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
Phase: PHASE2
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences

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The information contained in this document, particularly unpublished data, is the property or 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.
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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 
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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:
 
 
 
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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:
 
 
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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 
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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).
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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.
PPD
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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.
PPD
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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:
 
 
 
 
CCI

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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.
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
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 
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.
 
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 
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.
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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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 106
18 June 2019
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

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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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Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 119
18 June 2019
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

Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 120
18 June 2019
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]

Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 121
18 June 2019
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.
Amendment 3
CONFIDENTIAL
Page 122
18 June 2019
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.
Amendment 3
CONFIDENTIAL
Page 123
18 June 2019
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)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 124
18 June 2019
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

Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 125
18 June 2019

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.

Tenofovir Alafenamide (TAF)
Protocol GS-US-320-3912
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 126
18 June 2019
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.