Treatment Assessments
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Follow-Up Week 4
28
4
41
Follow-Up Week 8
56
42
69
Follow-Up Week 12
84
70
97
Follow-Up Week 16
112
98
125
Follow-Up Week 20
140
126
153
Follow-Up Week 24
168
154
181
3.7.3.
Selection of Data in the Event of Multiple Records for an Analysis Visit Day 
Depending on the statistical analysis method, single values are required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rule(s) will be used. 
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For baseline of the randomized phase, the last available record on or prior to the first dose of 
study drug will be selected. For DXA BMD, it is defined as the last value on or prior to Study 
Day 14. If there are multiple records with the same time or no time recorded on the same day for 
numeric observations, average will be computed for that day. If there are multiple records with 
the same time or no time recorded on the same day for categorical observations, the most 
conservative value will be taken, eg, negative will be selected over positive for HBeAg and 
HBsAg, and positive will be selected over negative for HBeAb and HBsAb.
The following specified rules will be used for postbaseline visits:

Alanine aminotransferase (ALT): The largest value will be included in the analysis when 2 
or more ALT values occur within the same visit window.

BMD: The latest record in the window will be selected.

HBV DNA (IU/mL): The record closest to the nominal day for that visit will be selected. If 
there are 2 records equidistant from the nominal day, the latest will be selected. If there is 
more than 1 record on the selected day, the geometric mean will be taken.

Serology: For HBeAg, HBeAb, HBsAg, and HBsAb, the record closest to the nominal day 
for that visit will be selected. If there are 2 records equidistant from the nominal day, the 
latest will be selected. If there is more than 1 record on the selected day, the most 
conservative value will be taken, ie, positive will be selected over negative for HBeAg and 
HBsAg, and negative will be selected over positive for HBeAb and HBsAb.
For all other laboratory parameters: 

If multiple valid non-missing numeric observations exist in a window, then records will be 
chosen as follows:
The record closest to the nominal day for that visit will be selected. If there are 2 records 
equidistant from the nominal day, the latest will be selected. If there is more than 1 record 
on the selected day, the average will be taken.

If multiple valid non-missing categorical observations (eg, safety ECG results) exist in a 
window, then records will be chosen as follows:
The most conservative value (eg, abnormal will be selected over normal for safety ECG) 
within the window will be selected. In the event that 2 values within a window are of 
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SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
Version 1.0 
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Key study dates (first subject screened, first subject randomized, last subject randomized, last 
subject last visit for the primaiy endpoint, and last subject last visit for the clinical study repo1i) 
will be provided. 
The number and percentage of subjects enrolled in each randomization stratum will be 
summarized based on interactive voice response system/web response system (IXRS) data. If 
there are discrepancies between IXRS and screening laborato1y data with regard to stratum 
assignment, a listing of the discrepancies will be provided. 
The summaiy of subject disposition will be provided by treatment group and overall. This 
sunnnaiy will include the number of subjects screened, screen failure subjects who were not 
randomized, subjects who met all eligibility criteria and were not randomized, subjects in the 
Randomized Anal sis Set sub· ects randomized but not treated, subjects in the Safety Analysis 
Set 
Study Drug Completion 
• 
Prematurely discontinued randomized study treatment (with summaiy of reasons for 
discontinuing treatment) 
• 
Completed randomized study treatment 
I 
I 
Study Completion 
• 
Entered 24-week treatment-free follow-up period 
• 
Prematurely discontinued study (with summaiy of reasons for discontinuing study) 
• 
Completed protocol-planned duration of the study 
No inferential statistics will be generated. A data listing of reasons for premature study 
drng/study discontinuation will be provided. 
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4.2.
Extent of Study Drug Exposure and Adherence
Exposure data described below will be summarized for the randomized phase 
 
4.2.1.
Duration of Exposure to Randomized Study Drug
Duration of exposure to randomized study drug will be defined as (last dose date of randomized 
study drug – first dose date of randomized study drug + 1), regardless of temporary interruptions 
in study drug administration, and will be expressed in weeks (recorded to 1 decimal place, 
eg, 4.5 weeks). If subjects are still on randomized study drug, the latest of randomized study drug 
start and end dates, and the clinic and laboratory visit dates (excluding the 
 
 treatment-free follow-up visit dates) will be used to impute the last dose 
date of randomized study drug for calculating the duration of randomized study drug exposure.
Duration of exposure to randomized study drug will be summarized using descriptive statistics 
(sample size, mean, SD, median, Q1, Q3, minimum, and maximum) and as the number and 
percentage of subjects exposed for specified periods, eg, ≥ 4 weeks (28 days), ≥ 8 weeks (56 
days), etc. 
Summaries will be provided by treatment group for subjects in the Safety Analysis Set. 
No inferential statistics will be provided. 
4.2.2.
Adherence to Randomized Study Drug
Study drug regimen adherence will be computed based on tablet counts for the TAF group only. 
The numbers of tablets of study drug dispensed and returned are captured on study drug 
accountability forms.
Adherence (%) of study drug regimen will be calculated as follows:
prescribed
 tablets
of
Number 
 taken
 tablets
of
Number 
100
(%)
Adherence


[2]
period
dispensing
each
at 
prescribed
 tablets
of
No.
[1]
period
dispensing
each
at 
 taken
 tablets
of
No.
100




[1]
Number of tablets taken at a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number 
of tablets prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same 
dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number of 
tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable 
dispensing periods.
[2]
Number of tablets prescribed at a distinct dispensing period for a study drug is calculated as the daily number of tablets 
prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. 
Total number of tablets prescribed is determined by summing the number of tablets prescribed from all evaluable dispensing 
periods.
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The duration of treatment at a dispensing period for a study drng is calculated as the 
minimum of (a) the last returned date of the same dispensing period for the study drng, 
Version 1.0 
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(b) date of premature discontinuation of the study chug, and (c) next dispensing date of the 
study chug, minus dispensing date of the study chug. 
The next dispensing date is the following dispensing date of the study chug regardless of the 
bottle return date. 
For a record where the number of tablets returned was missing (with "Yes" answered for 
"Was bottle returned?" question), it is assumed the number of tablets returned was 0. If the 
number of tablets dispensed was missing or any study ch11g bottle was not returned or the bottle 
return status was unknown for the same dispensing date, then all records for the same dispensing 
date for that study chug will be excluded from both denominator and numerator calculation. 
Adherence up to Week 48 visit will be calculated for each subject for the entire randomized 
dosing period up to the date of pe1manent discontinuation of the randomized study chug for 
subjects who prematurely discontinued randomized study chug or completed randomized study 
chug or using all data available for subjects remaining on randomized study ch11g. 
The number and percentage of subjects who return at least 1 bottle and have calculable 
adherence during the study, descriptive statistics for adherence up to Week 48 visit for a study 
chug regimen (sample size, mean, SD, median, Ql, Q3, minimum, and maximum) along with the 
number and percentage of subjects belonging to adherence categories ( eg, < 80%, 
80% to 
< 90%, 
90% to < 95%, 
95%) will be provided by treatment group for the Safety Analysis 
Set. No inferential statistics will be provided. 
-
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4.3. 
Protocol Deviations 
Version 1.0 
Final 
A listing will be provided for subjects in the Randomized Analysis Set who violated at least 
1 inclusion or exclusion criterion. The listing will include the unmet criteria. A listing of subjects 
who received the wrong study ti·eatment will also be provided. 
Protocol deviations occuning after subjects entered the study are documented dming routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason will be summarized by ti·eatment group for the Randomized Analysis Set. 
A by-subject listing will be provided for those subjects with impo1iant protocol deviations. 
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4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct, including in some cases the disruption in the regular visit 
schedules. Some subjects were unable to attend onsite visits due to shelter in place guidelines, 
site closures, or other reasons. This section describes how special situations due to COVID-19 
will be handled in the analysis.
4.4.1.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviations related to 
COVID-19 if applicable. A separate listing will be provided for subjects with non-important 
protocol deviations related to COVID-19 if applicable.
4.4.2.
Missed and Virtual Visits due to COVID-19
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order.
Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields.  A detailed 
explanation of the algorithm is given in Appendix 2.


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5.
BASELINE CHARACTERISTICS  
5.1.
Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex, race, and ethnicity) and baseline characteristics 
(eg, body weight, height, and body mass index [BMI]) will be summarized by treatment group 
and overall, using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and 
maximum) for continuous data and by the number and percentage of subjects for categorical 
data. Age is calculated as age in years at the first dose of study drug. The summaries of 
demographic data and baseline subject characteristics will be provided for the Safety Analysis 
Set. A by-subject demographic listing will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
The following baseline disease characteristics will be summarized by treatment group and 
overall using descriptive statistics:

BMI categories (< 18.5 kg/m2 [underweight], ≥ 18.5 - 25.0 kg/m2 [normal], 
≥ 25.0 - 30.0 kg/m2 [overweight], and ≥ 30.0 kg/m2 [obese])

HBV DNA (IU/mL)

HBV DNA categories (< 20 IU/mL, ≥ 20 to < 69 IU/mL, ≥ 69 IU/mL)

ALT (U/L)

ALT level based on central laboratory normal range (≤ upper limit of normal [ULN], > ULN 
- 5 × ULN, > 5 × ULN – 10 × ULN, > 10 ULN)

ALT level based on 2018 American Association for the Study of Liver Diseases (AASLD) 
normal range with the ULN as 25 U/L for female and 35 U/L for male (≤ ULN, > ULN − 5 × 
ULN, > 5 × ULN − 10 × ULN, > 10 ULN)

Estimated GFR by CG (mL/min), CKD-EPI creatinine (mL/min/1.73 m2), CKD-EPI Cystatin 
C (mL/min/1.73 m2) and Cr EDTA (mL/min/1.73 m2) methods

Chronic kidney disease (CKD) stage by estimated GFR by CG, CKD-EPI creatinine, CKD-
EPI Cystatin C and Cr EDTA methods 

HBeAg status (positive, negative)

HBeAb status (positive, negative)

HBsAg status (positive, negative)

HBsAb status (positive, negative)


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
Previous TDF use experience (yes, no) and TDF use at Day 1

Previous Lamivudine use experience (yes, no) and Lamivudine use at Day 1

Years positive for HBV 

Years of liver transplant

Fibrotest score

Fibrosis stage by fibrotest score (0 - 0.48, 0.49 - 0.74, 0.75 - 1)

Proteinuria by urinalysis (dipstick) (Grade 0, Grade 1, Grade 2, Grade 3)

Vitamin D 

Clinical BMD status (normal, osteopenia, osteoporosis)

Hip fracture and major osteoporotic fracture probabilities estimated using FRAX® 
(see Section 7.3.4)
The stages of CKD by estimated GFR are defined as follows:

Stage 1:  ≥ 90 

Stage 2:  ≥ 60 and < 90 

Stage 3:  ≥ 30 and < 60 
Stage 3a: ≥ 45 and < 60 
Stage 3b: ≥ 30 and < 45 

Stage 4: ≥ 15 and < 30 

Stage 5: < 15 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
A listing of medical history data will be provided for the Randomized Analysis Set.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
The analysis of the primary efficacy endpoint was performed previously; this analysis will also 
be repeated in the Final Analysis for completeness.
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with HBV DNA < 20 IU/mL at 
Week 24.
6.1.2.
Analysis of the Primary Efficacy Endpoint
The primary efficacy analysis will be conducted after the last randomized subject reaches 
Week 24 or discontinues study drug prematurely. A Missing = Failure (M = F) approach will be 
employed. In this approach, all missing data will be treated as not achieving the primary 
endpoint (ie, having HBV DNA ≥ 20 IU/mL).
6.1.3.
Secondary Analysis of the Primary Efficacy Endpoint
Sensitivity analyses will be performed for the primary endpoint using Missing = Excluded 
(M = E) approach. In this approach, all missing data will be excluded in the computation 
(ie, missing data points will be excluded from both the numerator and denominator in proportion 
computation).
6.2.
Other Efficacy Endpoints
The analysis of the secondary and other efficacy endpoints at Weeks 24 and 48 was performed 
previously; the analysis will also be repeated in the Final Analysis for completeness.
6.2.1.
Definition of Secondary and Other Efficacy Endpoints
The secondary efficacy endpoint is:

The proportion of subjects with plasma HBV DNA < 20 IU/mL at Weeks 48
Other efficacy endpoints include: 

The proportion of subjects with normal ALT (by central laboratory and AASLD criteria) at 
Weeks 24 and 48

The proportion of subjects with ALT normalization (by central laboratory and AASLD 
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
The change from baseline in ALT at Weeks 24 and 48
ALT normalization is defined as ALT > ULN (by central laboratory normal range or 2018 
AASLD normal range) at baseline but within normal range at a postbaseline visit
6.2.2.
Analysis Methods for Secondary and Other Efficacy Endpoints
All the secondary and other efficacy endpoints involving proportions will be analyzed using the 
same statistical method (M = F) applied to the analysis of the primary efficacy endpoint. 
Sensitivity analyses will be performed using the M = E approach as well. 
In addition, the proportion of subjects with HBV DNA < 20 IU/mL and the proportion of 
subjects with normal ALT (by central laboratory and AASLD criteria, M = F) will be separately 
plotted with 95% CI over time for FAS. Median (Q1, Q3) and mean (95% CI) of change from 
baseline in ALT (U/L) will also be plotted over time using observed data for FAS.
6.3.
Changes from Protocol-Specified Efficacy Analyses
Change from baseline in ALT was added in the SAP as other efficacy endpoints to fully explore 
the treatment effect of TAF versus TDF. Proportion of normal ALT and ALT normalization by 
visit evaluated using central laboratory and 2018 AASLD ULN were also added. 
The Randomized Analysis Set was not defined in the protocol but is added in the SAP.
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SAFETY ANALYSES 
Version 1.0 
Final 
For the final safety analysis, exposure and cumulative safety data (ti·eatment-emergent AEs, 
ti·eatment-emergent laborato1y abno1malities etc will be summarized for the randomized hase 
based on the Safe 
Anal sis Set, 
B -visit summai tables will be presented for the entire study u-eatment period 
), based on subjects in the Safety Analysis, staiting from the 
randomized phase baseline. 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
Clinical and laborato1y AEs will be coded using the cunent version ofMedDRA. System organ 
class (SOC), high-level group te1m (HLGT), high-level tenn (HLT), prefe1Ted te1m (PT), and 
lower-level te1m (LL T) will be provided in the AE dataset. 
7.1.2. 
Adverse Event Severity 
AEs ai·e graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or 
Grade 4 (life threatening) according to toxicity criteria specified in Appendix 5 of the clinical 
study protocol. The severity grade of events for which the investigator did not record severity 
will be categorized as "missing" for tabular summaries and data listings, and will be considered 
the least severe for the pmposes of s01ting for data presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs ai·e those for which the investigator answers "Yes" to the question "Related to 
Study Treatment?" in the eCRF. Events for which the investigator did not record relationship to 
study diug will be considered related to study diug for summa1y pmp ose. Data listings will show 
relationship as missing. 
7.1.4. 
Relationship of AEs to Study Procedure 
AEs for which 'Yes' is mai·ked for question 'Related to Study Procedures?' in the eCRF will be 
identified and included in AE listing. 
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7.1.5. 
Serious Adverse Events 
Version 1.0 
Final 
Serious adverse events (SAEs) are those identified as serious in the eCRF, where 'Yes' was 
marked for 'AE serious'. Serious adverse events captured and stored in the clinical database will 
be reconciled with the SAE database from the Gilead Global Patient Safety Department before 
data finalization. 
7.1.6. 
7.1.6.1. 
Treatment-Emergent Adverse Events 
Definition of Treatment-Emergent Adverse Events 
Summaries of treatment-emergent AEs will be provided for randomized 
-
Treatment-emergent AEs occmTing during the randomized phase are defined as: 
• 
Any AE with onset date on or after the randomized study drn staii date and no later than the 
minimum of the randomized study drng stop date + 3 days 
, for those who discontinued randomize stu y 
u g pennanent y, or 
• 
Any AE with onset date on or after the randomized study drng staii date for those who ai·e 
still on the randomized study chu g, or 
• 
Any AE leading to randomized study chug discontinuation. 
I 
I 
I 
7.1.6.2. 
Incomplete Dates 
If an AE onset date is incomplete or completely missing, the followin 
define treatment-emergent AE during the randomized phase 
Events with Missing Onset Day and/or Month 
The event is ti·eatment-emergent during the randomized phase if the following criteria ai·e met: 
• 
The month and yeai· ( or yeai-) of onset date is the same as or after the month and yeai· 
( or yeai-) of the first dose of the randomized study chu g, and 
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• 
For those who discontinued the randomized study drng pennanently only: the month 
and year ( or year) of onset date is the same as or before the mo~ 
the minimum of the randomized study drng stop date+ 3 days-
and 
• 
AE End date is as follows: 
-
The (complete) end date is on or after the first dose date of the randomized study drng, or 
-
The month and year ( or year) of end date is the same or after the month and year ( or year) 
I 
I 
I 
of the first dose of randomized study drng, or 
-
End date is completely missing 
Events with Completely Missing Onset Date 
An AE with a completely missing onset date is defined as treatment-emergent AE during the 
randomized phase if end date is as follows: 
• 
The (complete) end date is on or after the first dose date of the randomized study drng, or 
• 
The month and year ( or year) of end date is the same or after the month and year ( or year) of 
the first dose of the randomized study chug, or 
• 
End date is completely missing 
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I 
I 
7.1.7. 
Summaries of Adverse Events and Deaths 
Version 1.0 
Final 
A brief summaiy of AEs (ie, the number and percentage of subjects) will be presented by 
treatment group for the following: (1) any treatment-emergent AE, (2) any Grade 3 or 4 
treatment-emergent AE, (3) any Grade 2, 3 or 4 treatment-emergent AE, ( 4) any treatment-emergent 
study chug-related AE, (5) any Grade 3 or 4 treatment-emergent study drng-related AE, 
(6) any Grade 2, 3 or 4 treatment-emergent study chug-related AE, (7) any treatment-emergent SAE, 
(8) any treatment-emergent study chu g-related SAE, (9) any treatment-emergent AE leading to 
premature study ch11g discontinuation, (10) any treatment-emergent AE leading to dose 
modification or study chu g intenuption, and (11) any treatment-emergent death. 
Treatment-emergent death during the randomized phase refers to death that occurs between the 
first dose date of the randomized stud ch11 and the minimum of the last dose date of the 
randomized study ch11g + 3 days 
who discontinued randomized stu 
Summaries (number and percentage of subjects) of AEs (by SOC, HLT [if specified below], 
and PT) will be pro . d d b ti tm t 
d 
11 
. 
th S £ t An 1 . S t £ r the 
• 
• 
! 
randomized phase 
as 
follows: 
• 
All treatment-emergent AEs summarized by SOC, HLT, and PT 
• 
Any Grade 3 or 4 ti·eatment-emergent AEs 
• 
Any Grade 2, 3, or 4 ti·eatment-emergent AEs 
• 
All treatment-emergent study chu g-related AE summarized by SOC, HLT, and PT 
• 
Any Grade 3 or 4 ti·eatment-emergent study chug-related AEs 
• 
Any Grade 2, 3, or 4 ti·eatment-emergent study chug-related AEs 
• 
All treatment-emergent SAEs 
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
All treatment-emergent study drug-related SAEs

All treatment-emergent AEs leading to premature discontinuation from study drug

All treatment-emergent AEs leading to dose modification or study drug interruption
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC (and HLT) will be ordered alphabetically, with PT sorted by decreasing total frequency. 
For summaries by severity grade, the most severe event will be selected. 
In addition to the by-treatment summaries, data listings will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Study drug-related SAEs

Deaths

AEs leading to premature discontinuation of study drug

AEs leading to dose modification or study drug interruption
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
entire study period based on Safety Analysis. Analysis will be based on values reported in 
conventional units. No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided by treatment group for each laboratory test during the entire study period specified in 
the study protocol as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window

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7.2.1.1.
Metabolic Assessments
For the lipid panel and glucose measurements, only those under fasting status will be 
summarized.
Fasting lipid data (including total cholesterol, LDL, HDL and triglycerides) will also be analyzed 
using the following Adult Treatment Panel (ATP) III categories {National Cholesterol Education 
Program (NCEP) 2001}:

For total cholesterol (mg/dL): < 200 (desirable), 200-239 (borderline high), and 
≥ 240 (high)

For LDL (mg/dL): < 100 (optimal), 100-129 (near optimal/above optimal), 130-159 
(borderline high), 160-189 (high), and ≥ 190 (very high)

For HDL (mg/dL): < 40 (low), 40-59 (normal), and ≥ 60 (high)

For triglycerides (mg/dL): < 150 (normal), 150-199 (borderline high), 200-499 (high), and 
≥ 500 (very high)
The number and proportion of subjects for the above categories of each lipid parameter will be 
summarized by its baseline category for each treatment group at each visit.
7.2.1.2.
Calcium Correlated for Albumin
Calcium corrected for albumin will be calculated and summarized. The following formula will 
be used when both serum calcium and albumin results for a given blood draw are available and 
serum albumin value is < 4.0 g/dL. 
Calcium corrected for albumin (mg/dL) = serum calcium (mg/dL) + 0.8 × (4.0 – albumin (g/dL)).
When albumin value is ≥ 4.0 g/dL, the actual calcium results will be used. Toxicity grading for 
calcium will be applied based on the corrected values.
7.2.2.
Graded Laboratory Values
The criteria specified in the protocol will be used to grade laboratory results as Grade 0, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life-threatening). Grade 0 
includes all values that do not meet criteria for an abnormality of at least Grade 1. Some 
laboratory tests have criteria for both increased and decreased levels; analysis for each direction 
(ie, increased, decreased) will be presented separately. 
For triglycerides, LDL, and total cholesterol, the protocol-specified toxicity grade scale is for 
fasting test values; non-fasting lipid results (or lipid results without known fasting status) will not 
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If any laborato1y toxicity grading scale overlaps with nonnal reference ranges ( eg, Grade 1 scale 
overlaps with n01mal reference ranges), laborato1y values within n01mal range will not be graded 
except for lipid tests. 
7.2.2.1. 
Treatment-Emergent Laborato1y Abno1malities 
Treatment-emergent laborato1y abno1malities occmTing in the randomized phase are defined as 
values that increase by at least 1 toxicity grade from baseline at any post~ 
includin the minimum of the randomized study diug stop date + 3 days-
' for those who discontinued randomized study diug prematmely, or values 
that increase by at least 1 toxicity grade from baseline at any postbaseline visit for those who are 
still on the randomized study diug. If the relevant baseline laborato1y data are missing, any 
laborato1y abnonnality of at least Grade 1 will be considered treatment-emergent. 
Fasting glucose and nonfasting glucose are graded based on different grading scales. 
Treatment-emergent laborato1y abno1malities will be summarized for fasting glucose and 
nonfasting glucose separately. 
7.2.2.2. 
Treatment-Emergent Marked Laborato1y Abnonnalities 
Treatment-emergent marked laborato1y abno1malities occmTing in the randomized phase are 
defined as values that worsen by at least 3 grades from baseline at any postba~ 
to 
and includin the minimum of the randomized study diug stop date + 3 days -
, for those who discontinued randomized study diug prematmely, 
or values that worsen by at least 3 grades from baseline at any postbaseline visit for those who 
are still on randomized study diug. If relevant baseline laborato1y data are missing, any 
laborato1y abnonnalities of at least Grade 3 or 4 will be considered as treatment-emergent 
marked laborato1y abnonnalities. 
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7.2.2.3. 
Summaries of Laborato1y Abno1malities 
Version 1.0 
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Laborato1y data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit. 
The following summaries (number and percentage of subjects) of laborato1y abno1malities will 
be provided by treatment group sub· ects cate orized accordin to most severe abnonnality 
grade) for the randomized phase 
• 
Treatment-emergent laborato1y abno1m alities 
• 
Treatment-emergent Grade 3 and 4 laborato1y abnonnalities 
• 
Treatment-emergent marked laborato1y abno1m alities 
For all summaries of laborato1y abno1malities, the denominator is the number of subjects with 
any non-missing postbaseline value in the given study period. A listing of treatment-emergent 
Grade 3 or 4 laborato1y abno1malities will be provided. 
7.2.3. 
ALT Elevation 
An ALT elevation is defined as sernm ALT > 2 x baseline value and > 10 x ULN, with or 
without associated symptoms. Confmned ALT elevation (ALT flare) is defined as ALT 
elevations at 2 consecutive postbaseline visits. All treatment-emergent ALT elevations including 
confinned ALT elevations will be summarized for the randomized hase 
nontreatment-emergent ALT elevations will be included in a listing. 
If the first of 2 consecutive results is in the randomized phase and the second is out of the 
randomized phase (ie, in the-
TFFU phase), then the result will be considered to be 
confinned in the randomized phase (assuming both values meet the criterion). And if the 
criterion is met by the last value in the randomized phase and no assessments are available after 
due to the subject exiting the study or data not yet available, then the result will also be 
considered to be confomed. 
7.2.4. 
Liver-related Laboratory Evaluations 
Liver-related abno1malities after initial study diug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laborato1y 
test values for postbaseline measmements: 
• 
Aspartate aminotransferase (AST): (a) > 3 ULN; (b) > 5 x ULN 
• 
ALT: ( a) > 3 x ULN; (b) > 5 x ULN 
• 
AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN 
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Total bilirnbin: > 2 x ULN 
• 
AST or ALT > 3 x ULN and total bilirnbin > 2 x ULN 
Version 1.0 
Final 
For individual laborato1y tests, subjects will be counted once based on the most severe 
postbaseline values. For both the composite endpoint of AST or ALT and total bilirnbin, subjects 
will be counted once when the criteria are met at the same postbaseline visit date. All treatment-
~
ent liver-related abnonnalities will be summarized for the randomized phase 
-
· A listing of subjects who met at least 1 of the above criteria will be provide 
7.3. 
Bone Safety Analysis 
The BMD-related analyses for randomized hase summaries will be based on subjects in the Hip 
or S ine DXA Anal sis Set, 
will be based on subjects in 
the 
Spine DXA ~
-ies for the entire study treatment 
per10 w1 
e ase on su ~ects in the-
Spine DXA Analysis Set. The 
analyses of bone biomarkers fracture events and bone events will be based on subjects in the 
Safe 
Anal sis Set 
will be based on sub· ects in the 
7.3.1. 
Bone Mineral Density (BMD) 
Observed BMD values will be used for all the analyses described below. 
Percentage change from baseline in hip BMD and spine BMD during the entire study treatment 
period will be summarized by treatment group and visit using descriptive statistics for subjects in 
the Hip and Spine DXA Analysis Sets, respectively. 
For each subject and each visit, the clinical BMD status will be defined for hip and spine BMD 
based on the coITected t-score in Table 7-1. 
Table 7-1. 
Normal, Osteopenia, and Osteoporosis as Defined by T-score 
Clinical Status 
BMDT-score 
Normal 
t-score c::: - 1.0 
Osteopenia 
- 2.5 
t-score < - 1.0 
Osteoporosis 
t-score < - 2.5 
The number and percentage of subjects in each clinical BMD status (no1mal, osteopenia, and 
osteoporosis) will be summarized by visit and by baseline clinical status for both hip and spine. 
The number and percentage of subjects in each catego1y based on percentage change from 
baseline in hip BMD and spine BMD (> 7% decrease,> 5% to :::; 7% decrease,> 3% to :::; 5% 
decrease,> 1 % to :::; 3% decrease,> 0 to :::; 1 % decrease, 0 to :::; 1 % increase, > 1 % to :::; 3% 
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increase, > 3% to ≤ 5% increase, > 5% to ≤ 7% increase, > 7% increase) will be summarized by 
treatment group and visit. 
The above analyses will be repeated in the subgroups based on baseline renal function 
(eGFRCKD-EPI < 50 ml/min/1.73m2 and ≥ 50 ml/min/1.73m2).
Median (Q1, Q3) and mean (95% CI) of percentage change from baseline in observed hip and 
spine BMD over time will be plotted by treatment group for the entire study treatment period for 
subjects in the DXA Analysis Set. Listings of hip and spine DXA results will be provided. 
7.3.2.
Bone Biomarkers
Bone biomarkers include serum CTX, P1NP, PTH, OC, and bsAP.
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone 
biomarkers will be summarized by treatment group and visit using descriptive statistics during 
the entire study period. 
Median (Q1, Q3) percentage change from baseline in bone biomarkers over time will be plotted 
by treatment group for the entire study treatment period for subjects in the Safety Analysis Set. A 
listing of bone biomarker data will be provided.
7.3.3.
Fracture Events
The PTs for fracture events were defined based on HLGT of Fractures from current version of 
MedDRA. Treatment-emergent fracture events will be summarized based on the identified PTs 
from the HLGT. The number and percentage of subjects who experienced fracture events will be 
summarized by treatment group for the randomized phase 
. A data 
listing of fracture events will be provided.
7.3.4.
Assessment of Fracture Probability
Fracture probabilities will be assessed using FRAX®, a computer based algorithm developed by 
the World Health Organization (WHO; http://www.shef.ac.uk/FRAX).
The FRAX algorithm is based on individual patient models that integrate the risks associated 
with clinical risk factors as well as BMD at the femoral neck. The algorithm provides both the 
10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture 
(clinical spine, forearm, hip, or shoulder fracture).
The FRAX model is constructed from real data in population-based cohorts around the world 
that have a limited age range. For an age below 40 or above 90 years, the tool will calculate the 
probability of fracture at the age of 40 or 90 years, respectively. Due to the age limitation, 
2 sets of analyses of fracture probabilities will be performed.
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In the first set of analysis, summaries of baseline and change from baseline in the 10-year 
probabilities of hip fracture, as well as major osteoporotic fracture will be presented by treatment 
group and visit for subjects aged between 40 and 90 years for the randomized phase. 
In the second set of analysis, the above-specified analysis will be performed to include all 
subjects, where subjects with an age below 40 or above 90 years will be treated as having an age 
of 40 or 90 years, respectively, in computing their fracture probabilities.
Data listings of fracture risk assessment questionnaire and FRAX fracture probabilities will be 
provided.
7.3.5.
Bone Events
The PTs for bone events were defined based on the Medical Search Term (MST) of Bone 
Disorders on current version of MedDRA. The number and percentage of subjects who 
experienced treatment-emergent bone events will be summarized by treatment group for the 
randomized phase 
. A data listing of bone events will be provided.
7.4.
Renal Safety Analysis
7.4.1.
Confirmed Renal Abnormalities
Confirmed renal abnormalities are defined as follows:

Confirmed increase from baseline in creatinine of at least 0.5 mg/dL or

Confirmed increase from baseline in creatinine of at least 0.3 mg/dL or

Baseline eGFRCKD-EPI ≥ 50 mL/min/1.73 m2 and confirmed postbaseline eGFRCKD-EPI 
< 50 mL/min/1.73 m2 or

Confirmed eGFRCKD-EPI < 30 mL/min/1.73 m2 or

Confirmed phosphorous < 2 mg/dL 
Treatment-emergent confirmed renal abnormalities will be summarized for randomized phase 
. All confirmed renal abnormalities including those occurred 
during the 24-week treatment-free follow-up period will be listed.
7.4.2.
Serum Creatinine and Serum Cystatin C
The baseline and change from baseline in serum creatinine and serum cystatin C will be 
summarized using descriptive statistics for the entire study period. 
Median (Q1, Q3) and mean (95% CI) of change from baseline in observed serum creatinine over 
time will be plotted by treatment group for the entire study period for subjects in the Safety 
Analysis Set.
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A positive shift in serum creatinine values was observed due to a lot calibration change on 01 
July, 2018, occurring across Covance laboratory sites worldwide. A correction was therefore 
applied to records on or after 01 July, 2018 to serum creatinine, following the regression 
equation specified in Table 7-2. The corrected serum creatinine values will be used for the 
analyses of serum creatinine, serum creatinine toxicity, eGFR estimated by the Cockcroft Gault 
formula, eGFR by the CKD-EPI method and other relevant parameters. 
The corrected values must be in the same unit as the original values after going through the 
regression formula in Table 7-2.

If the unit of serum creatinine is “μmol/L”, then use the formula directly. 

If the unit of serum creatinine is “mg/dL”, the values should be converted to “μmol/L” before 
using the formula. 
After the correction, unit of serum creatinine should be converted back to “mg/dL” for summary 
and comparison purpose. 
Table 7-2.
Method of Serum Creatinine Correction
Regional Lab Center
Accession Numbera
Regular Regression for Serum 
Creatinine (μmol/L)b, c
Indianapolis 
starts with 65
Y=1.002×X+1.77
Geneva 
starts with 62 or 63
Y=1.025×X+2.62
Shanghai 
starts with 67
Y=0.971×X+5.42
Singapore 
starts with 64 or 66
Y=1.009×X−1.42
Japan 
start with 68
Y=1.033×X+7.25
a
Accession numbers specified which regional lab center tested the sample. For example, samples with accession number 
starting with 65 were tested in Indianapolis Auto Chemistry Center.
b
X and Y are the serum creatinine values from previous lot before 01 July, 2018 and serum creatinine values from new lot on 
or after 01 July, 2018, respectively. 
c
The serum creatinine correction is based on the unit of umol/L. The unit should be converted to mg/dL for summary 
purposes. 
7.4.3.
Estimated Glomerular Filtration Rate
The following formulae will be used to calculate eGFR: 

CG:
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (SCr 
(mg/dL) × 72),
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eGFRcKD-EPI,creatinine (mL/min/1.73 m2) = 141 x min(SCr/K,I)« x max(SCr/K,I)-1.209 x 0.993Age 
x 1.018 (if female) x 1.159 (ifblack), 
where K is 0.7 for females and 0.9 for males, a, is -0.329 for females and-0.411 for males, 
min indicates the minimum of SCr/K or 1, and max indicates the maximum of SCr/K or 1 
{Levey 2009}. 
• 
CKD-EPI Cystatin C based: 
eGFRcKD-EPI,cysC (mL/min/1.73 m2) = 133 x min(SCys/0.8, I)-0-499 x max(SCys/0.8, I)-1328 x 
0.996age [ x 0.932 if female], 
where SCys is sennn cystatin C. 
Change from baseline in eGFRcG, eGFRCKD-EPL creatinine and eGFRcKD-EPI. cysC at each postbaseline 
visit will be provided during the entire study treatment period. 
The number and proportion of subjects with decrease from baseline of ~ 25% and ~ 50% in 
eGFRcG, eGF 
. 
. 
The number and proportion of subjects in each stage of chronic kidney disease (CKD) will be 
summarized by baseline stages of CKD at each postbaseline visit for the entire study treatment 
period based on subjects in the Safety Analysis. 
The stages of CKD by estimated GFR by CG, CKD-EPI creatinine, CKD-EPI Cystatin C are 
defined in Section 5.2. 
Median (QI, Q3) change from baseline in eGFRcG, eGFRCKD-EPLcreatinine and eGFRcKD-EPI,cysC 
over time will be plotted for the entire study treatment period for subjects in the Safety Analysis 
Set. 
7.4.4. 
Treatment-emergent Proteinuria (Dipstick) 
Treatment-emergent proteinuria b urinal sis di 
for the randomized phase 
treatment-emergent proteinuria will be provided. 
will be summarized by treatment group 
. A listing of subjects with 
7.4.5. 
Urine RBP to Creatinine Ratio and Beta 2 Microglobulin to Creatinine Ratio 
Baseline, postbaseline, change from baseline and percentage change from baseline in urine RBP 
to creatinine ratio and beta-2-microglobulin to creatinine ratio will be summarized by treatment 
group and visit using descriptive statistics during the entire study treatment period. Median (QI, 
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Q3) percentage change from baseline over time will be plotted by treatment group for the entire 
study treatment period for subjects in the Safety Analysis Set.
7.4.6.
Proteinuria by Quantitative Assessment
Baseline, postbaseline, changes from baseline, and percentage change from baseline in UPCR 
and UACR will be summarized by treatment group and visit using descriptive statistics, for the 
entire study treatment period. The number and proportion of subjects with UPCR ≤ 200 mg/g 
versus > 200 mg/g will be summarized by baseline category for each postbaseline visit during 
the entire study period {KDIGO Guideline Development Staff 2013} .
The number and proportion of subjects with UACR < 30 mg/g versus ≥ 30 mg/g will be 
summarized by baseline category for each postbaseline visit during the entire study period 
{KDIGO Guideline Development Staff 2013}.
Median (Q1, Q3) percentage change from baseline over time will be plotted by treatment group 
for the entire study treatment period for subjects in the Safety Analysis Set.
7.4.7.
Other Renal Biomarkers
Other renal biomarkers include TmP/GFR, FEPO4, and FEUA.
TmP/GFR based on serum creatinine {Barth 2000} will be calculated as follows:


86
.0
)
8.0
(
1
/
3.0
/
86
.0
/
4
4









TRP
if
SPO
TRP
TRP
GFR
TmP
TRP
if
SPO
TRP
GFR
TmP
where TRP (tubular reabsoprtion of phosphate) is calculated by:
UCr
SCr
SPO
UPO
TRP



4
4
1
where SCr is serum creatinine concentration (mg/dL), UPO4 is urine phosphate concentration 
(mg/dL), SPO4 is serum phosphate concentration, and UCr is urine creatinine concentration 
(mg/dL).
Urine FEPO4 will be calculated as follows:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Urine FEUA will be calculated as follows:
FEUA (%) = (SCr × UUa) / (SUa × UCr) × 100 (%)
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The baseline, postbaseline, and change from baseline in TmP/GFR, FEPO4, and FEUA will be 
summarized by treatment group and visit using descriptive statistics during entire study period. 
7.4.8.
Cr EDTA
In addition, the baseline, postbaseline, and change from baseline of surface area corrected value 
(mL/min/1.73 m2) from Cr EDTA renal scan will be summarized by treatment group and visit 
using descriptive statistics during the entire study treatment period. 
The number and proportion of subjects in each stage of chronic kidney disease (CKD) will be 
summarized by baseline stages of CKD at each postbaseline visit for the entire study treatment 
period based on subjects in the Safety Analysis.
The stages of CKD by estimated GFR by Cr EDTA is defined in Section 5.2.
7.5.
Body Weight
Body weight at each visit and change from baseline in body weight will be summarized using 
descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group for each postbaseline analysis window, during the randomized phase, 
 
 and the entire study treatment period separately. In the case of multiple values in 
an analysis window, data will be selected for analysis as described in Section 3.7.3.
7.6.
Prior Hepatitis B Medications
Prior HBV medications will be summarized by treatment group. No inferential statistics will be 
computed. A listing of prior HBV medications will also be provided.
7.7.
Concomitant Medications
Concomitant medications (ie, medications other than study drug that are taken while receiving 
study drug) will be coded using the WHO Drug Dictionary. 
Summaries of concomitant medications using the number and percentage of subjects for each 
treatment group will be provided by WHO preferred name for the randomized phase based on 
the Safety Analysis Set 
 
. Subject will be counted only once for each preferred name. The summary will be 
ordered by overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
If the start or stop date of concomitant medications is incomplete, the month and year 
(or year alone if month is not recorded) of start or stop date will be used to determine if the 
medications are concomitant as follows. 
The medication is concomitant for the randomized phase if the month and year of start or stop 
(or year of the start or stop) of the medication do not meet any of following criteria:
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The month and year of sta1t of the medication is after the date of the last dose of randomized 
studydmg 
• 
The month and year of stop of the medication is before the date of the first dose of 
randomized study dmg 
I 
I 
If the strut and stop date of the medications are not missing, and the strut date is not after the last 
dose date of the randomized study diug and the stop date is not before the first dose date of the 
randomized study di11g, or the medications ru·e mru·ked as ongoing and strut date is on or before 
the last dose date of the randomized study di11g, the medications ru·e considered concomitant 
during the randomized phase. 
7.8. 
Other Safety Measures 
A data listing will be provided for subjects experiencing pregnancy during the study. 
7.9. 
Changes From Protocol-Specified Safety Analyses 
Treatment-emergent AE and lab abnonnality in randomized phase was defined as any AE or lab 
abnonnality that begins on or after the first dose date of study diug up to the last dose date in the 
protocol, and is updated in this SAP. Treatment-emergent AE occuning in the randomized phase 
is defined as any AE with onset date on or after the first dose date of the ran- omized stud and 
no later than the minimum of the randomized study di11g stop date + 3 days 
, if applicable for the randomized phase. Treatment-emergent a orato1y 
abnonnalities occuning in the randomized phase are defined as values that increase by at least 
1 toxicity grade from baseline at any postbaseline visit u to and includin the minimum of the 
randomized study di11g stop date + 3 days 
for the 
randomized phase. This change was made as labs perfo1med 1-2 days after study di11g stopped 
were being excluded causing the measurement for the timepoint to be missed, even though 
protocol specified visit windows allowed for labs to be perfonned in a sho1t period after the 
study diug was stopped. 
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8.
REFERENCES
Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the 
algorithm performs better than the nomogram. Ann Clin Biochem 2000;37 ( Pt 
1):79-81.
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the 
Evaluation and Management of Chronic Kidney Disease. Kidney international. 
Supplement 2013;3 (1):v-150.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150 (9):604-
12.
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. 
National Institute of Health  May, 2001.


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9.
SOFTWARE
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, 
listings, and figures.
FRAX® (WHO Collaborating Center for Metabolic Bone Disease, University of Sheffield, UK) 
is to be used for the 10-year probabilities of hip fracture or a major osteoporotic fracture.


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10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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11.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
Data Collection of COVID-19 Data


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Appendix 1.
Study Procedures Table
Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
TFFUq
Visit
Windowsa
± 3 
Days
± 7 
Days
Written Informed 
Consent
X
Review of 
Inclusion/Exclusion 
Criteria 
X
X
Medical History, 
including HBV 
history
X
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination 
including vital signs, 
and weight 
X
X
X
X
X
Height
X
Symptom-directed 
Physical Exam
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXAc (spine & hip) 
X
X
X
FRAX® Fracture 
Risk Assessment 
Tool
X
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Screening
(−45 Days)
BL
4
4 + 24 Hrs
8
8 + 24 Hrs
12
20
24
36
48
TFFUq
Visit
Windowsa
± 3 
Days
± 7 
Days
Cr EDTA renal scan
X
X
Study Drug 
Accountability
X
X
X
X
X
X
X
Study Drug 
Dispensed/Retrieved 
X
X
X
X
X
X
X
X
Dosing in-clinicd
X
X
Serum Chemistry 
and Liver Function 
Testse
X
X
X
X
X
X
X
X
X
X
eGFRCKD-EPI 
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
Cystatin C 
(for estimated GFR)
X
X
X
X
X
X
X
Plasma HBV DNA 
Levels 
X
X
X
X
X
X
X
X
X
X
Serum HBsAg 
(qualitative)f
X
X
X
X
X
Serum HBeAg 
(qualitative)f
X
X
X
X
X
Sample collection for 
HBV Resistance 
Surveillanceg
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
X
X
Fibrotest® 
X
X
X
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Screening 
(-45 Days) 
BL 
4 
4 +24Hrs 
8 
8+24Hrs 
12 
20 
24 
36 
TFFUq 
Visit 
± 3 
±7 
'Windows• 
Days 
Days 
VitaminD 
X 
X 
Whole blood for 
X 
X 
PBMC 
PlasmaPKm 
X 
X 
X 
X 
X 
X 
X 
Fasting Blood for 
X 
X 
X 
X 
Bone Biomarkersh 
Fasting Blood for 
X 
X 
X 
X 
Renal Biomarkersh 
Fasting Urine for 
X 
X 
X 
X 
Renal Biomarkersi 
Fasting Metabolic 
X 
X 
Panel0 
Serum Pregnancy 
X 
Testj 
Urine Pregnancy 
X 
X 
X 
X 
X 
X 
X 
X 
Testj 
Urinalysis 
X 
X 
X 
X 
X 
X 
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b 
C 
d 
e 
f 
g 
h 
' 
m 
n 
0 I' 
Screening 
(-45 Days) 
BL 
4 
4 + 24 Hrs 
8 
8 + 24 Hrs 
12 
20 
24 
36 
Visit 
'Windows• 
TI1e out of visit window is± 3 days until Week 48, 
± 3 
Vital signs include blood pressm·e, pulse, respiration rate, an temperattu·e. 
±7 
Days 
TI1e initial DXA will be performed dtuing Screening and should be completed at least 14 days prior to the first dose of study dmg. The Week 48 DXA window is - 3 days 
only. DXA is requit·ed for Early Discontinuation (ED) visit if not done within the last 24 weeks. 
It is prefen-ed that subjects take theit· study dmg according to a moming dosing schedule; subjects who elect to dose in the evening the previous day are not requit·ed to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 8 visits. 
Senun chemistry and Liver Ftmction Tests: alkaline phosphatase, AST, ALT, GGT, total bilit·ubin, direct and indit·ect bilirubin, total protein, albtuuin, LDH, CPK, 
bicarbonate, BUN, calcitun, chloride, creatinine, glucose, pho~ituu, potassitun, soditun, m-ic acid, and amylase (reflex lipase testing is performed in subjects 
with total amylase > 1.5 x ULN). At Baseline, Weeks 24, 48,- -ED, subject will be fasting for senun glucose and metabolic panel. Coagulation panel will be 
done at Screening and then as a reflex only test for ALT flares. 
Qualitative HBsAg and HBeAg will be pe1fo1med at Screening, Baseline (BL), Weeks 24, 48, 
and ED. HBeAb and HBsAb testing will be 
pe1fo1med as reflex testing as needed. 
Sequence analysis of the HBV pol/RT for possible resistance mutation(s) may be attempted for any subject that experiences vit·enua (HBV DNA > 69 IU/mL). 
Blood for selected bone biomarkers and renal biomarkers will be collected in a fasted state. Requit·ed for ED visit if the last sample was collected > 24 weeks prior. 
U,ine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected > 24 weeks prior. 
For female subjects of childbea,ing potential, the senun beta-HCG test will be performed at Screening. Urine test will be performed at all other visits as indicated. 
Positive mine test will be confirmed with senun test. Pregnanc tests should include revention cotmselino. 
and 
Early D,scontrnuation V1S1ts, 1 applicable. 
At Weeks 8 and 24 the plasma PK samples should be collected between 15 minutes and 4 hours post-dose. 
At Screening, a-fetoprotein (AFP) will be measured and subjects with an AFP >50 ng/mL or other frndings conceming HCC must tmdergo iniaging test (eg, CT scan) to mle 
out HCC. 
' 
. . 
' 
. 
. 
q 
discontinue ti·eatinent prematurely 
will be 
followed every 4 weeks for 24 weeks off treatinent in accordance with TFFU visits or tmtil · 
CONFIDENTIAL 
Page 53 
11 June 2021 


TAF
Version 1.0
GS-US-320-3912 Statistical Analysis Plan – Final Analysis
Final
CONFIDENTIAL
Page 54
11 June 2021
Appendix 2.
Data Collection of COVID-19 Data
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by Clinical 
Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic.  If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
Determination of Missed and Virtual Visits
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 1).  The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit will be assigned as follows:
i.
If COVID-19 terms are identified through NLP and the visit date is missing, then 
result is ”Missed Visit”
ii.
If COVID-19 and Virtual terms are identified through NLP for a visit, then result 
is “Virtual Visit”. When there are multiple records for the same subject and the 
same visit, if one record could be categorized as “Virtual Visit”, all records 
associated with this subject and this visit will be categorized as “Virtual Visit”
iii.
Otherwise result is missing
Table 1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE
   


GS-US-320-3912 Final SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
12-Jun-2021
05:11:08
Clinical Research eSigned 14-Jun-2021
15:55:41
PPD
PPD

Prot_000.pdf: 
Study Title: 
Sponsor: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Open Label Study to Evaluate the 
Efficacy and Safety ofTenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fmnarate (TDF)-containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
TBD 
Chronic Hepatitis B 
GS-US-320-3912 
Name: 
Telephone: 
Fax: 
PPD 
PPD 
PPD 
I 
Gilead Medical Monitor: 
Name: 
Anuj Ga,agar, MD PhD 
PPD 
Telephone: 
Fax: 
PPD 
Protocol Version/Date: 
Original: 
07 Jtme 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly tmpublished 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 inf01mation is only to be used 
by you in connection with authorized clinical studies of the investigational dmg described in the 
protocol. You will not disclose any of the inf01mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessruy to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 2
07 June 2016
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....................................................................14
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................20
1.2.1.
General Information .............................................................................................................20
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................20
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................23
1.3.
Rationale and Risk/Benefit Assessment for this Study ..........................................................................41
1.4.
Rationale for Dose Selection..................................................................................................................42
1.5.
Compliance ............................................................................................................................................42
2.
OBJECTIVES.....................................................................................................................................................43
3.
STUDY DESIGN................................................................................................................................................44
3.1.
Endpoints ...............................................................................................................................................44
3.1.1.
Primary Endpoints................................................................................................................44
3.1.2.
Secondary Endpoints............................................................................................................44
3.1.3.
Other Endpoints of Interest ..................................................................................................44
3.2.
Study Design..........................................................................................................................................44
3.3.
Study Treatments ...................................................................................................................................45
3.4.
Duration of Treatment............................................................................................................................46
3.5.
End of Study...........................................................................................................................................46
3.6.
Biomarker Testing..................................................................................................................................46
3.6.1.
Biomarker Samples to Address the Study Objectives ..........................................................46
3.6.2.
Biomarker Samples for Optional Future Research...............................................................46
3.6.3.
Biomarker Samples for Optional Genomic Research...........................................................47
3.6.4.
Intensive PK Substudy .........................................................................................................47
4.
SUBJECT POPULATION..................................................................................................................................48
4.1.
Number of Subjects and Subject Selection ............................................................................................48
4.2.
Inclusion Criteria....................................................................................................................................48
4.3.
Exclusion Criteria...................................................................................................................................49
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................50
5.1.
Randomization, and Treatment Codes ...................................................................................................50
5.2.
Description and Handling of Tenofovir Alafenamide (TAF).................................................................50
5.2.1.
Formulation..........................................................................................................................50
5.2.2.
Packaging and Labeling .......................................................................................................50
5.2.3.
Storage and Handling...........................................................................................................51
5.3.
Dosage and Administration of TAF.......................................................................................................51
5.4.
Prior and Concomitant Medications.......................................................................................................51
5.5.
Accountability for Tenofovir Alafenamide (TAF).................................................................................53
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................53
6.
STUDY PROCEDURES ....................................................................................................................................54


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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Gilead Sciences, Inc.
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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................54
6.2.
Pretreatment Assessments......................................................................................................................54
6.2.1.
Screening Visit (Day −45 to Day 1 of Treatment) ...............................................................54
6.2.2.
Baseline Assessments (Day 1)..............................................................................................56
6.3.
Treatment Assessments..........................................................................................................................57
6.3.1.
Study Week Assessments (Weeks 4-48) ..............................................................................57
6.3.2.
Study Week Assessments Weeks for Optional Treatment Extension Phase 
(Weeks 60-144)....................................................................................................................59
6.3.3.
Early Discontinuation (ED) Visit .........................................................................................60
6.4.
Post-Treatment Assessments..................................................................................................................61
6.4.1.
All Other Subjects Who Discontinue Study Drug................................................................61
6.5.
Assessments for Premature Discontinuation from Study.......................................................................61
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................62
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................62
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................63
6.9.
Resistance Surveillance..........................................................................................................................63
6.10.
End of Study...........................................................................................................................................63
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................64
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
7.1.1.
Adverse Events.....................................................................................................................64
7.1.2.
Serious Adverse Events........................................................................................................64
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................65
7.2.2.
Assessment of Severity ........................................................................................................66
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................66
7.4.
Gilead Reporting Requirements.............................................................................................................68
7.5.
Toxicity Management ............................................................................................................................68
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................69
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................69
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................69
7.5.4.
Management of Bone Evaluation.........................................................................................69
7.5.5.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................70
7.5.6.
Management of Ocular Safety..............................................................................................71
7.6.
Special Situations Reports......................................................................................................................72
7.6.1.
Definitions of Special Situations..........................................................................................72
7.6.2.
Instructions for Reporting Special Situations.......................................................................72
8.
STATISTICAL CONSIDERATIONS................................................................................................................75
8.1.
Analysis Objectives and Endpoints........................................................................................................75
8.1.1.
Analysis Objectives..............................................................................................................75
8.1.2.
Primary Endpoint .................................................................................................................75
8.1.3.
Secondary Endpoint .............................................................................................................76
8.1.4.
Other Endpoints of Interest ..................................................................................................76
8.2.
Analysis Conventions.............................................................................................................................76
8.2.1.
Analysis Sets ........................................................................................................................76
8.3.
Data Handling Conventions ...................................................................................................................77
8.4.
Demographic Data and Baseline Characteristics ...................................................................................77
8.5.
Efficacy Analysis ...................................................................................................................................78
8.5.1.
Primary Analysis..................................................................................................................78


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
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8.5.2.
Secondary Analyses .............................................................................................................78
8.6.
Safety Analysis.......................................................................................................................................78
8.6.1.
Primary Safety Analysis.......................................................................................................78
8.6.2.
Secondary Safety Analyses ..................................................................................................78
8.6.3.
Extent of Exposure...............................................................................................................78
8.6.4.
Adverse Events.....................................................................................................................78
8.6.5.
Laboratory Evaluations ........................................................................................................79
8.7.
Pharmacokinetic Analysis......................................................................................................................79
8.8.
Biomarker Analysis................................................................................................................................79
8.9.
Sample Size............................................................................................................................................79
8.10.
Data Monitoring Committee ..................................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................90
Appendix 1.
Investigator Signature Page....................................................................................................91
Appendix 2.
Study Procedures Table..........................................................................................................92
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule...................................................95
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................96
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............97
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................119


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 5
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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................25
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) ........................................26
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) ...................................................................................................................................28
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) .............................29
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set) ...........................................................31
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................32
Table 1-7.
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)...........................................................................................................................33
Table 1-8.
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)...........34
Table 1-9.
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) ..........................................36
Table 1-10.
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)...................37
Table 1-11.
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) .........................39
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution.....................................52
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................45


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 6
07 June 2016
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy 
and Safety of Tenofovir Alafenamide (TAF) versus 
Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in 
Subjects with Chronic HBV Infection and Stage 2 or Greater 
Chronic Kidney Disease Who Have Received a Liver Transplant
Clinical Trials.gov 
Identifier:
TBD
Study Centers Planned:
Approximately 1 center in New Zealand
Objectives:
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 24

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at 
Week 24
The secondary objectives of this study are as follows: 

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the percent change 
from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in serum creatinine at Weeks 24 and 48

To evaluate the safety of TAF 25 mg QD versus 
TDF-containing regimens as determined by the change from 
baseline in eGFRCKD-EPI at Week 48

To evaluate the efficacy of TAF 25 mg QD versus 
TDF-containing regimens in maintaining viral suppression at
Week 48


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Original 
This is a randomized, open-label, single center Phase 2 study to 
evaluate the safety and efficacy ofT AF 25 mg QD versus TDF in 
adult chronic hepatitis B infection (CHB) subjects with Stage 2 or 
greater chronic kidney disease and have received a liver transplant. 
Approximately 60 subjects will be randomized in a 1: 1 ratio to 
either continue current treatment regimen with TDF alone or in 
combination with other approved antivirals or to receive TAF 
25 mg PO daily. At least 50 subjects will be enrolled with 
eGFRcKD-EPI < 50 ml/min/1.73m2 . 
Randomization will be stratified by baseline renal function 
(eGFRCKD-EPI < 50 mllmin/1.73m
2 and 2: 50 ml/min/1.73m
2
) 
• 
Treatment Arm A: approximately 30 subjects administered 
TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 30 subjects to continue 
administration ofTDF alone or in combination with other 
approved antivirals as per local practice 
PPD 
The primary analysis will occur at Week 24 with the primary 
efficacy endpoint being the maintenance of viral suppression 
(HBV DNA < 20 IU/mL). 
Page 7 
07 June 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
Approximately 60 
Final 
Original 
Adult subjects with CHB who are cunently virally suppressed, 
receiving TDF alone or in combination with other approved 
antivirals, with Stage 2 or greater chronic kidney disease and have 
received a liver transplant. 
TAP will be administered orally once daily for 48 weeks for 
subjects in Treatment Arm A. PPD 
Inclusion Criteria 
Subjects must meet.!!! of the following inclusion criteria to be 
eligible to pa1ticipate in the study: 
1) Must have the ability to understand and sign a written infmmed 
consent fmm; consent must be obtained prior to initiation of 
study procedures 
2) Adult male or non-pregnant female subjects, over 18 years of 
age based on the date of the screening visit 
3) Documented evidence of chronic HBV infection prior to 
transplantation 
4) Prima1y or secondary (re-transplant), liver alone or liver and 
kidney transplant recipient from deceased or living donor 
5) Liver Transplant~ 12 weeks prior to screening 
6) Maintained on TDF alone or in combination with other 
approved antivirals for HBV prophylaxis or treatment 
7) Have been on approved HBV OA V treatment for at least 
12 weeks post-transplant prior to screening, with 
HBV DNA < LLOQ at screening 
8) Screening eGFRcKD-EPI < 90 ml/mi..n/1. 73m2 
9) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in 
Appendix 6 
10) Women considered of child bearing potential (see Appendix 6) 
must have a negative sennn pregnancy test at Screening and a 
negative urine test at Baseline before dosing 
11) Must be willing and able to comply with all study requirements 
Page8 
07 June 2016 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 9
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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible to participate in the study:
1) Multi-organ transplant that includes heart or lung recipient 
(subjects who have their liver transplant as part of a 
liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular 
carcinoma (HCC) post-transplant and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic 
encephalopathy, hepatorenal syndrome, hepatopulmonary 
syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at 
screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on 
anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
6) Co-infection with HIV or HCV
7) Recent (within 4 weeks of Screening) episode or infection 
requiring systemic antibiotics
8) Use or planned use of T-cell depleting/masking antibodies, 
systemic antineoplastic agents, cyclosporine > 300 mg/day, or 
use of any prohibited medications listed in Section 5.4 within 
28 days of the Baseline/Day 1 visit
9) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g., basal cell skin cancer, etc.) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not 
eligible
10) Significant cardiovascular, pulmonary, or neurological disease
11) Use of investigational agents within 3 months of screening, 
unless allowed by the Sponsor
12) Use of any prohibited medications as described in Table 5-1
13) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
14) Known hypersensitivity to study drugs, metabolites or 
formulation excipients 
Final 
Original 
15) Lactating females or those who may wish to become pregnant 
during the course of the study 
• 
Screening Visit 
• 
Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 20, 
24, 36 and 48,PPD 
~--------------------------------~ 
Screening assessments include: 
• 
Safety laboratory tests (chemistry, hematology, and 
coagulation) 
• 
HBV DNA levels 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed) 
• 
HCV, HDV and HIV testing 
• 
Alpha-fetoprotein (AFP) 
• 
Serum Renal Biomarkers including phosphate, Cystatin C, 
• 
Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobulin, uric acid and phosphate 
• 
Serum Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-terminal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathyroid hormone. 
• 
Hip and Spine DXA Scan 
• 
Urinalysis, urine drug screen, serum beta human chorionic 
• 
gonadotropin (~-hCG, for all female subjects of 
child-bearing potential) 
• 
Physical examination (with height and body weight), 
medical history, vital signs, concomitant medications, and 
adverse events 
On-treatment assessments include: 
• 
Safety laboratory tests (chemistry, hematology, and 
coagulation),urine pregnancy tests (for all female subjects of 
child-bearing potential), urinalysis, physical examination, vital 
signs, concomitant medications, and adverse events 
• Serum Renal Biomarkers including Qhos hate, Cystatin Cat 
Baseline, Weeks 4, 12, 24, 48, PPD 
and Early 
.....__ __________ __, 
Discontinuation (ED) 
Page 10 
07 June 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Original 
• 
Urine Biomarkers e.g., total protein, creatinine, albumin, retinol 
binding protein, beta-2 microglobulin, uric acid and phosphate 
at Baseline, Weeks 4, 12, 24, 48. PO 
and ED 
• 
• 
Senun Bone Biomarkers including C-type collagen sequence, 
procollagen type 1 N-terminal propeptide, osteocalcin, bone 
specific alkaline phosphatase, and parathY!·oid hoxmone at 
Baseline, Weeks 4, 12, 24, 48, PPD 
and ED 
and ED 
• 
Fracture Risk Assessment will be evaluated at Baseline 
• 
HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testino will be petfotmed as needed) 
at Baseline and Weeks 24, 48 PPD 
and ED 
• 
HBV DNA levels at Baseline and at each study visit thereafter, 
PPD 
• 
PBMC specimens are collected at Baseline, Weeks 24, and 48 
PPO 
• 
Health Related Quality of Life (HRQoL) Survefs (S?l6, 
CLDQ, and WPAI) at Baseline, Weeks 24, 48, PPD 
and ED 
• 
Single plasma PK samples at each treatment visits through 
Week48 
See Section 6 for fmther infotmatiou. 
Page 11 
07 June 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Original 
Open label TAF will be supplied as 25 mg tablets for daily oral 
administration 
Open-label TDF alone or in combination with or without other 
antivirals administered per local practice 
Adverse events (AEs) and clinical laboratory tests will be collected 
at every visit and summarized through treatment extension Phase at 
Week 144. The proportion of subjects in each treatment arm with 
an AE leading to early discontinuation of study drug(s) and 
proportion of subjects with serious adverse events will be 
summarized through Weeks 24, 48,PPD 
~----------------~ 
The primary safety endpoint is: 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus 
TDF-containing regimens at Week 24 
The secondary safety end points are: 
• 
Percent change from baseline in hip and spine bone mineral 
density (BMD) ofTAF 25 mg QD versus TDF-containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD 
versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus 
TDF-containing regimens at Week 48 
The primary efficacy endpoint is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
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Pharmacokinetics: 
All subjects will have single plasma PK samples drawn at each 
treatment visit through Week 48. At Weeks 8 and 24 the PK sample 
should be collected between 15 minutes and 4 hours post-dose. 
Statistical Methods: 
Sample Size: 
PPD 
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. The 
response rate for each treatment arm will be summarized. 
A two-sided 95% confidence interval adjusted for the 
randomization stratification factor (the adjusted Mantel-Haenszel 
proportions), for the difference (TAF ~ TDF) in the proportion of 
subjects who maintained viral suppression (HBV DNA< 20 IU/mL) 
at Week 24 will be constructed. 
The change from baseline in eGFRcKD-EPI at Weeks 24 and 48 will 
be summarized. 
The percent change from baseline in hip and spine BMD at 
Weeks 24 and 48 will be summarized. The change from baseline in 
serum creatinine at Weeks 24 and 48 will be summarized. All 
secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Ql, Q3, 
minimum, and maximum). All categorical secondary endpoints will 
be summarized by number and percentage of subjects who meet the 
endpoint. 
This is an exploratory study. No formal sample size calculation was 
performed. 
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
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
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)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI/C
Cobicistat
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
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry
E2
Estradiol


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EC
Ethics Commitee
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)
IRB
Institutional review board
IV
Intravenous


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IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction


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TAF
tenofovir alafenamide
TAF Fumarate
tenofovir alafenamide fumarate, GS-7340-03
TDF
tenofovir disoproxil fumarate
TFV
tenofovir
TFV-DP
tenofovir diphosphate
TLOVR
Time to loss of virologic response
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
TSH
Thyroid stimulating hormone
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


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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 et al 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 et al 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 {World Health Organization (WHO) 2015b}, {Schweitzer et al 2015}. 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 et al 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) et al 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%) {Sarin et al 2015}, 
{Fattovich et al 2008}. 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 et al 2008}, {Sokal et al 2013}. Importantly, not all subjects will experience 
all phases of infection {Terrault et al 2015}. 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 


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followed by loss of HBeAg with seroconversion to anti-HBe. In the inactive CHB phase, 
subjects have undetectable or low levels 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 develop in the 
precore or core promoter region of the virus {Sarin et al 2015}. HBeAg-negative CHB affects 
about 10% of pediatric subjects {Sokal et al 2013}. The goal of anti-HBV therapy, in children as 
in adults, is to improve long-term survival and quality of life by reducing disease progression to 
cirrhosis, decompensated liver disease, and HCC {Sarin et al 2015}, {Sokal et al 2013}. As 
seroclearance of HBsAg is a rare spontaneous occurrence in children with CHB, durable 
anti-HBe seroconversion in HBeAg-positive subjects is considered a good 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 et al 2015}. As in adults, reduction of viremia to levels below assay 
detection can lead to reduced inflammation and slowing or reversal of fibrosis 
{Sokal et al 2013}, {Marcellin et al 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 {World Health Organization (WHO) 2015a}, 
{Marcellin et al 2013}. 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) 2012}, {Liaw et al 2012}. 
Additionally, while development of resistance to entecavir (ETV) is low in treatment-naive 
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 et al 2009}. In contrast, resistance 
to tenofovir disoproxil fumarate (TDF; Viread®) has not been documented through 6 years of use 
{Kitrinos et al 2014}.
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) 2012}, 
{Liaw et al 2012}, {Lok et al 2009}. Although highly effective, use of TDF is associated with 
nephrotoxicity and bone-related toxicity in some subjects.


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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 {Babusis et al 2013}, {Murakami et al 2015}, {Agarwal et al 2015}, {Ruane et al 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 the 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 et al 2015}. 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. A New Drug Application (NDA) for TAF 25 mg tablets was filed 
on 11-January, 2016 for the treatment of CHB in adults.
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 next generation 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 (GS-7340), in blood and biological 
fluids.
For further information on TAF (GS-7340), refer to the current investigator’s brochure for TAF.
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. 


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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 et al 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 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 et al 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, (GS-7340), 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.
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.


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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 tenofovir in the cells of the lymphoreticular system. The 
primary route of elimination of tenofovir 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. Tenofovir was the major 
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of 
tenofovir in dogs and fecal elimination of tenofovir in rats and dogs are negligible.
Tenofovir 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. 
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 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. 


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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, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program
for CHB includes 2 ongoing Phase 3 studies in hepatitis B e antigen (HBeAg)-negative and
HBeAg-positive subjects with CHB, a Phase 1b antiviral activity and safety/tolerability study in
subjects with CHB, as well as several Phase 1 safety, PK/pharmacodynamics (PD), and drug
interaction studies in healthy subjects (including Chinese and Japanese subjects) and in subjects
with impaired renal or hepatic function. 
In some studies, TAF was administered as a single agent or as part of the F/TAF,
FTC/RPV/TAF, or E/C/F/TAF FDC tablets. 
TAF clinical studies are listed below: 

GS-US-320-0101, a Phase 1b study to evaluate the pharmacokinetics, safety, viral kinetics,
and anti-HBV activity of TAF in treatment-naive adults with CHB (completed)
{Agarwal et al 2015}

GS-US-320-1228, a Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability
of TAF in healthy Japanese and non-Japanese subjects (completed)


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
GS-US-320-1229, a Phase 1 study to evaluate the pharmacokinetics of a single dose and
repeat doses of TAF 25 mg in healthy Chinese subjects (completed; data analysis is ongoing)

GS-US-320-1382, a Phase 1 study to evaluate the effect of food on a single dose of 
TAF 25 mg in healthy subjects (completed)

GS-US-320-1615, a Phase 1 study to evaluate the pharmacokinetics of a single dose of 
TAF 25 mg in subjects with severe hepatic impairment and subjects with normal liver 
function (completed)

GS-US-320-0108, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg once
daily versus TDF 300 mg once daily for the treatment of HBeAg-negative subjects with CHB
(ongoing)

GS-US-320-0110, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg once 
daily versus TDF 300 mg once daily for the treatment of HBeAg-positive subjects with CHB 
(ongoing)

GS-US-120-0108, a Phase 1, open-label, parallel-design study to evaluate the
pharmacokinetics of TAF in subjects with severe renal impairment (completed)

GS-US-120-0109, a Phase 1 mass balance study to evaluate the pharmacokinetics,
metabolism and excretion of TAF in healthy subjects (completed)

GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with
normal, mild, and moderately impaired hepatic function (completed)

GS-US-120-1538, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and MDZ (oral and intravenous) in healthy subjects (completed)

GS-US-120-1554, a Phase 1 pharmacokinetic study that evaluated the drug interaction
potential between TAF and RPV in healthy subjects (completed)

GS-US-311-1386, a Phase 1 study that evaluated the effect of food on the PK of TAF and
FTC when administered as an F/TAF fixed-dose combination tablet in healthy subjects
(completed)

GS-US-311-1387, a Phase 1 study that evaluated the drug-drug interaction (DDI) potential
between CBZ and TAF administered as F/TAF in healthy subjects (completed)

GS-US-311-1790, a Phase 1 study that evaluated the DDI potential between F/TAF or
GS-9883 and norgestimate/ethinyl estradiol in healthy female subjects (completed)
Please refer to the latest version of the investigator’s brochure for additional information.


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An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below 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, subjects 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 are 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) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase from 
Week 144 to Week 384 (8 year total study period).
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen
(Number of Subjectsa)
Data Presented
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 


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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 and GS-US-320-0110 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%
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


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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 (upper limit of normal range: ≤ 30 U/L for males and ≤ 19 U/L
for females {Lok et al 2009}, {Terrault et al 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 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 all time points from Week 8 onward using the 
M = F method.
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 at 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.


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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. 
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.


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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 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 polymorphic site substitutions, and 
2 had a conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated 
with resistance to TFV were detected 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.
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; 


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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).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures 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.


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Table 1-5. 
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set) 
GS-US-320-0108 and GS-US-320-0110 
TAF25 mg 
TDF300 mg 
Duration of Exposure to Study Regimen (Weeks) 
(N = 866) 
(N = 432) 
N 
866 
432 
Mean (SD) 
58.9 (14.71) 
59.0 (15.58) 
Median 
56.1 
56.1 
Q1, Q3 
48.1, 64.4 
48.1,64.7 
Min, Max 
0.1,96.3 
0.1, 96.3 
Total Exposure to Study Drug n(%) 
2': 4 Weeks [28 days] 
860 (99.3%) 
426 (98.6%) 
2': 8 weeks [56 days] 
858 (99.1 %) 
426 (98.6%) 
2': 12weeks [84 days] 
854 (98.6%) 
423 (97.9%) 
2': 16 Weeks [112 days] 
851 (98.3%) 
422 (97.7%) 
2': 20 Weeks [140 days) 
851 (98.3%) 
422 (97.7%) 
2': 24 Weeks [168 days] 
851 (98.3%) 
419 (97.0%) 
2': 28 Weeks [196 days) 
849 (98.0%) 
418 (96.8%) 
2': 32 Weeks [224 days) 
843 (97.3%) 
418 (96.8%) 
2': 36 Weeks [252 days] 
838 (96.8%) 
418 (96.8%) 
2': 40 Weeks [280 days] 
835 (96.4%) 
418 (96.8%) 
2': 44 Weeks [308 days] 
832 (96.1%) 
418 (96.8%) 
2': 48 Weeks [336 days] 
669 (77.3%) 
346 (80.1 %) 
p p D 
Duration of exposure to blinded study drug was the munber of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date ofblinded study drug. 
Source: TAF Week 48 ISS, Table 4 
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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-6 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).
Table 1-6.
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


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Common Adverse Events
Table 1-7 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)
Table 1-7.
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.


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Serious Adverse Events
Table 1-8 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.
Table 1-8.
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.


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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 %)
Table 1-9 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.


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Table 1-9.
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
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 


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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 1-10 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).
Table 1-10.
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


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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 1-11 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 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 1-11.
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 (TAF 22.8%, 


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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.
1.3.
Rationale and Risk/Benefit Assessment for this Study
While the number of liver transplants for CHB consequences is low in the United States 
(~350/year), in countries with high prevalence of CHB, HBV remains the most important cause of 
liver transplantation {Lee et al 2015}. Without prophylaxis, patients with CHB receiving a liver 
transplant have near universal re-infection of the graft {Samuel et al 1993}. Current practice is to 
treat prior and post-transplant patients with oral nucleos(t)ide polymerase inhibitors and 
Hepatitis B Immunoglobulin (HBIG) to prevent infection of the new liver. Study 203-0107 
demonstrated in a small group of post-liver transplant patients that treatment with TDF/FTC alone 
was equivalent to TDF/FTC + HBIG after 72 weeks of follow-up {Teperman et al 2013}.With 
these interventions, infection of the graft has been reduced to < 10% {Katz et al 2010}. While 
practice patterns for continuation of HBIG can vary by center, all patients must remain on lifelong 
nucleos(t)ide analog treatment. 
After receiving a liver transplant, the majority of patients develop some degree of chronic kidney 
disease, with over 18% having a GFR< 30 ml/min within 5 years of transplant mainly as a result 
of the use of calcineurin inhibitors (CNI) {Lucey et al 2013}, {Ojo et al 2003}. CNIs are a 
mainstay of immunosuppression immediately after transplantation and can lead to acute or 
chronic kidney injury through hemodynamic changes or direct nephrotoxic effects. While some 
centers reduce or eliminate CNIs from immunosuppressive regimens over time, many continue 
patients lifelong on CNIs. Even in those patients who stop CNIs, the renal effects are often not 
reversible. This persistent renal dysfunction, therefore, can complicate antiviral treatment with 
medications such as TDF. 
For these patients who have received a liver transplant and have renal insufficiency, TAF may 
provide an alternative to currently used treatments by achieving viral suppression while resulting 
in improved safety of bone and renal parameters compared to TDF-based regimens.


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1.4.
Rationale for Dose Selection
A 25-mg dose of TAF was selected for use in the Phase 3 noninferiority studies based upon the 
magnitude of HBV DNA decline, systemic TFV exposure, and the safety profile. In
Study GS-US-320-0101, the magnitude of HBV DNA decreases observed over 28 days in
subjects with CHB given TAF at doses of 8, 25, 40, and 120 mg were similar indicating a lack of 
dose effect; these decreases were also comparable with the TDF 300-mg dose, which is the dose 
of TDF approved for treatment of CHB. In subjects who received TAF 25 mg, reduced systemic 
TFV exposures (approximately 92%) were observed relative to those who received the TDF 
300-mg dose, which is consistent with data in HIV-infected subjects who received TAF 25 mg as 
a single agent in Study GS-US-120-0104.
The selection of 25 mg TAF dose in this study is further supported by the results from the 
dedicated severe renal impairment study (GS-US-120-0108). In that study, plasma TAF exposure 
in subjects with severe renal impairment was less than 2-fold higher than TAF exposure in 
matched controls with normal renal function. For TFV, mean AUC was ~6-fold higher in renally 
impaired subjects as compared to matched controls. Importantly, TFV exposure was within the 
range of TFV exposures achieved following administration of a TDF-containing regimen in 
subjects with normal renal function. As such, dose adjustment of TAF in severe renal impairment 
was not warranted.
The PK/PD relationship between TAF plasma exposure and efficacy was also explored using 
data from the Phase 3 Studies GS-US-320-0108 and GS-US-320-0110. Importantly, in both 
studies virologic suppression (HBV DNA < 29 IU/mL) was uniform across the categories of 
TAF exposures, with no trends in exposure-response relationship observed.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The primary objectives ofthis study are: 
Final 
Original 
• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
CONFIDENTIAL 
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Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
3. 
STUDY DESIGN 
3.1. 
Endpoints 
3.1.1. 
Primary Endpoints 
The primary safety endpoint is: 
Final 
Original 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy endpoint is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
3.1.2. 
Secondary Endpoints 
The secondary safety end points are: 
• 
Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week48 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
3.1.3. 
Other Endpoints of Interest 
3.2. 
Study Design 
This is a randomized, open label study to evaluate the antiviral activity ofT AF 25 mg QD versus 
TDF 300 mg QD containing regimens. Approximately sixty (60) subjects will be randomized in 
a 1:1 ratio (A: B) to the treatment arms for 48 weeks. At least 50 subjects will be enrolled with 
eGFRcKD-EPI < 50 ml/min/1.73m
2
. 
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Tenofovir Alafenamide (TAF) 
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PPD 
Final 
Original 
Approximately 60 adult CHB subjects with Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be eligible for emollment. 
The primary analysis will occur at Week 24 with the primmy efficacy endpoint being the 
maintenance of viral suppression (HBV DNA < 20 IU/mL). 
Figure 3-1. 
Study Schema 
Screening 
~ 
Randomization 1:1 (A:B) 
t 
t 
Arm A: TAF 25 mg QD 
Arm B: TDF 300 mg QD alone or in 
combination with other approved antivirals 
I 
I 
Week 48 Open Label TAF 25 mg QD 
[PPD 
l/Early Discontinuation Visit 
3.3. 
Study Treatments 
Approximately 60 subjects with CHB and Stage 2 or greater chronic kidney disease and have 
received a liver transplant will be assigned to one of the two treatment mms (A:B) for 48 weeks. 
Randomization will be stratified by baseline renal ftmction ( eGFR.cKn.EPI < 50 m1l min/1. 73m2 
and~ 50 m1l min/1. 73m2). 
• 
Treatment Arm A: approximately 30 subjects administered TAF 25 mg oral daily 
• 
Treatment Arm B: approximately 30 subjects to continue administration of TDF alone or in 
combination with other approved antivirals per local practice 
PPD 
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Tenofovir Alafenamide (TAF) 
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3.4. 
Duration of Treatment 
Final 
Original 
The duration of the study treatment is 48 weeks with an initial screening period of 45 days. 
Subsequent to screening, subjects will be randomized to receive T AF or TDF alone or in 
combination with ap_£roved antivirals per local practice. PD 
3.5. 
End of Study 
The end of the study will be the last subjects' last observation or visit. 
3.6. 
Biomarker Testing 
3.6.1. 
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 exploratory systemic and/or tissue specific biomarkers with study dmg 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the bone and renal biomarkers - such as, C-type collagen sequence (CTX) and procollagen 
type 1 N-tenninal propeptide (P1NP), retinol binding protein and beta-2-microglobulin. 
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 cunent 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. Samples 
may be stored by Gilead Sciences for a period of 15 year·s. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 60 subjects, who are 18 years or older, with chronic hepatitis B, currently virally 
suppressed with Stage 2 or greater chronic kidney disease and have received a liver transplant. 
They will be randomized 1:1 to receive TAF 25 mg or continue with TDF alone or in 
combination with other approved antivirals for 48 weeks. All subjects will be treated with TAF 
25 mg oral daily for 96 weeks after the first 48 weeks. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
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, over 18 years of age based on the date of the 
screening visit
3) Documented evidence of chronic HBV infection prior to transplantation 
4) Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from 
deceased or living donor 
5) Liver Transplant ≥ 12 weeks prior to screening
6) Maintained on TDF alone or in combination with other approved antivirals for HBV 
prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 12 weeks post-transplant prior to 
screening, with HBV DNA < LLOQ at screening
8) Screening eGFRCKD-EPI < 90 ml/min/1.73m2
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 6
10) Women considered of child bearing potential (see Appendix 6) must have a negative serum 
pregnancy test at Screening and a negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Multi-organ transplant that includes heart or lung recipient (subjects who have their liver 
transplant as part of a liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant
and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal 
syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin ≥ 4 × ULN
e) Platelet count < 50,000/mL
6) Co-infection with HIV or HCV
7) Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics
8) Use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents, 
cyclosporine > 300 mg/day, or use of any prohibited medications listed in Section 5.4 within 
28 days of the Baseline/Day 1 visit
9) Malignancy within 5 years prior to screening, with the exception of specific cancers that are 
cured by surgical resection (e.g., basal cell skin cancer, etc) or hepatocellular carcinoma. 
Subjects under evaluation for possible malignancy are not eligible
10) Significant cardiovascular, pulmonary, or neurological disease
11) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
12) Use of any prohibited concomitant medications as described in Table 5-1
13) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
14) Known hypersensitivity to study drugs, metabolites or formulation excipients
15) Lactating females or those who may wish to become pregnant during the course of the study


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, and Treatment Codes
The randomization will be performed via an Interactive Voice Response System (IVRS) or 
Interactive Web Response System (IWRS), whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. Eligible subjects (n = 60) will be randomized in a 1:1 ratio to receive either TAF 
or continue on TDF alone or in combination with other approved antivirals for 48 weeks.
Randomization will be stratified by baseline renal function (eGFRCKD-EPI < 50 ml/min/1.73m2
and ≥50 ml/min/1.73m2).
5.2.
Description and Handling of Tenofovir Alafenamide (TAF)
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (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. 
5.2.2.
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 material. Each bottle is enclosed with 
a white, continuous-thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed, and aluminum-faced liner. 
Study drug(s) to be distributed to centers in NZ 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.
All labels for TAF 25 mg bottles to be distributed in centers in the US and other participating 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and EU Guidelines to Good Manufacturing Practice, Annex 13 
Investigational Medicinal Products and/or other local regulations as applicable.


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5.2.3. 
Storage and Handling 
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Study dmg TAF should be stored at controlled room temperature of25°C (77°F); excursions are 
permitted bet\veen 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 mugs should be stored in a securely locked 
area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study dtug(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 dt11g contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling. 
5.3. 
Dosage and Administration ofTAF 
Subjects will be randomly assigned (1: 1) to receive one of the following treatments: 
• 
Treatment Arm A: approximately 30 subjects adtninistered TAF 25 mg QD 
• 
Treatment Arm B: approximately 30 subjects to continue adtninistration of TDF alone or in 
combination with other approved antivirals alone or in combination with other approved 
antivirals per local practice 
PD 
It is prefened that subjects take their study dtug according to a moming dosing schedule; 
however, evening dosing is allowable. 
T AF tablets are to be adtninistered orally with or without food, taken at approximately the same 
time each day. 
5.4. 
Prior and Concomitant Medications 
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. 
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of tTeatment: 
• 
Investigational agents or devices for any indication 
• 
Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscamet, cisplatin, pentamidine) 
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
Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)

Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [≤ 1 week of use], immunosuppressant, or immunomodulating 
agents

Bisphosphonates
Treatment-experienced subjects (defined as subjects meeting all entry criteria [including HBV 
DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any nucleoside or 
nucleotide analogue) receiving oral antiviral treatment at Screening must continue their treatment 
regimen until the time of randomization/Baseline/Day 1, when it will be discontinued.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of TAF.
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. 
Examples of representative medications which are prohibited or to be used with caution
from 21 days prior to Day 1 through the end of treatment are listed below:
Table 5-1.
Disallowed and Concomitant Medications to Be Used with Caution
Medication Class
Prohibited Medications
Medications to Be Used with Caution
Anticonvulsantsa
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungalsb
Itraconazole, Ketoconazole
Antimycobacterialsa
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplementsa
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
a
May result in a decrease in the concentration of TAF 
b
May result in an increase in the concentrations of TAF


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5.5.
Accountability for Tenofovir Alafenamide (TAF)
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
Investigational product accountability records will be provided to the study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit and/or bottles number dispensed

Record the date, quantity of used and unused IMP kit and/or bottles returned, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the 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 kits and/or 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. 
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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. 
The investigator must document any deviation from protocol procedures and notify the sponsor. 
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 be randomized 
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 3.2. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen ifthere 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 
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements. 
6.2.1. 
Screening Visit (Day -45 to Day 1 of Treatment) 
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: 
PPD 
• 
Obtain medical history, including Hepatitis B history and treatment history 
• 
Review of inclusion/exclusion criteria 
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
Review of AEs and concomitant medications

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), body weight, and height

Perform DXA scan of spine and hip. DXA scan will be performed at any time during the 
Screening period and should be completed at least 14 days prior to the first dose of the study 
drug, in order to ensure an acceptable pre-dose DXA scan

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed 
as needed)
Other viral serology (HCV, HIV and HDV)
Estimated creatinine clearance 
Serum β-hCG pregnancy test (for all female subjects of child-bearing potential)
Alpha-fetoprotein (AFP). Subjects with an AFP >50 ng/mL or other findings concerning 
HCC must have an appropriate evaluation (e.g., CT scan) to rule out HCC prior to being 
able to enter into the study

Obtain urine sample for urinalysis, and urine drug screen 

Record any serious adverse events (SAE) and all adverse events (AE) related to protocol 
mandated procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
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.


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6.2.2.
Baseline Assessments (Day 1)
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 medical history, HBV history and HBV treatment history on any changes since 
screening visit

Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit

Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight

Review of inclusion/exclusion criteria

Review of AEs and concomitant medication

Complete the “Fracture Risk Assessment” (FRAX®) eCRF

Cr EDTA Renal Scan 

Obtain blood samples for laboratory assessments as follows:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
Quantification of plasma HBV DNA levels
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed)
Estimated creatinine clearance
Blood sample for Vitamin D assessment 
Blood sample for Fibrotest®
Blood sample for PBMC 
Blood sample for PK
Plasma, serum, and urine for storage
HBV resistance surveillance


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• Fasting blood sample for bone, renal 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 
• Urine sample for urinalysis, pregnancy test (for females of child-bearing_potential; in case of 
a positive urine test, a serum pregnancy test will be done), f PD 
I 
PPD 
6.3. 
Treatment Assessments 
6.3.1. 
Study Week Assessments (Weeks 4-48) 
The following evaluations will be performed at Weeks 4-48 unless specified; 
• 
Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects at visit (Weeks 24, and 48 only) 
• 
Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight (Weeks 12, 24, and 48 only) 
• 
Perform symptom-driven physical examination including vital signs, and body weight 
(Weeks 4, 8, 20, and 36 only) 
• 
Review of AEs and concomitant medications 
• 
Cr EDTA Renal Scan (Week 48 only) 
• 
Perform DXA scan of spine and hip (Weeks 24 and 48 only) 
• 
Perform study drug accountability 
• 
Dispense study drugs 
• 
Obtain blood samples for laboratory assessments as follows: 
-
Safety laboratory tests (serum chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) (Weeks 24 and 48 only) 
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Estimated creatinine clearance (by MDRD) 
-
Blood sample for Fibrotest® (Weeks 24 and 48 only) 
-
Blood sample for Vitamin D assessment (Weeks 24 and 48 only) 
-
Blood sample for AFP (Weeks 24 and 48 only) 
-
Blood sample for PK 
-
Blood sample for PBMC (Weeks 24 and 48 only) 
-
Plasma, serum, and urine for storage 
-
HBV resistance surveillance 
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• 
Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose. Subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing, the plasma PK samples from these subjects can be collected anytime 
(not timed) (Weeks 8 and 24 only) 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for bone and renal biomarkers -no food or drinks, except water, at 
least 8 hours prior to blood collection (Weeks 4, 12, 24, and 48 only) 
• 
Fasting urine sample for renal biomarkers (Weeks 4, 12, 24, and 48 only) 
• 
Fasting blood sample for 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 (Weeks 24 and 48 only) 
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6.3.3. 
Early Discontinuation (ED) Visit 
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The ED visit should be performed within 14 days from notification of study discontinuation 
• 
Provide Health Related Quality of Life surveys (HRQoL): SF-36, CLDQ, WPAI to be 
completed by subjects 
• 
Perform complete physical examination including, vital signs (blood pressure, pulse, 
respiration rate and temperature), and body weight 
• 
Review of AEs and concomitant medications 
• 
Perform DXA scan of spine and hip 
• 
Perform study drug accountability 
• 
Obtain blood samples for laboratory assessments as follows: 
-
Safety laboratory tests (serum chemistry, hematology, and coagulation) 
-
Quantification of plasma HBV DNA levels 
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-
Qualitative HBsAg and HBeAg (HBsAb and HBeAb reflex testing will be performed as 
needed) 
-
Estimated creatinine clearance 
-
Blood sample for Fibrotest® 
-
Blood sample for Vitamin D assessment 
-
Blood sample for AFP 
-
HBV resistance surveillance 
• 
Urine pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis 
• 
Fasting blood sample for bone and renal biomarkers- no food or drinks, except water, at 
least 8 hours prior to blood collection 
• 
Fasting urine sample for renal biomarkers 
• 
Fasting blood sample for 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 
6.4. 
Post-Treatment Assessments 
6.4.1. 
All Other Subjects Who Discontinue Study Drug 
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug will be followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.5. 
Assessments for Premature Discontinuation from Study 
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. 
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6.6. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
Final 
Original 
• 
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 
• 
Subjects with confirmed creatinine clearance of< 30 mL/min at any time during the study 
will have their study drug permanently discontinued 
• 
Lack of efficacy (virologic failure) 
• 
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 48 are not permitted to discontinue 
study drug prior to the Week 48 visit 
• 
Discontinuation of study drug for subjects 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 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 6 
• 
Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC) 
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6.8. 
Urine, Serum and Plasma for Storage 
Final 
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A portion of the blood samples collected at each visit stru.ting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its research pmtners for HBV 
genotyping/phenotyping assays or their development, for 
· 
the amount of HBV in the 
for measurement of antiviral 
levels in the 
testmg on 
A p01iion of the mine samples collected at each visit statiing at Baseline will be frozen and 
stored. These stored mine smnples may be used by SponsolPPD 
-
(in addition to the tests planned for the study). 
,___ ___________ _. 
At the conclusion of this study, these samples may be retained in storage by 
Gilead Sciences, Inc. for a period up to 15 years. 
6.9. 
Resistance Surveillance 
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for resistance 
mutations may be attempted for all viremic subjects (HBV DNA ~ 69 IU/mL). 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 virology sample for potential resistance smveillance will be collected at each study visit. 
6.10. 
End of Study 
The end of this study will be the last subject's last observation (or visit). 
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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

Persistent or significant disability/incapacity


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
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 are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub investigator 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 sub investigator 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 (e.g., 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 (e.g., 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 5). 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 
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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 rep01ted. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30 days 
period; however, if the investigator leams of any SAEs that occur after study paliicipation 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 
infonnation to Gilead DSPH within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE inf01mation electronically, ie, the eCRF 
database is not fimctioning, record the SAE on the paper serious adverse event rep01ting 
f01m and submit within 24 hours to: 
Gilead DSPH: 
Fax: 
Email: 
Medical Monitor: 
Name: 
Telephone: 
Fax: 
Email: 
+1 (650) 522-5477 
Safety _FC@gilead.com 
Anuj Gaggar, MD PhD 
PPD 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instmctions in the eCRF completion guidelines. 
• If an SAE has been rep01ted via a paper fonn because the eCRF database has been locked, no 
fmther action is necessruy. 
• 
For fatal or life-threatening events, copies of hospital case rep01ts, autopsy reports, and other 
documents are also to be subtnitted 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 infonnation may be requested to ensure the timely completion of accurate safety 
rep01ts. 
• 
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 
f01m. 
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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 4.

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 5)

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.
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). 


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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, 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. 
7.5.6.
Management of Ocular Safety
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.


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Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
develops signs or symptoms of posterior uveitis, investigators should contact the Gilead 
Medical Monitor to discuss the need for additional ophthalmologic evaluation including dilated 
fundoscopy and optical coherence tomography (OCT).
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, and pregnancy reports regardless of an 
associated AE.  
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.  
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 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.


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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. 
Any premature termination of pregnancy ( eg, a spontaneous abortion, an induced therapeutic 
ab01iion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedme should be recorded as the AE tenn. 
A spontaneous ab01iion is always considered to be an SAE and will be rep01ied as described in 
Sections 7 .1.1 and 7 .1.2. Fmihennore, any SAE occmTing as an adverse pregnancy outcome post 
study must be rep01ied to Gilead DSPH. The subject should receive appropriate monitoring and 
care 1mtil the conclusion of the pregnancy. The outcome should be rep01ted to Gilead DSPH 
using the pregnancy outcome rep01t fotm. If the end of the pregnancy occms after the study has 
been completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact 
information is as follows: Email: Safety _FC@gilead.com and Fax: + 1 ( 650) 522-5477. 
Pregnancies of female pminers of male study subjects exposed to Gilead or other study dmgs 
must also be repotied and relevant infotmation should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome fotms within 24 homs. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occms after the study 
has been completed, the outcome should be repotied directly to Gilead DSPH, fax number 
+1 (650) 522-5477 or email Safety_FC@gilead.com. Refer to Appendix 6 for Pregnancy 
Precautions, Definition for Female of Childbem·ing Potential, and Contraceptive Requirements. 
7.6.2.2. 
Repotiing Other Special Situations 
All special situations repotis (SSRs) will be recorded in the eCRF database within the timelines 
outlined in the eCRF completion guideline. 
Electronic Special Situations Report ( eSSR) Reporting Process 
• 
Site persollllel record all SSR data in the eCRF database and from there transmit the SSR 
inf01mation to Gilead DSPH within24 homs 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 SSR inf01mation electronically, i.e., the eCRF 
database is not fimctioning, record the SSR on the paper serious adverse event reporting fotm 
and subtnit within 24 homs to: 
Gilead DSPH: 
Email: 
Fax: 
Gilead Medical Monitor: 
Name: 
Phone: 
Fax: 
Email: 
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Safety _FC@gilead.com 
+1 (650) 522-5477 
Anuj Gag ar MD PhD 
PPD 
PPD 
1-'1-'U 
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
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

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 7.3 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.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives ofthis study are: 
Final 
Original 
• 
To evaluate the safety and tolerability of TAF 25 mg QD versus TDF -containing regimens as 
determined by the change from baseline in eGFRcKD-EPI at Week 24 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 24 
The secondary objectives ofthis study are: 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the percent change from baseline in hip and spine bone mineral density (BMD) at 
Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in serum creatinine at Weeks 24 and 48 
• 
To evaluate the safety of TAF 25 mg QD versus TDF -containing regimens as determined by 
the change from baseline in eGFRcKD-EPI at Week 48 
• 
To evaluate the efficacy ofTAF 25 mg QD versus TDF-containing regimens in maintaining 
viral suppression at Week 48 
8.1.2. 
Primary Endpoint 
The primary safety endpoint is: 
• 
Change from baseline in eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing regimens at 
Week24 
The primary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24 
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8.1.3. 
Secondary Endpoint 
The secondary safety end points are: 
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• 
Percent change from baseline in hip and spine bone mineral density (BMD) ofT AF 25 mg 
QD versus TDF-containing regimens at Weeks 24 and 48 
• 
Change from baseline in serum creatinine of TAF 25 mg QD versus TDF -containing 
regimens at Weeks 24 and 48 
• 
Change from baseline in serum eGFRcKD-EPI ofT AF 25 mg QD versus TDF -containing 
regimens at Week 48 
The secondary efficacy end point is: 
• 
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48 
8.1.4. 
Other End points of Interest 
8.2. 
Analysis Conventions 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The primary analysis set for efficacy analysis is the Full Analysis Set (F AS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the treatment actually received. All data collected during treatment will be included 
in the safety summaries. 
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8.2.1.3. 
Phrumacokinetics 
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The PK analysis set will include all subjects who ru·e randomized and have received at least 
one dose of study medication and for whom concentration data of any analytes of interest 
( eg, TAF and TFV) ru·e available. The PK analysis set will be used for analyses of concentration 
data. 
PD 
8.2.1.4. 
Biomru·kers 
The Biomru·ker analysis set will include all subjects who have evaluable biomarkers data. 
8.3. 
Data Handling Conventions 
For the primruy endpoint missing data will be handled using a missing= failure approach, unless 
othe1wise specified. 
For key seconda1y safety endpoints, an analysis will be perf01med using the Last Observation 
Canied F01wru·d (LOCF) method to impute the missing data. 
For other categorical secondmy efficacy endpoints, missing data will be handled using a 
missing= failure approach. For the dmg resistant mutations endpoint, a missing= excluded 
approach will be employed. 
Sensitivity analyses will be perfonned as wananted. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall. 
Demographic smnmaries will include sex, race/ethnicity, randomization stratification group, and 
age. 
Baseline data will include a smnmruy of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (:S ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
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8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when the study subjects complete 24 weeks of 
the treatment period or discontinue prematurely. The response rate of each treatment arm will be 
presented. A two-sided 95% confidence interval, adjusted for the randomization stratification 
factor (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) in the 
proportion of subjects who maintained viral suppression (HBV DNA < 20 IU/mL) at Week 24 
will be constructed.
8.5.2.
Secondary Analyses
The approach used for primary efficacy analysis will be applied for secondary efficacy analysis 
as in Section 8.5.1.
8.6.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last 
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment will be included in data listings.
8.6.1.
Primary Safety Analysis
The change from baseline in eGFRCKD-EPI at Week 24 will be summarized.
8.6.2.
Secondary Safety Analyses
The change from baseline in eGFRCKD-EPI at Week 48 will be performed. 
The percent change from baseline in hip and spine BMD at Weeks 24 and 48 will be summarized.
The change from baseline in serum creatinine at Weeks 24 and 48 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 by treatment group. 
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.


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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 
treatment up to the date of last dose oftreatment. 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 by treatment group. 
8.6.5. 
Laboratory Evaluations 
Selected laboratory data (using 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 5. 
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 and including the date of last 
dose of treatment will be summarized by treatment group. If baseline data are missing, then any 
graded abnormality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing. 
8.7. 
Phannacokinetic Analysis 
Pharmacokinetic parameters will be listed and summarized for T AF and TFV using descriptive 
statistics ( eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation. 
PPD 
8.8. 
Biomarker Analysis 
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1 
N-terminal propeptide (P1NP), and selected renal biomarkers, including urine retinol binding 
protein, and urine beta-2-microglobulin, will be summarized by treatment group and visit using 
descriptive statistics. 
8.9. 
Sample Size 
This is an exploratory study. No formal sample size calculation was performed. 
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8.10.
Data Monitoring Committee
A data monitoring committee (DMC) will review the progress of the study and perform review 
of safety data once after 30 subjects have completed 12 weeks of treatment, and provide 
recommendation to Gilead whether 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, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design.
Subsequent meetings will be held on an ad hoc basis. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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. 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) 
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 IEC. The investigator will not begin any study subject activities until 
approval from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IEC 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 IEC approved consent form for documenting 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 IEC or 


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local requirements. For genomic testing, the consent form will inform subjects about genomic 
testing and sample retention, and their right to receive clinically relevant genomic analysis 
results.
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, the IEC, 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.
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, IEC
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);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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
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 
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 


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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 QA, 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 IEC, 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.
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 IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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.
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.


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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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antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of 
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Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective Lymphoid Cell 
and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-
7340. Mol Pharm 2013;10 (2):459-66.
Centers for Disease Control (CDC), Division of Viral Hepatitis. Viral Hepatitis Surveillance 
United States, 2013.  2013.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection [published version]. J 
Hepatology 2012;57:167-85.
Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on 
disease progression and prognostic factors. J Hepatol 2008;48 (2):335-52.
Foran JA. Principles for the Selection of Doses in Chronic Rodent Bioassays. Environ Health 
Perspect 1997;105 (1):18-20.
G. B. D. Mortality Causes of Death Collaborators. Global, regional, and national age-sex specific 
all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a 
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Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
2015;1 (4):505-27.
Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis B virus infection after 
liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? 
Systematic review and meta-analysis. Transpl Infect Dis 2010;12 (4):292-308.
Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al. No detectable 
resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with 
chronic hepatitis B. Hepatology 2014;59 (2):434-42.
Lee SG, Moon DB, Hwang S, Ahn CS, Kim KH, Song GW, et al. Liver transplantation in Korea: 
past, present, and future. Transplant Proc 2015;47 (3):705-8.


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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. 
Hepatol International 2012;6:531-61.
Lok AS, McMahon BJ. AASLD Practice Guideline Update: Chronic hepatitis B: update 2009. 
Hepatology 2009;50 (3):661-2.
Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, Blumberg E, et al. Long-term management 
of the successful adult liver transplant: 2012 practice guideline by the American 
Association for the Study of Liver Diseases and the American Society of 
Transplantation. Liver Transpl 2013;19 (1):3-26.
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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Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of Efficient 
Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus 
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(6):3563-9.
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Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


Gilead Sciences, Jnc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Original 
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of 
Tenofovir Alafenamide (T AF) versus Tenofovir Disoproxil Fumarate (TDF~ontaining 
Regimens in Subjects with Chronic HBV Infection and Stage 2 or Greater Chronic Kidney 
Disease Who Have Received a Liver Transplant 
GS-US-320-3912, Original, 07 June 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
Anuj 
aggar, 
PhD 
Author 
Date 
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. I 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, Inc. I will discuss this material with them to ensure 
that they are fully 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 
Screening 
(-45 Days) 
Visit Windows 
Written Informed Consent 
X 
Review of Inclusion/Exclusion Criteria 
X 
Medical History, including HBV history 
X 
Review Concomitant Medications 
X 
Adverse Events 
X 
Complete Physical Examination including 
X 
vi tal signs, and weight 
Height 
X 
Symptom-directed Physical Exam 
Body weight 
X 
Vital Signs b 
X 
Randomization 
DXAc (spine & hip) 
X 
FRAX
00 Fracture Risk Assessment Tool 
Cr EDT A renal scan 
Study Drug Accountability 
Study Drug Dispensed/Retrieved 
Dosing in-clinicd 
Serum Chemistry and Liver Function Tests• 
X 
Estimated Creatinine Clearance 
X 
Hematology 
X 
CONFIDENTIAL 
BL 
4 
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 
8 
+24 Hrs 
8 
+24 Hrs 
12 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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24 
36 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
48 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Original 
PPD 
ED 
r---
r--
--
r---
--
X 
f---
X 
r---
X 
r---
f---
f---
X 
r---
X 
--
r---
X 
--
f---
r---
X 
f---
X 
r---
--
X 
r---
X 
--
X 
07 June 2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Cystatin C (for estimated eGFR) 
Plasma HBV DNA Levels 
Senun HBsAg (qualitativel 
Serum HBeAg (qualitative i 
Sample collection for HBV Resistance 
Surveillanceg 
HIV-1, HDV, HCV 
a-fetoprotein 
Fibrotest® 
Vitamin D 
Whole blood for PBMC 
Plasma PKm 
Fasting Blood for Bone Biomarkersh 
Fasting Blood for Renal Biomarkersh 
Fasting Urine for Renal Biomarkers; 
Fasting Metabolic Pane~ 
Serum Pregnancy Tes~ 
Urine Pregnancy Testi 
Ulinalysis 
Uline dmg screen 
lPPD 
Senun, and plasma for storage 
CONFIDENTIAL 
Scl'eening 
4 
(-45 Days) 
BL 
4 
+24 H1·s 
Visit Windows• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 93 
8 
8 
+24 Hl'S 
12 
20 
24 
36 
48 
±3 Days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Original 
PPD 
ED 
X 
X lx 
l x 
X 
I 
~ 
X 
X 
X 
X 
X 
l x 
X 
07 Jtme2016 


' 
Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
Final 
Original 
Scl'eening 
4 
8 
PPD 
(-45 Days) 
BL 
4 
+24 H1·s 
8 
+24 Hl'S 
12 
20 
24 
36 
48 
ED 
-
Visit Windows• 
±3 Days 
Urine for Storage 
X 
X 
X 
X 
X 
X 
X 
X 
~ 
Health Related Quality of Life Smveys1 
X 
X 
X 
Imaging Test" 
X 
PPD 
a 
b 
c 
d 
e 
f 
g 
h 
m 
n 
The out of visit window is ± 3 days nntil Week 48 and ± 14 days thereafter. 
Vital signs include blood pressm·e, pulse, respu·ation rate, and temperatme. 
The initial DXA will be petfonned dm·mg Screening and should be completed at least 14 days prior to the first dose of study drug. The Week 48 DXA wmdow is- 3 days 
only. DXA is required for Early Disconfmuation (ED) visit if not done withm the last 24 weeks. 
It is prefen·ed that subjects take theu· study drug accordmg to a moming dosing schedule; subjects who elect to dose u1 the evenmg the previous day are not requu·ed to have 
m-clmic dosing and provide the single PK sample bemg collected at Week 4 and 8 visits. 
Senun chemistty and Liver Ftmction Tests: alkalille phosphatase, AST, ALT, GGT, total bilirubm, direct and mdu·ect bilimbin, total protem, albtlllill, LDH, CPK, 
bicarbonate, BUN, calcimn. chloride, creatinme, gluc.ose, phosphorus, ma 1esimn, potassimn, sodimn, m1c acid, and amylase (reflex lipase testu1g is perfonned m subjects 
with total amylase > 1.5 x ULN). At Baselme, Weeks 24, 48 PPD 
ED, subject will be fasting for senm1 glucose and metabolic paneL Coagulation panel will be done 
at Screenmg and then as a reflex only test for ALT flares. 
Qualitative HBsAg and HBeAg will be petfonned at Baselille (BL), Weeks 24, 48, PO 
ED. HBeAb and HBsAb testmg will be perfom1ed as reflex testu1g as 
needed. 
Sequence analysis of the HBV pol!R T for possible resistance mutation(s) may be attempted for any subject that experiences vire1nia (HBV DNA > 69 IU/mL). 
Blood for selected bone biomarkers and renal biomarkers will be collected m a fasted state. Requu·ed for ED visit if the last sample was collected> 24 weeks prior. 
Ut1ne for selected renal biomarkers will be collected m a fasted state. Required for ED visit if the last sample was collected > 24 weeks pt-ior. 
For female subjects of childbearu1g potential, the senun beta-HCG test will be petformed at Screenmg. Uru1e test will be performed at all other visits as mdicated. 
Positive m-ine test will be confumed with senuntest Pregnancy tests should mclude P:.;;r.;.ev.;..·e;.;;n;.;.tt;.;;'o.;;n;..c;.;·O;..tlll=se;.;lill
;;;;' ~<>.;.·-------------------. 
Heaftli Related"Quahty of LiFe smveys incluaed'm thts study are: SF-36, CLDQ, and"WPAI. The smveys win be adlnmistered at BL, WeeKs 24, 48, 96, PP and 
Early Discontmuation Visits, if applicable. 
At Weeks 8 and 24 the plasma PK samples should be collected between 15 minutes and 4 homs post-dose. 
At Screenmg, a-fetoprotem (AFP) will be measm·ed and subjects with an AFP >50 ng/mL or other flndmgs concenill1g HCC must tmdergo illlaging test (e.g., CT scan) to rule 
out HCC. 
CONFIDENTIAL 
Page 94 
07 Jtme2016 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-3912 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page 95 
Final 
Original 
07 June 2016 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 96
07 June 2016
Appendix 4.
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 recurrences that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 97
07 June 2016
Appendix 5.
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 98
07 June 2016
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 99
07 June 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatermia 
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 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 100
07 June 2016
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 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 101
07 June 2016
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
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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 102
07 June 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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/Lto <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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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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.


Tenofovir Alafenamide (TAF)
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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


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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
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


Tenofovir Alafenamide (TAF)
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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)


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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Gilead Sciences, Inc.
Original
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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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
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Gilead Sciences, Inc.
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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 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 
weakness 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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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)
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


Tenofovir Alafenamide (TAF)
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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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 117
07 June 2016
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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 118
07 June 2016
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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Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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Appendix 6.
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 orchiectomy 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.


Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 121
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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.